Supramolecular Polymers for Biomedical Applications

Abstract

To provide a supramolecular biomedical polymer which is particularly suitable for the production of porous biomedical implants that need high strength, elasticity, durability, and slow biodegradation, and to provide a supramolecular biomedical polymer obtainable via the above method.SOLUTION: There is provided a method for producing a supramolecular biomedical polymer having an ultimate tensile strength of at least 35 MPa, as determined by test method ASTM D 1708-96 with a crosshead speed of 20 mm / min, the method comprising reacting a compound F' according to Formula (1) with a diisocyanate compound C', a functionalized polymer A' and a compound B'.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present invention relates to a method for the preparation of supramolecular polymers and to supramolecular polymers obtainable via said method. The present invention further relates to biomedical porous implants comprising said supramolecular polymers, their preparation and their use in methods of medical treatment, for example in the treatment of cardiovascular diseases in mammals and in the treatment of pathologies requiring reconstructive surgery, support or augmentation of mammalian tissues.

[0002] [Background of the invention] A wide variety of biodegradable (often designated bioabsorbable or biomedical) materials are known, mostly based on aliphatic polyesters such as polycaprolactone and their copolymers (Uhrich et al., Chem. Rev. 99, pp. 3181-3198, 1999). In the context of the present invention, the terms "biomedical", "bioabsorbable" and "biodegradable" have the same meaning and are considered interchangeable. The mechanical properties of current biodegradable materials are generally strongly related to their high molecular weight, above 100 kDa, the presence of chemical crosslinks, and the presence of crystalline "hard" domains in their polymers. Although crystalline domains are beneficial for the initial high strength of the material, they have a strong influence on the biodegradation process of the material, because the biodegradation of crystalline domains is generally very slow, and moreover because they can cause an immune response. In addition, crystalline domains can have a negative influence on the long-term elastic behavior of the material due to their tendency to induce fatigue properties.

[0003] To obtain desired material properties, the need for high molecular weight polymers usually implies the need for high processing temperatures, which is undesirable since pyrolytic processes are more likely to occur at higher temperatures.

[0004] Moreover, the presence of ester bonds in biodegradable materials, including polyesters such as polycaprolactone, makes them susceptible to (enzymatic) hydrolysis and therefore premature destruction of biomedical implants, i.e. biodegradable implants for use inside the human or animal body, that comprise these polymers. In other words, biodegradable materials that comprise polyesters may have such a fast rate of biodegradation that they are not suitable for use in biomedical implants.

[0005] The mechanical performance required for a biomedical implant depends on the intended implantation site in the body. Flexible implants are required when the implantation site is, for example, the abdominal wall, a cardiovascular site, an organ or the skin. Typical elongations occurring in the human abdominal wall average 32% and can reach 69% in extreme cases in women. Young's moduli in the range of 5-10 MPa are typically found in the abdominal wall of animals (Deeken et al., J. Mech. Behav. Biomed. Mat. 74, 411, 2017, incorporated herein by reference). The elastic modulus found in the leaflets of human heart valves has values ​​ranging from 10 to 14 MPa (at maximum strains up to 30%) and an ultimate tensile strength of 2 to 4 MPa (Stradins et al., Eur. J. Cardio-Thorac. Surg. 26, 634, 2004, and Hasan et al., J Biomech 47, 1949, 2014, incorporated herein by reference). The mechanical behavior of human skin is characterized by an average elastic modulus of 83 MPa and an ultimate tensile strength of approximately 22 MPa at elongations up to 170% (Annaish et al., J. Mech. Behav. Biomed. Mat. 5, 139, 2012, incorporated herein by reference).

[0006] The durability of a biomedical implant is also important for its performance because it must be able to withstand millions of movements during its lifetime and must be highly fatigue resistant. For example, heart valves undergo complex cyclical loads with high mechanical demands approximately 30 million times per year, thereby pumping 3-5 L of blood per minute through the valve (see Hasan et al., J Biomech 47, 1949, 2014).

[0007] Another important parameter for the performance of a biomedical implant is its deformation behavior, which is the mechanical response of a biomedical implant towards stress or elongation, which is characterized by high ultimate tensile strength combined with low initial stress at low elongation in flexible soft tissues that are often non-linear (Mazza et al., J. Mech Behav. Biomed. Mat. 48, 100, 2015, incorporated herein by reference).

[0008] When the biomedical implant is a porous implant, the polymer that makes up the biomedical implant must exhibit even higher elastic modulus and tensile strength to compensate for the loss in mechanical performance of the biomedical implant due to porosity.

[0009] The present invention relates to biomedical supramolecular polymers that contain a moiety capable of forming at least four H-bridges in a row, preferably together with another moiety capable of forming at least four H-bridges in a row, leading to physical interactions between different polymer chains. The physical interactions originate from multiple hydrogen-bonding interactions (also called supramolecular interactions) between individual moieties capable of forming at least four H-bridges in a row, or between a moiety capable of forming at least four H-bridges in a row and another moiety capable of forming hydrogen bonds, thereby forming self-complementary units that preferably contain at least four hydrogen bonds in a row. A unit capable of forming at least four hydrogen bonds in a row, i.e., a four hydrogen-bonding unit, is abbreviated as "4H unit" as used herein. Sijbesma et al. (US Pat. No. 6,320,018 B1, Science 278, pp. 1601-1604, 1997, both of which are incorporated herein by reference) disclose 4H units based on 2-ureido-4-pyrimidone (UPY). These 2-ureido-4-pyrimidones are derived from isocytosine.

[0010] A low molecular weight supramolecular polymer based on telechelic polycaprolactone (PCL) end-capped with 4H units based on 6-methylisocytosine has been disclosed by Dankers et al. (Nature Materials 4, 5688, 2005, incorporated herein by reference). DSC thermograms of this supramolecular material reveal high crystallinity of the PCL backbone, which has a negative effect on elasticity and strongly limits the durability of the material. Dankers et al. further characterized the mechanical behavior of a supramolecular material containing PCL with several 4H units along the backbone (see Biomaterials 27, 5490, 2006, incorporated herein by reference). This study revealed that the highly crystalline telechelic PCL with 4H units had a Young's modulus of about 130 MPa but broke already after about 14% elongation, while the much less crystalline chain-extended PCL derivative with 4H units had a low Young's modulus of only about 3 MPa and an elongation at break of 576% (cf. table 1 on page 5495). Both Dankers' materials have only one melting point above about 40° C. for the unannealed, virgin material. Similar chain-extended aliphatic polyester derivatives with 4H units are disclosed in WO 2005 / 042641 A1, where also low Young's moduli were obtained (cf. table on page 39).

[0011] US Patent Application Publication No. 2009 / 00130172, incorporated herein by reference, discloses several supramolecular biodegradable materials containing 4H units mixed with bioactive molecules containing 4H units for biomedical applications, such as coatings with controlled release of drugs. Among the materials disclosed are PCL-based materials published by Dankers et al. (Nature Materials 4, 5688, 2005 and Biomaterials 27, 5490, 2006), as well as other biodegradable polyester derivatives containing 4H units, such as polyadipate-based polymer chains extended with isophorone diisocyanate (IPDI)-functional 4H units in Examples 8, 12, 13 and 15. However, all these polyester-based supramolecular biodegradable materials are characterized by poor mechanical behavior, either being insufficiently strong (Young's modulus less than 10 MPa) or insufficiently elastic (elongation at break less than 50%).

[0012] US Patent Application Publication No. 2004 / 0087755A1, incorporated herein by reference, discloses polyurethane polymers end-capped with 4H units based on 6-methylisocytosine, alkyldiol chain extenders and 4,4'-methylenebis(phenylisocyanate) (MDI), which may be used as hot melt adhesives or TPU foams. These materials have limited tensile strengths ranging from about 2 to about 8 MPa (Table 2), or stresses at 100% elongation between about 2 and about 3.2 MPa (Table 6). Most importantly, the aromatic MDI in these polyurethane materials precludes their potential use as biomedical biodegradable materials, since MDI is known to result in degradation products that may include highly toxic aniline and its derivatives.

[0013] US Patent Application Publication No. 2012 / 116014A1, incorporated herein by reference, describes a method for the preparation of a supramolecular polymer containing 1 to 50 4H units, the polymer comprising a supramolecular polymer of the formula 4H-(LF i ) r(In the formula, 4H represents a 4H unit, L represents a divalent, trivalent, tetravalent or pentavalent linking group, F i represents a reactive group, and r is 1 to 4), i and reacting said 4H building block with a prepolymer containing a reactive group complementary to said 4H building block, said reaction mixture containing said 4H building block and said prepolymer containing less than 10 wt. % of a non-reactive organic solvent based on the total weight of the reaction mixture. Most preferably, r is 2 and L is a divalent C1-C 20 The 4H building blocks are preferably prepared from precursors of isocytosine or melamine derivatives and diisocyanates, where the diisocyanates are most preferably isophorone diisocyanate (IPDI) or methylenedicyclohexane 4,4-diisocyanate (HMDI). The supramolecular polymers according to US 2012 / 116014 A1 are preferably used in coating and adhesive compositions. The supramolecular polymers obtained according to the preferred methods disclosed in US 2012 / 116014 A1 are very stiff (high Young's modulus) and have low elasticity, so that they are in fact not suitable for use in biomedical implants due to their low fatigue resistance.

[0014] WO 2014 / 185779 A1 discloses biodegradable supramolecular polymers comprising 4H units, low molecular weight diols, diisocyanates and biodegradable polymeric diols, in particular hydroxyl-terminated polycaprolactone and poly(ethylene glycol), which can be used for biodegradable implants. However, the presence of polycaprolactone makes these supramolecular polymers highly susceptible to (enzymatic) hydrolysis of the ester bonds that constitute these polycaprolactones. Thus, implants based on these polycaprolactone-based supramolecular polymers degrade too quickly in vivo for certain biomedical applications. When implants based on these materials are used as cardiovascular implants, too fast degradation can lead to aneurysms after implantation, or when they are used to treat prolapse, too fast degradation can lead to hernias. Moreover, the mechanical performance of the disclosed polycaprolactone-based supramolecular polymers is insufficient for certain biomedical applications. The Young's moduli range from 30 to 80 MPa, while the ultimate tensile strengths are all equal to or lower than 21 MPa. On the other hand, the presence of poly(ethylene glycol) blocks in the supramolecular polymers leads to too stiff polymers with low tensile strengths below 15 MPa and high water absorption, which also leads to accelerated degradation.

[0015] It is therefore an object of the present invention that there is a need for supramolecular biodegradable materials having high mechanical strength and / or high elasticity combined with durability and controlled slow bioabsorption for biomedical applications, in particular for use in biomedical implants. It is therefore an object of the present invention to provide supramolecular biodegradable materials that meet these requirements, as well as methods for the preparation of these materials.

[0016] Another object of the present invention is to provide strong, flexible and durable supramolecular biodegradable polymers having better (thermo)mechanical properties than those of the prior art, as well as methods for preparing such polymers.

[0017] Yet another object of the present invention is to provide durable biomedical supramolecular polymers that can be used in biomedical implants and tissue engineering scaffolds that are strong enough to be suitable for implantation in pathologies requiring structural support, e.g., tissue injuries requiring surgical intervention.

[0018] Moreover, it is an object of the present invention to provide a method for preparing porous structures, such as biomedical implants and tissue engineering scaffolds, from supramolecular biodegradable materials.

[0019] Yet another object of the present invention is to provide a method for preparing a porous structure from a supramolecular biodegradable material in a biomedically acceptable manner, so that said porous structure can be used as an implantable scaffold for regenerative medicine, the implant being gradually replaced by the patient's own functional tissue.

[0020] [Summary of the invention] The inventors of the present invention have found that a method for the preparation of supramolecular biodegradable materials, in which specific 4H units are combined with a polymer backbone that is not bioabsorbable per se, results in supramolecular biopolymers for biomedical use that have excellent mechanical properties such as strength, elasticity and durability, and at the same time, surprisingly, are biodegradable in a controlled manner due to their unique chemical structure containing the 4H units.

[0021] The present invention therefore relates in a first aspect to a method for the preparation of a biomedical supramolecular polymer having an ultimate tensile strength of at least 35 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, and in a second aspect to a biomedical supramolecular polymer having an ultimate tensile strength of at least 35 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, obtainable by said method, which method comprises the step of reacting a polymer having a tensile strength of at least 35 MPa with a crosshead speed of 20 mm / min according to formula (1): [ka] Compound F' by Formula O=C=N=R 3 -N=C=O diisocyanate compound C', Formula P-(FG1) w and a functionalized polymer A' according to Formula FG2-R 4 - Compound B' by FG2 reacting with During the ceremony, X is O or S; k is an integer from 1 to 20; n is an integer from 0 to 8, R 1 is C1~C 13 is an alkylene group, R 2 is a functional group selected from OH, SH and NH2, FG1, FG2 and FG3 are functional groups independently selected from OH and NH2; w is in the range of about 1.8 to about 2; The functionalized polymer A' has a number average molecular weight M of about 250 to about 10,000 Da, as determined from its hydroxyl number. n having P is a polymer, provided that it is not poly(ethylene glycol) or polycaprolactone; R 3 Cyclic or linear C4-C 20 C4-C containing alkylene group or ester 20 is an alkylene group, R 4 is C2~C 44 Alkylene, C6~C 44 Arylene, C7~C 44 Alkarylene and C7~C 44 arylalkylene, wherein the alkylene, arylene, alkarylene and arylalkylene groups are optionally supplemented with 1 to 5 heteroatoms selected from the group consisting of O, N and S; wherein the molar ratio of compounds A', B', C' and F', represented as A':B':C':F', is between 1:1.5:3.5:1 and 1:2:4:1.

[0022] In a third aspect, the present invention relates to a biomedical porous implant comprising a biomedical supramolecular polymer obtainable by the method defined herein before.

[0023] In a fourth aspect, the present invention relates to a method for the manufacture of a biomedical porous implant having a non-woven mesh structure comprising a biomedical supramolecular polymer obtainable by a method as defined hereinbefore, said method for the manufacture of a biomedical porous implant comprising: a) providing a biomedical supramolecular polymer obtainable by the method defined hereinbefore, b) dissolving the biomedical supramolecular polymer according to (a) in a solvent mixture suitable for electrospinning; c) electrospinning the polymer solution according to (b) onto a target; d) isolating the biomedical porous implant from the target as a sheet, cylinder or complex 3D structure. Includes.

[0024] In a fifth aspect, the present invention relates to a biomedical porous implant as defined herein before or obtainable by an electrospinning method as defined herein before, for use in the treatment of a cardiovascular disease, said treatment comprising replacing part of an artery or vein, or part or all of a venous, pulmonary, mitral, tricuspid or aortic valve, in a mammalian subject, with said biomedical porous implant, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

[0025] In a sixth aspect, the present invention relates to a biomedical porous implant as defined herein before or obtainable by an electrospinning method as defined herein before, for use in the treatment of a cardiovascular disease, said treatment comprising placing said implant at an intracardiac or intravascular site in a mammalian subject, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

[0026] In a seventh aspect, the present invention relates to a biomedical porous implant as defined herein before or obtainable by the electrospinning method as defined herein before for use in the treatment of conditions requiring reconstructive surgery, support or augmentation, preferably prolapse, pelvic organ prolapse, compartment syndrome, constrictive pericarditis, hemopneumothorax, hemothorax, dural injuries, and hernias, such as abdominal, diaphragmatic, hiatal, pelvic, anal, intracranial, Spigelian herniations, and herniations of the nucleus pulposus of the intervertebral disc, and stress urinary incontinence, said treatment comprising the surgical implantation of the biomedical porous implant at a site in a mammalian subject requiring reconstructive surgery, support or augmentation, said biomedical porous implant acting as a scaffold for the formation of new tissue.

[0027] General definition "Hydroxyl number" is defined as the number of milligrams of potassium hydroxide required to neutralize the acetic acid taken in the acetylation of 1 gram of a chemical that contains free hydroxyl groups. Hydroxyl number is a measure of the content of free hydroxyl groups in a chemical, and is usually expressed in units of milligrams of the mass of potassium hydroxide (KOH) that is equivalent to the hydroxyl content of 1 gram of the chemical. P-(FG1) w The molecular weight, as used herein, is equal to (2 x 56.1 x 1000) / (hydroxyl number).

[0028] The term "scaffold", as used herein, refers to a porous structure comprising biomedical supramolecular polymers that is used to guide cellular organization, growth and differentiation in the process of forming new functional tissue at the site of defective or damaged tissue, typically used in conjunction with surgical intervention.

[0029] The term "durable" in the context of "durable biomedical supramolecular polymer" or "durable biomedical supramolecular material" or "durable biomedical implant" as used herein refers to a material that has sufficiently high fatigue resistance for its application.

[0030] The term "obtainable by" is considered to be synonymous with "obtained by."

[0031] The term "one-step reaction," as used herein, refers to a "one-pot reaction" in which all reactants are present at the same time and added substantially simultaneously, as opposed to a reaction that includes "sequential reaction steps," in which subsequent reactants, possibly in different reaction vessels, are added after (at least partial) completion of the previous reaction step.

[0032] The urea moiety, as depicted in this document, has the formula: -NR-C(=X)-NR- in which X is O or S, preferably O, and in which both moieties R are selected independently of one another from a hydrogen atom or a linear alkyl group, preferably from a hydrogen atom. It should be understood that this is in part due to

[0033] The amide moiety, as shown in the document, has the formula: -NR-C(=X)- (wherein X and R are as described above). It should be understood that this is in part due to

[0034] The urethane moiety, as shown in this document, has the formula: -NR-C(=X)-X- in which R is as described above and in which both atoms X are selected, independently of one another, from O or S, in which X is preferably O. It should be understood that this is in part due to

[0035] The ester moiety, as shown in the document, has the formula: -C(=X)-X- in which both atoms X are selected independently of one another from O or S, where X is preferably O. It should be understood that this is in part due to

[0036] The carbonate moiety, as depicted in the document, has the formula: -XC(=X)-X- in which all three atoms X are selected independently from O or S, in which X is preferably O. It should be understood that this is in part due to

[0037] The amine moiety, as shown in the document, has the formula: -NR2- (wherein R is as described above). It should be understood that this is in part due to

[0038] The ether moiety, as shown in the document, has the formula: -X- (wherein X is as described above). It should be understood that this is in part due to

[0039] An isocyanate group is to be understood as a -N=C=X group, where X is as defined above.

[0040] (Self-)contained units capable of forming at least four hydrogen bonds in principle form non-conjugated moieties with each other. When (self-)contained units are capable of forming four hydrogen bonds in a row, they are used in their abbreviated form "4H units". However, it is within the scope of the present invention that (self-)contained units (including 4H units) can form non-conjugated moieties with other materials capable of forming less than four hydrogen bonds. Units capable of forming at least four hydrogen bonds can form non-self-contained or self-contained linking groups. "Non-self-contained" means, for example, that a 4H unit (I) forms a linking moiety (I)-(II) with a unit (II), where (II) is a different 4H unit. "Self-contained" means that two 4H units (I) form a linking moiety (I)-(I). It is preferred that the 4H units are self-contained. The units according to the compound F' of formula (I) form (self-)contained units when incorporated into the biomedical supramolecular polymer according to the present invention.

[0041] The terms "bioresorbable", "biodegradable" and "biodegradation" as used herein relate to the cell-mediated degradation, enzymatic degradation, and hydrolytic oxidative degradation of the biomedical supramolecular polymer and / or the biomedical porous implant comprising the biomedical supramolecular polymer. The term "biodegradable" may also relate to the removal of the biomedical supramolecular polymer and / or the biomedical porous implant comprising the biomedical supramolecular polymer from living tissue.

[0042] The term "tissue" as used herein refers to a solid biological tissue that is part of an individual living mammal, such as a human. The tissue may be a hard or soft tissue, such as ligament, tendon, fibrous tissue, fascia, fat, muscle, nerve and cardiovascular tissue.

[0043] The term "room temperature" as used in this document has its ordinary meaning, ie, it refers to a temperature within the range of about 20°C to about 25°C.

[0044] M n The molecular weights of these are expressed in Daltons (Da).

[0045] [Mode for carrying out the invention] Method for preparing supramolecular polymers for biomedical applications In a first aspect, the present invention provides a method for the preparation of a biomedical supramolecular polymer having an ultimate tensile strength of at least 35 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, comprising the steps of: [ka] Compound F' by Formula O=C=NR 3 -N=C=O diisocyanate compound C', Formula P-(FG1) w and a functionalized polymer A' according to Formula FG2-R 4 - Compound B' by FG3 reacting with During the ceremony, X is O or S; k is an integer from 1 to 20; n is an integer from 0 to 8, R 1 is C1~C 13 is an alkylene group, R 2 is a functional group selected from OH, SH and NH FG1, FG2 and FG3 are functional groups independently selected from OH and NH2; w is in the range of about 1.8 to about 2; The functionalized polymer A' has a number average molecular weight M of about 250 to about 10,000 Da, as determined from its hydroxyl number. n having P is a polymer, provided that it is not poly(ethylene glycol) or polycaprolactone; R 3 Cyclic or linear C4-C 20 C4-C containing alkylene group or ester 20 is an alkylene group, R4 is C2~C 44 Alkylene, C6~C 44 Arylene, C7~C 44 Alkarylene and C7~C 44 arylalkylene, wherein the alkylene, arylene, alkarylene and arylalkylene groups are optionally interrupted by 1 to 5 heteroatoms selected from the group consisting of O, N and S; and wherein the molar ratio of compounds A', B', C' and F', represented as A':B':C':F', is between 1:1.5:3.5:1 and 1:2:4:1.

[0046] The method results in biomedical supramolecular polymers with high (ultimate) tensile strength, high elasticity and high durability, which are highly suitable for biomedical applications.

[0047] The process for the preparation of biomedical supramolecular polymers preferably provides a Young's modulus (E) of at least 40 MPa, more preferably at least 50 MPa, and even more preferably at least 90 MPa, measured preferably between 0.25% elongation and 2.50% elongation, as determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min. mod ) is preferably a method for producing a supramolecular polymer for biomedical use having a Young's modulus (E mod ) is less than 180 MPa, more preferably less than 160 MPa, and most preferably less than 140 MPa, measured between 0.25% elongation and 2.50% elongation, as determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min. mod ) is between 40 MPa and 160 MPa, preferably measured between 0.25% elongation and 2.50% elongation, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0048] The method for producing a biomedical supramolecular polymer is preferably a method for producing a biomedical supramolecular polymer having an elastic modulus at 100% elongation of at least 7 MPa, more preferably at least 12 MPa, most preferably at least 15 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0049] The method for producing a biomedical supramolecular polymer is preferably a method for producing a biomedical supramolecular polymer having an ultimate tensile strength of at least 40 MPa, more preferably at least 45 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0050] The method for producing a biomedical supramolecular polymer is preferably a method for producing a biomedical supramolecular polymer having an elongation at break of at least 350%, more preferably at least 400%, most preferably at least 500%, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0051] The method of production of biomedical supramolecular polymers is preferably a method of production of biomedical supramolecular polymers having a fatigue resistance of at least 3 million cycles, preferably at least 6 million cycles, most preferably at least 12 million cycles before failure, determined using a uniaxial tensile tester with 10% elongation at a sample rate of 2 Hz or 10 Hz, preferably 10 Hz, on a 5x25 mm polymer strip between 0.2 mm and 1 mm thick, defining fatigue failure as the cycle where the stress response is less than 10% of the stress response at the first cycle.

[0052] The method for the preparation of biomedical supramolecular polymers is preferably a method for the preparation of biomedical supramolecular polymers having at least two thermal transitions selected from a glass transition and a melting point at temperatures between about 50° C. and about 125° C., and no thermal transitions between 0° C. and 45° C., preferably no thermal transitions between 0° C. and 40° C., and preferably no thermal transitions above 120° C., as determined by differential scanning calorimetry (DSC) at a heating rate of 20° C. / min. In a highly preferred embodiment, the method for the preparation of biomedical supramolecular polymers is a method for the preparation of biomedical supramolecular polymers having at least two thermal transitions selected from a glass transition and a melting point at temperatures between about 50° C. and about 125° C., and no thermal transitions between 0° C. and 45° C., as determined by differential scanning calorimetry (DSC) at a heating rate of 20° C. / min.

[0053] The method for the production of biomedical supramolecular polymers is preferably a method for the production of biomedical supramolecular polymers having an ultimate tensile strength and a modulus at 100% elongation with a deformation index defined by the ultimate tensile strength divided by the modulus at 100% elongation of at least 2.0, more preferably at least 2.5, most preferably at least 3.5, according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0054] The method for the preparation of a biomedical supramolecular polymer is preferably a method for the preparation of a biomedical supramolecular polymer having at least one of the preferred (thermo)mechanical properties selected from the group consisting of ultimate tensile strength, Young's modulus, modulus at 100% elongation, elongation at break, thermal transition, deformation index and fatigue resistance as previously described herein.

[0055] In a highly preferred embodiment, the method for the production of biomedical supramolecular polymers is a method for the production of biomedical supramolecular polymers having an ultimate tensile strength of at least 35 MPa, more preferably at least 40 MPa, most preferably at least 45 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, and a fatigue resistance of at least 3 million cycles, preferably at least 6 million cycles, most preferably at least 12 million cycles before failure, determined using a uniaxial tensile tester with 10% elongation at a sample rate of 2 Hz or 10 Hz, preferably 10 Hz, on a 5x25 mm polymer strip with a thickness between 0.2 mm and 1 mm, defining fatigue failure as the cycle where the stress response is less than 10% of the stress response at the first cycle.

[0056] In a highly preferred embodiment, the method for the preparation of a biomedical supramolecular polymer is a method for the preparation of a biomedical supramolecular polymer having all of the preferred (thermo)mechanical properties selected from the group consisting of ultimate tensile strength, Young's modulus, modulus at 100% elongation, elongation at break, thermal transition, deformation index and fatigue resistance as previously described herein.

[0057] In a highly preferred embodiment, the method for the preparation of biomedical supramolecular polymers comprises the steps of: i) a Young's modulus between 40 MPa and 160 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; ii) a modulus at 100% elongation of at least 7 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; iii) an ultimate tensile strength of at least 40 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; iv) an elongation at break of at least 350%, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; v) fatigue resistance of at least 3 million cycles before fatigue, as determined using a uniaxial tensile tester with 10% elongation at a sample rate of 10 Hz on 5×25 mm polymer strips with thickness between 0.2 mm and 1 mm, with fatigue failure defined as the cycle where the stress response is less than 10% of the stress response at the first cycle; and vi) at least two thermal transitions selected from a glass transition and a melting point at temperatures between 50° C. and 125° C., and no thermal transitions between 0° C. and 45° C., as determined by differential scanning calorimetry at a heating rate of 20° C. / min. The present invention relates to a method for producing a supramolecular polymer for biomedical use, the polymer comprising at least one of the following:

[0058] In a most preferred embodiment, the method for producing a biomedical supramolecular polymer is a method for producing a biomedical supramolecular polymer having all of the properties (i) to (vi).

[0059] Preferably, in the method, the functionalized polymer A', the compound B', the diisocyanate compound C' and the compound F' according to formula (1) are reacted in a one-step reaction, which requires that A', B', C' and F' are added more or less simultaneously to a reaction vessel.

[0060] It is preferred that the ratio of the molar amounts of compounds A', B', C' and F', represented as A':B':C':F', is between 1:1.5:3.5:1 and 1:2:3.97:1. In another preferred embodiment, the molar amount of C' is equal to about 0.8 to about 1.2 times the total molar amount of functionalized polymer A' plus compound B' plus compound F' according to formula (1).

[0061] In another embodiment, the method comprises reacting a functionalized polymer A', a compound B', a diisocyanate compound C' and a compound F' according to formula (1) in separate reaction steps.

[0062] Thus, one embodiment is a sequential reaction method for preparing a supramolecular polymer for biomedical applications, comprising: a) in a first step, a compound F' according to formula (1) is reacted with a compound of formula O=C=NR3 -Diisocyanate compound C' with N=C=O, and formula P-(FG1) W to form a prepolymer P1 comprising a compound F' according to formula (1), b) in a second step, a prepolymer P1 comprising a compound F′ according to formula (1) from step (a) is reacted with a compound of formula FG2-R 4 - reacting compound B' with FG3 and optionally diisocyanate compound C' to form a biomedical supramolecular polymer; It concerns the method.

[0063] In this sequential reaction, the functionalized polymer A', the compound F' according to formula (1) and the diisocyanate compound C' are preferably reacted in step (a) in a molar ratio represented by A':F':C' between 1:1:1 and 1:1:4, more preferably in a molar ratio represented by 1:1:3.5 and 1:1:4, most preferably 1:1:4, and in step (b) in a molar ratio represented by P1:B' between 1:1.5 and 1:2, with optionally adding in step (b) a further diisocyanate compound C' so that the molar amount of the diisocyanate compound C' is equal to the molar amount of the functionalized polymer A' plus the compound B' plus the compound F' according to formula (1).

[0064] In another embodiment, there is provided a sequential reaction method for preparing a biomedical supramolecular polymer, comprising the steps of: a) in a first step, in a first reaction vessel, a functionalized polymer A' is reacted with a diisocyanate compound C' to form a prepolymer P1, and in a second reaction vessel, a compound F' according to formula (1) is reacted with a diisocyanate compound C' to form a functionalized compound F', b) in a second step, reacting the prepolymer P1 with the functionalized compound F' together with 1.5 to 2 molar equivalents of compound B' and an additional 0 to 1 molar equivalent of a diisocyanate compound C', preferably an additional 0 molar equivalent of a diisocyanate compound C', A method is provided.

[0065] In this sequential reaction method, the functionalized polymer A' and the diisocyanate compound C' are reacted on the one hand, and the compound F' according to formula (1) and the diisocyanate compound C' are reacted on the other hand, preferably in step (a) with a molar ratio of 1:2 for the functionalized polymer A', the compound F' according to formula (1) and the diisocyanate compound C', respectively. The prepolymer P1 and the functionalized compound F' according to formula (1) are reacted preferably in step (b) with 1.5-2 molar equivalents of the compound B' and 0-4 molar equivalents of the diisocyanate compound C'.

[0066] Alternatively, the biomedical supramolecular polymer can be obtained by adding the functionalized polymer A', the compound B', the diisocyanate compound C' and the compound F' according to formula (1) in one or more steps, in any order.

[0067] Without wishing to be bound by theory, it is believed that the main course of the reaction is as shown in Scheme 1: [ka] (wherein z is the number average molecular weight M of the biomedical supramolecular polymer) n is about 3,000 to about 150,000 Da as determined by size exclusion chromatography in DMF containing 10 mM LiBr at 50° C. using PEO / PEG standards. It is preferred that z is in the range of 6 to 20, more preferably 10 to 18. where FG1, FG2, FG3 and R 2 represents OH and w=2.

[0068] Compound F' according to formula (1) R in compound F' according to formula (1) 1 The group is C1-C 13 It is an alkylene group. C1-C 13 The alkylene group can be cyclic, branched or linear. More preferably, R 1is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-hexyl, cyclohexyl, 3-ethylpentyl and tredecyl. 1 is methyl.

[0069] In compound F' according to formula (1), k is an integer from 1 to 20, preferably 2, 4 or 11, most preferably 2, and n is an integer from 0 to 8, preferably 0 or 1, most preferably 0. X can be oxygen (O) or sulfur (S), preferably oxygen.

[0070] In the compound F' according to formula (1), R 2 The functional groups present as are amino (NH2), thiol (SH) or hydroxyl (OH) groups, preferably primary amino or hydroxyl groups, most preferably hydroxyl groups.

[0071] In a highly preferred embodiment, in the compound F′ according to formula (1), R 1 is methyl, and a) k is 2, n is 0, and R 2 is OH, b) k is 2, n is 1, and R 2 is OH and X is O; c) k is 4 to 11, n is 0, and R 2 is OH, or d) k is 4 to 11, n is 0, and R 2 is NH2.

[0072] Diisocyanate compound C' The diisocyanate compound C' has the formula O=C=NR 3 -N=C=O(in the formula, R 3 Cyclic or linear C4-C 20 C4-C containing alkylene group or ester 20 More preferably, R 3 is a linear C4-C 20It is an alkylene group. Even more preferably, the diisocyanate compound C' is selected from the group consisting of 1,4-diisocyanatobutane (BDI), 1,6-diisocyanatohexane (HDI) and 1,12-diisocyanatododecane. Most preferably, the diisocyanate compound C' is 1,6-diisocyanatohexane.

[0073] In another embodiment of the invention, the diisocyanate compound C' is a lysine alkyl ester diisocyanate, more preferably L-lysine ethyl ester diisocyanate.

[0074] Functionalized Polymer A' The functionalized polymer A' has the formula P-(FG1) w where w is in the range of about 1.8 to about 2. FG1 is a functional group selected from OH and NH2, and the functionalized polymer A' is functionalized with either OH or NH2.

[0075] In a preferred embodiment, w is in the range of about 1.9 to about 2, more preferably in the range of about 1.95 to about 2. In the case where the functionalized polymer A' is truly difunctional, i.e., W=2, the functionalized polymer A' is represented as FG1-P-FG1.

[0076] In a highly preferred embodiment, the formula P-(FG1) w The polymer P in the functionalized polymer A' having the following structure is end-group functionalized with FG1.

[0077] The functionalized polymer A' has a number average molecular weight M, determined from its hydroxyl number, of about 250 to about 10,000 Da, more preferably about 500 to about 4,000 Da, even more preferably about 900 to about 2,100 Da, for example about 1,000 to about 2,000 Da, still more preferably about 950 to about 1,500 Da, and most preferably about 900 to about 1,200 Da, for example about 1,000 to about 1,200 Da. n has.

[0078] The polymer P in the functionalized polymer A' may be selected from all kinds of polymer backbones, provided that it does not include polycaprolactone or poly(ethylene glycol). Most preferably, the polymer A' is a linear polymer P that is functionalized with hydroxyl end groups, which implies that FG1 represents OH.

[0079] Preferably, the functionalized polymer A' is a hydrophobic polymer that is neither polycaprolactone nor poly(ethylene glycol) functionalized with FG1. In order to prevent the biomedical supramolecular polymer from biodegrading too quickly in an aqueous environment, such as the aqueous environment that constitutes living tissue, a hydrophobic functionalized polymer A' is preferred. According to the present invention, the hydrophobic polymer has a solubility in water at 25°C of less than 10 g / L, more preferably less than 1 g / L, most preferably less than 0.1 g / L. Alternatively, the hydrophobic polymer has a water contact angle of more than 70°, more preferably more than 75°, most preferably more than 80°, measured at 25°C using the static drop method, in which a contact angle goniometer is used to determine the contact angle, where the contact angle is defined as the angle between the surface of the solid polymer and the tangent of the oval of the water droplet at the edge of the droplet.

[0080] The functionalized polymer A' is preferably a polymer P-(FG1) functionalized with FG1. w where P is selected from the group consisting of polyethers, polyesters, polyorthoesters, polyamides, polypeptides, polyacrylates, polymethacrylates, polycarbonates, polybutadienes, hydrogenated polybutadienes, and copolymers of such polymers. More preferably, the functionalized polymer A' is a polymer P-(FG1) functionalized with FG1. w where P is selected from the group consisting of polyethers, polyamides, polycarbonates, polybutadienes, hydrogenated polybutadienes, polypeptides, and copolymers of such polymers. Even more preferably, the functionalized polymer A' is a polymer P-(FG1) functionalized with FG1. wwhere P is selected from the group consisting of polycarbonate, polybutadiene, hydrogenated polybutadiene, and copolymers of such polymers.

[0081] In one particular embodiment of the invention, the functionalized polymer A' is a polymer P-(FG1) functionalized with FG1. w where P is selected from the group consisting of polycarbonates, polyethers, and copolymers of such polymers. Most preferably, the functionalized polymer A' is a polycarbonate that is functionalized with FG1.

[0082] The polycarbonates functionalized with FG1 are preferably selected from hydroxy-terminated polycarbonates and copolycarbonates based on alkyldiol polycarbonates and hydroxy-terminated polycarbonates and copolycarbonates made by ring-opening polymerization of trimethylene carbonate, 1,3-dioxepan-2-one, 1,3-dioxanon-2-one and 1,3,8,10-tetraoxacyclotetradecane-2,9-dione. More preferably, the polycarbonates functionalized with FG1 are selected from hydroxy-terminated alkyldiol polycarbonates, most preferably hydroxy-terminated poly(1,6-hexanediol) carbonate.

[0083] In another particular embodiment of the invention, the functionalized polymer A' is selected from the group consisting of polyethers, with the proviso that it is not a poly(ethylene glycol) functionalized with FG1.

[0084] The polyether functionalized with FG1 is preferably selected from polypropylene glycol, poly(ethylene-co-propylene) glycol (random or block), poly(ethylene-block-propylene-block-ethylene) glycol (also known as Pluronics®), poly(tetramethylene ether) glycol (i.e. poly-tetrahydrofuran) and poly(ethylene-co-tetramethylene ether) glycol, whose end groups are functionalized with FG1, and copolymers thereof. More preferably, the polyether functionalized with FG1 is poly(tetramethylene ether) glycol, whose end groups are functionalized with FG1.

[0085] The polybutadienes functionalized (hydrogenated) with FG1 are preferably end-functionalized and selected from low cis, high cis, and high vinyl polybutadienes functionalized with FG1. Preferably, they are selected from the group consisting of polybutadienes functionalized with FG1 containing many vinyl structures at 1,2-position, polybutadienes functionalized and hydrogenated with FG1, or 1,2-polybutadienes functionalized and hydrogenated with FG1.

[0086] What has been surprisingly found is that when using functionalized polymers A' different from polycaprolactone or poly(ethylene glycol) functionalized with FG1, such as polycarbonate functionalized with FG1, polybutadiene functionalized with FG1, hydrogenated polybutadiene functionalized with FG1 and poly(tetramethylene ether) glycol functionalized with FG1, beneficial material performances for biomedical supramolecular polymers have been obtained in relation to their use in biomedical porous implants. More specifically, durability and resistance towards gamma and electron beam sterilization in relation to their elastic behavior. In addition, despite the relatively non-degradable nature of these functionalized polymers A', it has been found that the corresponding biomedical supramolecular polymers comprising a functionalized polymer A' backbone do indeed degrade after implantation in vitro due to their resistance to hydrolysis due to the lack of ester bonds in their polymer backbone. Without wishing to be bound by theory, it is believed that this in vitro degradation originates from the biodegradation of compound F' according to formula (1) contained in a biomedical supramolecular polymer.

[0087] Compound B' Compound B' has the formula FG2-R 4 -FG3 (in the formula, R 4 is C2~C 44 Alkylene, C6~C 44 Arylene, C7~C 44 Alkarylene and C7~C 44 arylalkylene, where the alkylene, arylene, alkarylene and arylalkylene groups are optionally interrupted by 1 to 5 heteroatoms selected from the group consisting of O, N and S. FG2 and FG3 are functional groups independently selected from OH and NH2.

[0088] Preferably, R 4 is C2~C 20It is an alkylene group, which is optionally interrupted by one or more, preferably 1 to 5, oxygen or nitrogen atoms. The alkylene group may be linear or cyclic.

[0089] More preferably, R 4 is a linear C2-C 20 More preferably, R is an alkylene group. 4 is selected from the group consisting of butylene, hexylene, octylene, decylene and dodecylene. Most preferably, R 4 is hexylene.

[0090] Preferably, FG2 and FG3 are the same, and more preferably, FG2 and FG3 are both OH.

[0091] Compound B' preferably has a molecular weight of about 130 to about 400 Da, more preferably a molecular weight of about 130 to about 190 Da.

[0092] Preferably, compound B' is a linear C2-C 12 Alkyl α,ω-diols, where the alkylene group is optionally interrupted by one or more, preferably 1 to 5, oxygen atoms. Even more preferably, compound B' is selected from 1,4-butanediol, 1,12-dodecyldiol and 1,6-hexanediol. Most preferably, compound B' is 1,6-hexanediol.

[0093] In another embodiment of the invention, FG2 is OH, FG3 is NH2, and R 4 is linear C2~C 20 More preferably, R is an alkylene group. 4 is selected from the group consisting of butylene, hexylene, octylene, decylene and dodecylene, and is most preferably hexylene.

[0094] method The process for the preparation of supramolecular polymers for biomedical applications according to the invention can be carried out in any manner known in the art, for example by reactive extrusion in solution or in bulk. The process, whether it is carried out in a one-step process or in a sequential process involving two or more reaction steps, is preferably carried out at a temperature between about 10° C. and about 140° C., more preferably between about 20° C. and about 120° C., most preferably between about 40° C. and about 90° C.

[0095] The process for the preparation of biomedical supramolecular polymers may be carried out in the presence of a catalyst. Examples of suitable catalysts that promote the reaction between isocyanates and hydroxyl groups are known in the art. Preferred catalysts include tertiary amines and metal-containing catalysts. Preferred tertiary amines are 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preferred metal-containing catalysts are tin(IV) compounds and zirconium(IV) compounds, preferably selected from the group consisting of tin(II) octoate, dibutyltin(IV) laurate, and zirconium(IV) acetoacetate. Most preferably, the catalyst is tin(II) octoate or zirconium(IV) acetoacetate. The amount of catalyst is generally less than about 1% by weight, preferably less than about 0.2% by weight, and most preferably between about 0.05% and 0.15% by weight, based on the total amount of reactants A', B', C' and F'.

[0096] In a preferred embodiment of the present invention, the process is carried out in the presence of a non-reactive polar organic solvent, where the amount of the non-reactive polar organic solvent is preferably at least about 20% by weight, more preferably at least about 40% by weight, even more preferably at least about 50% by weight, and most preferably at least about 70% by weight, based on the total weight of the reaction mixtures A', B', C' and F' formed in either a one-step process or a sequential process including two or more reaction steps. It is also preferred that the reaction mixture does not contain any inorganic solvents such as water. The non-reactive solvent is preferably selected from aprotic polar organic solvents, preferably tetrahydrofuran, dioxane, N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, propylene carbonate, ethylene carbonate and 2-methoxy-ethyl-acetate. Most preferably, the non-reactive polar organic solvent is dimethylsulfoxide or propylene carbonate.

[0097] The biomedical supramolecular polymers can be isolated per se, i.e., as a polymer in a solvent, or as a powder after precipitation in a non-solvent, chopped into pellets, spun into fibers, extruded into films, directly dissolved in a medium of choice, or transformed or formulated into any desired form.

[0098] In a highly preferred embodiment, the method for producing a biomedical supramolecular polymer comprises the steps of: [ka] Compound F' by Formula O=C=NR 3 -N=C=O diisocyanate compound C', Formula P-(FG1) w and a functionalized polymer A' according to Formula FG2-R 4 - Compound B' by FG3 reacting with During the ceremony, X is O or S; k is an integer from 1 to 20; n is an integer from 0 to 8, R 1 is C1~C 13 is an alkylene group, R 2 is a functional group selected from OH, SH and NH2, FG1, FG2 and FG3 are functional groups independently selected from OH and NH2; w is in the range of about 1.8 to about 2; The functionalized polymer A' has a number average molecular weight M of about 1000 to about 2000 Da, as determined from its hydroxyl number. n having P is a polymer, provided that it is not poly(ethylene glycol) or polycaprolactone; R 3 is a linear C4-C 20 is an alkylene group, R 4 is a linear C2-C 20 is an alkylene group, and wherein the molar ratio of compounds A', B', C' and F', represented as A':B':C':F', is between 1:1.5:3.5:1 and 1:2:4:1.

[0099] Supramolecular Polymers for Biomedical Applications In a second aspect, the present invention relates to a biomedical supramolecular polymer obtainable by the method defined hereinbefore, having an ultimate tensile strength of at least 35 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min. This second aspect may also be expressed as a biomedical supramolecular polymer obtained by the method defined hereinbefore, having an ultimate tensile strength of at least 35 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0100] The supramolecular polymers for biomedical purposes which are obtainable by the method defined hereinbefore preferably have a number average molecular weight M of about 3000 to about 150000 Da, more preferably about 4000 to about 60000 Da, even more preferably about 8000 to about 40000 Da, still more preferably about 10000 to about 30000 Da, most preferably about 10000 to about 20000 Da, determined by size exclusion chromatography in DMF containing 10 mM LiBr at 50° C. using PEO / PEG standards. n As known to those skilled in the art, the number average molecular weight M of a biomedical supramolecular polymer n can be adjusted by varying the molar amount of diisocyanate compound C' relative to the molar amount of further reactants.

[0101] The biomedical supramolecular polymers obtainable by the method defined herein before may be random polymers in which the structural units resulting from the reactants A', B', C' and F' occur in a random sequence. The biomedical supramolecular polymers may also be segmented polymers in which a regular sequence of structural units resulting from the reactants A', B', C' and F' may be found.

[0102] In a preferred embodiment of the present invention, the biomedical supramolecular polymer obtainable by the method defined hereinbefore absorbs less than about 2% by weight of water, based on the total weight of the biomedical supramolecular polymer, when a film layer of 0.1-0.4 mm thickness is immersed in an excess of demineralized water for 24 hours at 37° C. Such a film layer can be created by dissolving the biomedical supramolecular polymer in a volatile solvent, casting a layer of the solution on a surface, and evaporating the volatile solvent.

[0103] For applications in biomedical implants, such as prosthetic meshes and heart valves, the (thermo)mechanical properties of biomedical supramolecular polymers are of crucial importance.

[0104] Without wishing to be bound by theory, it is hypothesized that the lower levels of Young's modulus and modulus at 100%, defined infra for biomedical supramolecular polymers, are necessary to ensure sufficient strength and elasticity in biomedical implants comprising biomedical supramolecular polymers for their biomedical application, while the upper limit of Young's modulus is necessary to prevent said biomedical implant from being too stiff or even brittle, which would lead to low durability or even rupture of the biomedical porous implant at the fastening point to the tissue, for example rupture after stitching. Moreover, minimum values ​​of ultimate tensile strength and elongation at break, as well as extended fatigue behavior, are required for good durability of the biomedical implant and its desired durable performance before degradation while implanted in the body. In addition, the deformation behavior of the biomedical porous implant reflects the elastic behavior conforming to the tissue at the implantation site. In the present invention, this property is reflected in the value obtained from the ultimate tensile strength divided by the modulus at 100%.

[0105] Biomedical supramolecular polymers should certainly not exhibit thermal transitions at or around room temperature, since this could alter the mechanical properties of the implant during handling or while embedded in the body, whereas the presence of thermal transitions at higher temperatures reflects the presence of ordered domains in the polymer that contribute to the mechanical strength of the polymer.

[0106] The limiting values ​​of the mechanical properties of the biomedical supramolecular polymers according to the invention are based on values ​​obtained from untreated tissues such as cardiovascular and abdominal tissues, which are also given in the background of the present invention and in the loss of strength when going from solid materials to porous structures such as the nonwoven mesh structures of the preferred biomedical porous implants comprising the biomedical supramolecular polymers. The values ​​of the untreated tissues are multiplied by a function of about 10-20 to obtain the limiting values ​​of the biomedical supramolecular polymers. This multiplication is carried out in order to balance the effect on the mechanical properties of the porosity of the nonwoven mesh structures of the biomedical porous implants comprising the biomedical supramolecular polymers and to build in a safety margin to prevent the failure of the medical treatment.

[0107] Without wishing to be bound by theory, the strength reduction of the biomedical porous implant, compared to the strength reduction of the biomedical supramolecular polymer, depends on the amount of porosity and the specific topology of the porous structure, which can be said to be the strength reduction of the non-woven mesh structure is equal to 0.07-0.10 times the original strength reduction of the biomedical supramolecular polymer.

[0108] The biomedical supramolecular polymers obtainable by the method defined hereinbefore have high (extreme) tensile strength, high elasticity, high durability, making them highly suitable for biomedical applications.

[0109] The biomedical supramolecular polymers obtainable by the method defined hereinbefore preferably have a Young's modulus (E) of at least 40 MPa, more preferably at least 50 MPa, even more preferably at least 90 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, preferably measured between 0.25% elongation and 2.50% elongation. mod ). Preferably, the Young's modulus (E mod) is less than 180 MPa, more preferably less than 160 MPa, and most preferably less than 140 MPa, measured between 0.25% elongation and 2.50% elongation, as determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min. mod ) is between 40 MPa and 160 MPa, preferably measured between 0.25% elongation and 2.50% elongation, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0110] The biomedical supramolecular polymers obtainable by the method defined herein before have a modulus at 100% elongation of preferably at least 7 MPa, more preferably at least 12 MPa, most preferably at least 15 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0111] The biomedical supramolecular polymers obtainable by the process defined hereinbefore preferably have an ultimate tensile strength of at least 40 MPa, more preferably at least 45 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0112] The biomedical supramolecular polymers obtainable by the method defined herein before have an elongation at break of preferably at least 350%, more preferably at least 400% and most preferably at least 500%, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0113] The biomedical supramolecular polymers obtainable by the method defined herein before have a fatigue resistance of at least 3 million cycles, preferably at least 6 million cycles, most preferably at least 12 million cycles before fatigue, determined using a uniaxial tensile tester with 10% elongation at a sample rate of 2 Hz or 10 Hz, preferably 10 Hz, on 5x25 mm polymer strips with a thickness between 0.2 mm and 1 mm, defining fatigue failure as the cycle where the stress response is less than 10% of the stress response in the first cycle.

[0114] The biomedical supramolecular polymers obtainable by the method defined hereinbefore have at least two thermal transitions selected from a glass transition and a melting point at temperatures between about 50° C. and about 125° C., as well as no thermal transitions between 0° C. and 45° C., preferably no thermal transitions between 0° C. and 40° C., and preferably no thermal transitions above 125° C., as determined by differential scanning calorimetry (DSC) at a heating rate of 20° C. / min. In a highly preferred embodiment, the biomedical supramolecular polymers obtainable by the method defined hereinbefore have at least two thermal transitions selected from a glass transition and a melting point at temperatures between about 50° C. and about 125° C., as well as no thermal transitions between 0° C. and 45° C., as determined by differential scanning calorimetry (DSC) at a heating rate of 20° C. / min.

[0115] The biomedical supramolecular polymers obtainable by the method defined herein before have an ultimate tensile strength and a modulus at 100% elongation, with a deformation index defined by the ultimate tensile strength divided by the modulus at 100% elongation, preferably of at least 2.0, more preferably of at least 2.5 and most preferably of 3.5, according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min.

[0116] In a preferred embodiment, the supramolecular polymer for biomedical use obtainable by the method defined hereinbefore has at least one of the preferred (thermo)mechanical properties selected from the group consisting of ultimate tensile strength, Young's modulus, modulus at 100% elongation, elongation at break, thermal transition, deformation index and fatigue resistance as described hereinbefore.

[0117] In a highly preferred embodiment, the biomedical supramolecular polymer obtainable by the method defined herein before has an ultimate tensile strength of at least 35 MPa, more preferably at least 40 MPa, most preferably at least 45 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, and a fatigue resistance of at least 3 million cycles, preferably at least 6 million cycles, most preferably at least 12 million cycles before fatigue, determined using a uniaxial tensile tester with a sample rate of 2 Hz or 10 Hz, preferably 10 Hz, with 10% elongation on a 5x25 mm polymer strip with a thickness between 0.2 mm and 1 mm, defining fatigue failure as the cycle in which the stress response is less than 10% of the stress response in the first cycle.

[0118] In a highly preferred embodiment, the supramolecular polymer for biomedical use obtainable by the method defined hereinbefore has all the preferred (thermo)mechanical properties selected from the group consisting of ultimate tensile strength, Young's modulus, modulus at 100% elongation, elongation at break, thermal transition, deformation index and fatigue resistance as described hereinbefore.

[0119] In a highly preferred embodiment, the supramolecular polymers for biomedical applications obtainable by the method defined hereinbefore have the following properties (i) to (vi): i) a Young's modulus between 40 MPa and 160 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; ii) a modulus at 100% elongation of at least 7 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; iii) an ultimate tensile strength of at least 40 MPa, determined according to test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; iv) an elongation at break of at least 350%, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; v) fatigue resistance of at least 3 million cycles before fatigue, as determined using a uniaxial tensile tester with 10% elongation at a sample rate of 10 Hz on 5×25 mm polymer strips with thickness between 0.2 mm and 1 mm, with fatigue failure defined as the cycle where the stress response is less than 10% of the stress response at the first cycle; and vi) at least two thermal transitions selected from a glass transition and a melting point at temperatures between 50° C. and 125° C., and no thermal transitions between 0° C. and 45° C., as determined by differential scanning calorimetry at a heating rate of 20° C. / min. The present invention has at least one of the following:

[0120] In a most preferred embodiment, the supramolecular polymer for biomedical applications obtainable by the method defined hereinbefore has all of the properties (i) to (vi).

[0121] Biomedical Porous Implants Preferably, the biomedical supramolecular polymers obtainable by the methods defined herein before are melted and melt spun, extruded using fused deposition modeling, processed with 3D printing techniques such as laser sintering, or dissolved in volatile organic solvents and electrospun to obtain porous biomedical implants or tissue engineering scaffolds, which can also be obtained by solvent casting, salt leaching and thermally induced phase separation.

[0122] Therefore, in a third aspect, the present invention relates to a biomedical porous implant comprising a biomedical supramolecular polymer obtainable by the method defined herein before. In a preferred embodiment, the biomedical implant has a non-woven mesh structure obtained by electrospinning a biomedical supramolecular polymer obtainable from a solution by the method defined herein before.

[0123] Therefore, in a fourth aspect, the present invention relates to a method for the manufacture of a biomedical porous implant having a non-woven mesh structure comprising a biomedical supramolecular polymer obtainable by the method defined herein before, comprising: a) providing a biomedical supramolecular polymer obtainable by the method defined hereinbefore, b) dissolving the biomedical supramolecular polymer according to (a) in a solvent mixture suitable for electrospinning; c) electrospinning the polymer solution according to (b) onto a target; d) isolating the biomedical porous implant from the target as a sheet, cylinder or complex 3D structure. The present invention relates to a method comprising the steps of:

[0124] The method of electrospinning involves dissolving a biomedical supramolecular polymer in a suitable solvent, pumping said biomedical supramolecular polymer solution through a small orifice such as a needle, and then depositing the polymer solution onto a target by means of an electromagnetic field. The target can be a current collecting screen, a rotating mandrel, or a more complex 3D shape. Drying the polymer solution during the deposition step results in the formation of polymer fibers that impart a non-woven mesh structure by their accumulation.

[0125] The solution of biomedical supramolecular polymer used for electrospinning preferably contains 5-25% by weight of this biomedical supramolecular polymer, more preferably 10-20% by weight of this biomedical supramolecular polymer, most preferably 12-18% by weight of this biomedical supramolecular polymer. The solvent used to dissolve the biomedical supramolecular polymer preferably comprises at least two different solvents, most preferably at least three different solvents. The composition of the solvent and the concentration of the biomedical supramolecular polymer are chosen so that the biomedical supramolecular polymer is completely dissolved at the concentration used and its viscosity is in the right range for electrospinning, which means that it is fluid enough to be pumped through small orifices during the electrospinning process and is viscous enough to result in a biomedical supramolecular polymer solution jet forming a fiber.

[0126] In one embodiment, the first solvent is selected from organic volatile solvents such as chloroform, dichloromethane, tetrahydrofuran, methyl-tetrahydrofuran, acetonitrile, acetone, butanone, dimethyl carbonate, diethyl carbonate, ethyl acetate, propyl acetate and butyl acetate, and the second solvent is selected from polar protic solvents such as methanol, ethanol, propanol, butanol, formic acid, acetic acid, propionic acid, trifluoroacetic acid and hexafluoro-2-propanol. The optional third and further solvents can be any organic solvent but can also be water. Preferably, the electrospinning solution does not contain dimethylformamide or dimethylacetamide. The solvent mixture can include any ratio of the first solvent to the second solvent.

[0127] Preferably, the solution comprises: a) at least 50% by weight, more preferably at least 60% by weight, and most preferably at least 70% by weight of a first solvent, based on the total weight of the solvent comprising the electrospinning solution; b) at least 1 wt. %, more preferably at least 7 wt. %, even more preferably at least 18 wt. %, and most preferably at least 22 wt. % of a second solvent, based on the total weight of the solvent comprising the electrospinning solution; c) no third solvent, more preferably at least 0.1 wt. %, more preferably at least 1 wt. %, even more preferably at least 5 wt. %, and most preferably at least 10 wt. % of a third solvent, based on the total weight of the solvent containing the electrospinning solution; Includes.

[0128] Most preferably, the third solvent, if present, is a polar protic solvent that is not the second solvent.

[0129] Preferably, the fiber diameter after electrospinning is at least 2 micrometers, more preferably at least 3 micrometers, and most preferably at least 4 micrometers, while the fiber diameter is less than 10 micrometers, more preferably less than 7 micrometers. The fiber diameter determines the strength of the nonwoven mesh structure and mediates cell growth within the nonwoven mesh structure after implantation.

[0130] The biodegradability of biomedical porous implants containing biomedical supramolecular polymers can be evaluated using in vitro tests known in the art, such as ISO 10993-13. In particular, enzymatic and oxidative degradation can be followed in time by measuring the rate of loss of mass or molecular weight of the polymer, or by measuring changes in the tensile behavior or visual appearance of the implant. Accelerated enzymatic degradation can be studied at 37° C. in water containing lipase or esterase (10-100 U / mL), and oxidative degradation can be studied at 37° C. in water containing 20% ​​hydrogen peroxide and 0.1 M cobalt (II) chloride.

[0131] The biomedical porous implant comprising the biomedical supramolecular polymer is only partially and at least not completely biodegraded in situ, at the site of surgical application, after a period of about 2 months, preferably after a period of about 3 months, more preferably after a period of about 6 months, and most preferably after a period of about 9 months, wherein the degradation level is the fraction after a period of time determined by (mass of the biomedical porous implant before implantation - mass of the biomedical porous implant after a period of time) / mass of the biomedical porous implant before implantation x 100%.

[0132] Preferably, the biomedical porous implant is biodegraded to a level of at most about 50%, more preferably at most about 25%, and most preferably at most about 1% within a period of about 2 months, preferably within a period of about 3 months, more preferably within a period of about 6 months, and most preferably within a period of about 9 months.

[0133] The biomedical porous implants comprising biomedical supramolecular polymers obtainable by the method defined herein before can have any shape, such as a planar thin sheet, a tube, a ring, a disk, a cylinder, a valve or a more complex 3D shape, resembling the shape of the tissue that the biomedical porous polymers are intended to replace. Alternatively, the biomedical porous implants are thin flexible fibers that can be directly attached to the area to be treated. For all shapes, the film thickness or wall thickness of the nonwoven object is preferably between 100 micrometers and 1000 micrometers, more preferably between 200 micrometers and 800 micrometers, and most preferably between 250 micrometers and 600 micrometers.

[0134] In another preferred embodiment, the biomedical porous implant as defined hereinbefore or obtainable by the electrospinning method as defined hereinbefore comprises one to three lobule structures.

[0135] In yet another preferred embodiment, the biomedical porous implant as hereinbefore defined or obtainable by the electrospinning method as hereinbefore defined has the form of a sheet with 0-6 arms or extensions for attachment to a structure at the implantation site.

[0136] In one embodiment, the biomedical porous implant further comprises a support structure, for example a ring or stent, preferably made of a metal or metal alloy such as stainless steel or nitinol.

[0137] One or more therapeutic agents may be added to the biomedical supramolecular polymer. This may be done by simple mixing during processing or by any post-processing procedure such as dip-coating. The therapeutic agent may be any biological material or chemical or pharmaceutical composition that positively affects biological activity such as cell adhesion, tissue growth or anti-inflammatory activity. Non-limiting examples of therapeutic agents that may be added to the biomedical supramolecular polymer are drugs, hormones, oligopeptides, glycosaminoglycans (GAGs), RNA-based materials, siRNA, miRNA, DNA-based materials, cDNA, plasmids, or stem cells, progenitor cells, or any useful cell line known in the art. The therapeutic agent may also be an imaging agent known in the art and may be used in clinical imaging techniques such as MRI, CT scan and X-ray fluorescence. The therapeutic agent may be modified with one or more 4H units that are complementary to those used in the biomedical supramolecular polymer.

[0138] In one particular embodiment of the invention, the biomedical porous implant does not contain any therapeutic agents, peptides, fibrin, stem cells or imaging agents. Preferably, the biomedical porous implant does not contain any animal-derived material and / or material from a human donor.

[0139] Preferably, the biomedical porous implant comprises only one type of biomedical supramolecular polymer obtainable by the method defined herein before and no other biomedical supramolecular polymers, preferably comprises only one type of biomedical supramolecular polymer obtainable by the method defined herein before and no other synthetic polymers, most preferably comprises only one type of biomedical supramolecular polymer obtainable by the method defined herein before and no other synthetic polymers, biopolymers or peptides.

[0140] By biomedical porous implant is meant an implant with a certain porosity, where the porosity of a material refers to the volume fraction of the material that is composed of pores such as voids, gaps, holes, openings, and the remainder of the material volume is the biomedical supramolecular polymer as defined herein before. A high porosity favors the infiltration by and the adsorption of cells that will be cultured inside the biomedical porous implant, thereby forming new tissue. The porosity of the biomedical porous implant is preferably at least 70%, more preferably at least 80%, and most preferably at least 90%, where the porosity is measured gravimetrically, where the porosity is calculated using the following formula: porosity = (density of polymer - density of implant) / density of polymer x 100%, where the density of the polymer is the density of the biomedical supramolecular polymer used and the density of the biomedical porous implant is the weight of the biomedical porous implant divided by the volume of the biomedical porous implant.

[0141] The preferred mechanical properties, such as modulus of elasticity and tensile strength, of the biomedical supramolecular polymers defined herein above are deliberately chosen to be higher than the values ​​corresponding to the soft tissues required for the example they are to replace. However, the values ​​of these mechanical properties corresponding to the biomedical porous implants manufactured from the biomedical supramolecular polymers, such as non-woven mesh structures obtained by electrospinning, are generally lower than those of the original biomedical supramolecular polymers, for example they are still closer to the values ​​of the soft tissues.

[0142] In a preferred embodiment, the biomedical porous implant comprising a biomedical supramolecular polymer obtainable by the method defined herein before also preferably has a fatigue resistance of at least 3 million cycles, preferably at least 6 million cycles, most preferably at least 12 million cycles before fatigue, determined using a uniaxial tensile tester with a sample rate of 2 Hz or 10 Hz, preferably 10 Hz, and an elongation of 10% at a temperature of 23±2° C. or 37±2° C., preferably 37±2° C., on 5×25 mm pieces of said implant with a thickness between 0.2 mm and 1 mm and a sample rate of 2 Hz or 10 Hz, preferably 10 Hz, and a temperature of 23±2° C. or 37±2° C., preferably 37±2° C., with fatigue failure defined as the cycle in which the stress response is less than 10% of the stress response in the first cycle.

[0143] Medical Use The mechanical performances of the biomedical supramolecular polymers according to the invention, more particularly their ultimate tensile strength, fatigue resistance and thermal properties, make them suitable for producing biomedical porous articles, in particular medical porous implants that can be applied in soft tissue applications such as muscle, epithelial and cardiovascular tissue applications. The biomedical supramolecular polymers can be applied as films, as shaped bodies, as bulk materials or in the form of porous structures. Furthermore, the biomedical porous implants comprising the biomedical supramolecular polymers obtainable by the method defined herein before can be used in methods of support, augmentation and regeneration of living tissues in mammalian subjects.

[0144] In one embodiment of the present invention, the biomedical supramolecular polymer is processed by electrospinning into a medical porous implant, which is subsequently used as an in situ tissue engineering scaffold, meaning that after its implantation in an individual living mammalian body, such as a human, dog, cat or horse, mammalian tissue grows in said porous structure, thereby eliminating the need to grow tissue outside the mammalian body before implantation. Preferably, the biomedical supramolecular polymer is biodegradable, resulting in the degradation of the implant after its implantation in the body. As a result, the implant is replaced by tissue over time, and no surgical removal of the medical porous implant is required at a later stage, thus reducing clinical costs and suffering for the patient.

[0145] In a fifth aspect, the present invention relates to a biomedical porous implant as defined herein before or obtainable by an electrospinning method as defined herein before, for use in the treatment of a cardiovascular disease, said treatment comprising replacing part of an artery or a vein, or part or all of a venous, pulmonary, mitral, tricuspid or aortic valve, in a mammalian subject, with said biomedical porous implant, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

[0146] This fifth aspect may also be expressed as a method of treatment of a cardiovascular disease, said treatment comprising replacing, in a mammalian subject, a portion of an artery or a vein, or a portion or all of a venous, pulmonary, mitral, tricuspid or aortic valve, with a biomedical porous implant as defined hereinbefore or obtainable by the electrospinning method as defined hereinbefore, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

[0147] In a sixth aspect, the present invention relates to a biomedical porous implant as defined herein before or obtainable by an electrospinning method as defined herein before, for use in the treatment of a cardiovascular disease, said treatment comprising placing said biomedical porous implant at an intracardiac or intravascular site in a mammalian subject, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

[0148] This sixth aspect may also be expressed as a biomedical porous implant, a method for the treatment of a cardiovascular disease, said treatment comprising placing a biomedical porous implant as defined herein before or obtainable by the electrospinning method as defined herein before at an intracardiac or intravascular site in a mammalian subject, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

[0149] In a preferred embodiment, the cardiovascular disease is selected from the group consisting of chronic venous insufficiency, aortic stenosis, aortic insufficiency, pulmonary stenosis, pulmonary artery insufficiency, and combinations thereof.

[0150] In another preferred embodiment, the biomedical porous implant as defined hereinbefore or obtainable by the electrospinning method as defined hereinbefore for use in the treatment of cardiovascular diseases has one to three lobule structures.

[0151] In a seventh aspect it relates to a biomedical porous implant as defined herein before or obtainable by the electrospinning method as defined herein before for use in the treatment of conditions requiring reconstructive surgery, support or augmentation, preferably prolapse, pelvic organ prolapse, compartment syndrome, constrictive pericarditis, hemopneumothorax, hemothorax, dural injuries and hernias, such as abdominal, diaphragmatic, hiatal, pelvic, anal, intracranial, Spigelian herniations and herniations of the nucleus pulposus of the intervertebral disc, and stress urinary incontinence, said treatment comprising the surgical implantation of the biomedical porous implant at a site in a mammalian subject requiring reconstructive surgery, support or augmentation, said biomedical porous implant acting as a scaffold for the formation of new tissue.

[0152] This seventh aspect may also be expressed as a method of treatment of conditions requiring reconstructive surgery, support or augmentation, preferably prolapse, pelvic organ prolapse, compartment syndrome, constrictive pericarditis, hemopneumothorax, hemothorax, dural injuries and hernias, such as abdominal, diaphragmatic, hiatal, pelvic, anal, intracranial, Spigelian herniations and herniations of the nucleus pulposus of the intervertebral disc, and stress urinary incontinence, said treatment comprising the surgical implantation of a biomedical porous implant as defined herein before or obtainable by the electrospinning method as defined herein before, at the site of a mammalian subject requiring reconstructive surgery, support or augmentation, said biomedical porous implant acting as a scaffold for the formation of new tissue.

[0153] In a preferred embodiment, the biomedical porous implant as defined hereinbefore or obtainable by the electrospinning method as defined hereinbefore, for use in reconstructive surgery, treatment of pathologies requiring support or augmentation, has the form of a sheet with 0-6 arms or extensions for attachment to a structure at the implantation site.

[0154] In one embodiment, the biomedical porous implant comprising the biomedical supramolecular polymer is used for ligament reconstruction.

[0155] The biomedical porous implants comprising the biomedical supramolecular polymers may be delivered to the patient by any surgical procedure, including minimally invasive techniques such as endoscopic or laparoscopic surgery, as well as invasive techniques such as thoracic or open heart surgery.

[0156] Thus, the invention has been described with reference to certain embodiments discussed above, it will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those skilled in the art.

[0157] Moreover, in order to properly understand the scope of this document and its claims, the verb "comprise", when used in this specification, as well as in the claims and their conjugates, is used in an open-ended sense to mean that the items following the term are included, but not the exclusion of items not specifically mentioned. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that there is more than one of the element, unless the context clearly requires that there is one and only one of the element. Thus, the indefinite article "a" or "an" usually means "at least one". EXAMPLES

[0158] The following examples further illustrate preferred embodiments of the invention. Unless otherwise stated, chemicals were obtained from Sigma-Aldrich or Merck. The number average molecular weight M of the functionalized polymer A' n was determined from its hydroxyl number.

[0159] Example 1: Preparation of 5-(2-hydroxyethyl)-6-methyl-isocytosine 2-Acetylbutyrolactone (2.38 g, 19 mmol) and guanidine carbonate (3.3 g, 37 mmol) were refluxed in absolute ethanol (20 mL) in the presence of triethylamine (5.2 mL). The solution turned yellow and turbid. After heating at reflux overnight, the solid was filtered, washed with ethanol and suspended in water. The pH was adjusted to a value of 6-7 with HCl solution and the mixture was stirred for some time. The residue was filtered and rinsed with water and ethanol, followed by drying of the solid to obtain pure 5-(2-hydroxyethyl)-6-methyl-isocytosine. 1 H NMR (400 MHz, DMSO-d6): δ11.2 (1H), 6.6 (2H), 4.5 (1H), 3.4(2H), 2.5 (2H), 2.1 (3H). FT-IR (undiluted): ν (cm -1 ) 3333, 3073, 2871, 1639, 1609, 1541, 1487, 1393,1233, 1051, 915, 853, 789, 716.

[0160] Example 2: Preparation of 5-(4-hydroxybutyl)-6-methyl-isocytosine 2(i) Preparation of 2-(4-chlorobutoxy)tetrahydro-2H-pyran 4-Chlorobutan-1-ol (24 g, 220 mmol) and dihydropyran (22.3 g, 270 mmol) were dissolved in dichloromethane and pyridinium p-toluenesulfonate (5.2 g, 18 mmol) was added. The slightly cloudy solution was stirred at room temperature overnight to give a brownish solution, which was washed twice with water and dried over sodium sulfate. The solvent was evaporated to give the crude product, which was purified by vacuum distillation (70° C., 0.08 mbar) to give 35.5 g (83%) of a colorless oil.

[0161] 2(ii) Preparation of 2-(4-iodobutoxy)tetrahydro-2H-pyran 2-(4-Chlorobutoxy)tetrahydro-2H-pyran (33.5 g, 170 mmol, from step 2(i)), sodium iodide (78 g, 520 mmol) and sodium carbonate (11 g, 100 mmol) were refluxed in 800 mL of acetone for 56 h. The mixture was then concentrated and poured into 1 L of saturated sodium bicarbonate solution. The aqueous solution was extracted three times with hexane and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated to give 44.5 g (90%) of pure product.

[0162] 2(iii) Preparation of ethyl 2-acetyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hexanoate To a mixture of ethyl acetoacetate (24.1 g, 185 mmol) and potassium carbonate (35.4 g, 226 mmol) in acetone (300 mL) and DMF (60 mL) was added dropwise a solution of 2-(4-iodobutoxy)tetrahydro-2H-pyran (40.4 g, 142 mmol, from step 2(ii)) in acetone (300 mL). The mixture was stirred at room temperature for 64 h after which it was concentrated and partitioned between ethyl acetate and saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined ethyl acetate layers were washed with a 10% aqueous solution of sodium thiosulfate, brine and dried over sodium sulfate. The solvent was distilled to give 54 g of crude product which was used without further purification.

[0163] 2(iv) Preparation of 2-amino-6-methyl-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)pyrimidin-4(1H)-one A mixture of ethyl 2-acetyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hexanoate (40.7 g, 140 mmol, from step 2(iii)) and guanidine carbonate (27.5 g, 143 mmol) in ethanol (800 mL) was refluxed for 80 h. The mixture was concentrated to approximately 100 mL and 800 mL of chloroform was added. The slightly cloudy solution was washed with sodium bicarbonate solution, brine and dried over sodium sulfate. After evaporation of the solvent, the resulting solid was stirred in diethyl ether overnight. It was filtered, washed with diethyl ether and dried in vacuum to give 28 g (70%) of pure product as a white solid.

[0164] 2(v) Preparation of 5-(4-hydroxybutyl)-6-methyl-isocytosine 2-Amino-6-methyl-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)pyrimidin-4(1H)-one (28 g, 100 mmol, from step 2(iv)) and p-toluenesulfonic acid (20.8 g, 109 mmol) were stirred in 500 mL of methanol at 60° C. for 3 h. The solvent was evaporated and the resulting white solid was neutralized by stirring in 120 mL of saturated sodium bicarbonate solution. The solid was filtered off, washed with water and triturated twice with diethyl ether. The phosphorus pentoxide was dried in vacuum to give 5-(4-hydroxybutyl)-6-methyl-isocytosine 18 g (92%) as a white solid. 1 H NMR(399 MHz, DMSO) δ 10.88 (1H), 6.29 (2H), 4.32 (1H),3.39 (1H), 3.37 (2H), 2.25 (2H), 2.03 (3H), 1.39 (4H). LC-MS: m / z = 198 [M+1].FT-IR (undiluted): ν(cm -1 )3273, 3100, 2932, 1688, 1601, 1504, 1375, 1231, 1053, 974, 862, 806, 777

[0165] Example 3: Preparation of 5-(4-aminobutyl)-6-methyl-isocytosine 3(i) Preparation of tert-butyl (4-iodobutyl)carbamate Iodine (80.5 g, 320 mmol) was added portionwise to a solution of triphenylphosphine (83.2 g, 320 mmol) and imidazole (21.6 g, 320 mmol) in dichloromethane (1.5 L) at 0° C. The orange mixture was allowed to warm to room temperature, after which tert-butyl (4-hydroxybutyl)carbamate (50 g, 260 mmol) diluted in dichloromethane (300 mL) was added slowly. After stirring at room temperature for 3 h, the mixture was filtered over Celite and rinsed with dichloromethane. The orange filtrate was washed twice with 5% sodium thiosulfate solution to give a colorless organic layer, which was dried over magnesium sulfate. The solvent was drained in vacuum, and the resulting solid was thoroughly stirred overnight in 2 L of a 3:1 mixture of heptane and diethyl ether. After filtration and washing with the same solvent mixture, the filtrate was concentrated to give the crude product as a yellow oil. Purification was carried out by column chromatography on silica eluting with ethyl acetate:heptane (1:9) to give 56 g (71%) of a yellow oil.

[0166] 3(ii) Preparation of ethyl 2-acetyl-6-((tert-butoxycarbonyl)amino)hexanoate To a mixture of ethyl 3-oxobutanoate (28 g, 220 mmol, from step 3(i)) and potassium carbonate (36 g, 260 mmol) in acetone (250 mL) and DMF (40 mL) was added dropwise a solution of tert-butyl (4-iodobutyl)carbamate (50 g, 170 mmol) in acetone (250 mL). The mixture was stirred at room temperature for 20 h after which it was concentrated and partitioned between ethyl acetate and saturated ammonium chloride solution. The ethyl acetate layer was washed with brine and dried over sodium sulfate. The solvent was distilled to give a yellow oil (54 g). The crude product was used without further purification.

[0167] 3(iii) Preparation of tert-butyl (4-(2-amino-6-methyl-4-oxo-1,4-dihydropyrimidin-5-yl)butyl)carbamate A mixture of ethyl 2-acetyl-6-((tert-butoxycarbonyl)amino)hexanoate (54 g, 179 mmol, from step 3(ii)) and guanidine carbonate (27.5 g, 143 mmol) in ethanol (800 mL) was refluxed for 24 h. The clear solution was concentrated to 300 mL and diluted with 300 mL of water. The pH was adjusted to a value of 5.8 with hydrochloride solution. The precipitate was filtered off and washed with water. The residue was triturated with diethyl ether and dried under reduced pressure at 40° C. to give 33.5 g (63%) of the pure product as a white solid.

[0168] 3(iv) Preparation of 5-(4-aminobutyl)-6-methyl-isocytosine A mixture of tert-butyl (4-(2-amino-6-methyl-4-oxo-1,4-dihydropyrimidin-5-yl)butyl)carbamate (30 g, 101 mmol, from step 3(iii)) in dichloromethane (300 mL) was stirred and cooled to 0° C. Trifluoroacetic acid (62 mL, 810 mmol) was added dropwise to give a clear solution, which was stirred at room temperature for 4 h. The solvent and excess trifluoroacetic acid were removed by evaporation and coevaporation with methanol to give the trifluoroacetate salt of the product as a white solid. This solid was dissolved in 300 mL of methanol and cooled to 0° C., after which excess N,N-di-isopropylethylamine was added. After stirring for 2-3 h, the mixture was filtered and the residue was washed with methanol. The residue was stirred with excess N,N-di-isopropylethylamine in methanol. After filtration, the residue was stirred in chloroform overnight. The residue was filtered and dried to give 15.4 g (77%) of 5-(4-aminobutyl)-6-methyl-isocytosine. 1 H NMR(400 MHz, D2O) δ 2.77 (2H), 2.27 (2H), 2.03(3H), 1.49 (2H), 1.32 (2H). LC-MS: m / z = 197 [M+1]. FT-IR (undiluted): ν(cm -1) 3061, 2963, 2918,2845, 1692, 1628, 1586, 1372, 1233, 1140, 974, 951, 885, 802, 698.

[0169] Example 4: 5-(11- Hydroxy Preparation of undecyl-6-methyl-isocytosine 4(i) Preparation of ethyl 2-acetyl-13-hydroxytridecanoate Ethyl acetoacetate (16.8 g, 130 mmol) dissolved in 30 mL of acetone was added to a mixture of potassium carbonate (27.5 g, 200 mmol) and potassium iodide (1.65 g, 10 mmol) in 350 mL of acetone and 50 mL of DMF at 60° C. To the resulting mixture stirred at 60° C. 11 To a solution of 100 mL of 1-bromo-1-undecanol (25 g, 100 mmol) in acetone was added dropwise. After refluxing overnight, the mixture was cooled to room temperature and the precipitate was filtered off. The filtrate was evaporated to dryness, dissolved in ethyl acetate and washed twice with a half-saturated aqueous solution of ammonium chloride and once with brine. After drying over sodium sulfate, the solvent was evaporated to give 32.6 g of crude product, which was used without further purification.

[0170] 4(ii) 5-(11- Hydroxy Preparation of undecyl-6-methyl-isocytosine A mixture of ethyl 2-acetyl-13-hydroxytridecanoate (30 g, 100 mmol, from step 4(i)) and guanidine carbonate (14.4 g, 80 mmol) in ethanol (400 mL) was refluxed for 48 h. After cooling to room temperature, the precipitate was filtered off and the filtrate was evaporated to dryness. The resulting slurry was stirred in 600 mL of a half-saturated aqueous solution of sodium bicarbonate. After filtration, the residue was triturated with water and diethyl ether, respectively. The residue was dried under vacuum over phosphorus pentoxide as above to give 19.8 g (67%) of the product as a white solid. This was further purified by precipitation in water from DMSO and trituration with ethanol, respectively, to give 5-(11- Hydroxy undecyl-6-methyl-isocytosine. 1 H NMR (400 MHz, DMSO) δ 10.80 (1H), 6.28 (2H), 4.31 (1H), 3.37 (2H), 2.23 (2H), 2.02 (3H), 1.39 (2H), 1.24 (16H). LC-MS: m / z = 296 [M+1]. FT-IR (undiluted): ν(cm -1 ) 3316, 3127, 2916, 2849, 1682, 1602, 1381, 1244, 1142, 1051, 1034, 980, 872, 808, 779.

[0171] Example 5: Preparation of Polymer 1 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 1000 Da (20.0 g, 20.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (3.38 g, 20.0 mmol, compound F'), 1,6-hexanediol (4.72 g, 40.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (13.31 g, 79.2 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (40 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n = 14.6 kDa, Mw / Mn = 1.9.

[0172] Example 6: Preparation of Polymer 2 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 1000 Da (20.0 g, 20.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (3.38 g, 20.0 mmol, compound F'), 1,6-hexanediol (3.54 g, 30.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (11.64 g, 69.3 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (30 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n = 18.6 kDa, Mw / Mn = 1.9.

[0173] Example 7: Preparation of Polymer 3 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 1000 Da (20.0 g, 20.0 mmol, dried in vacuum, functionalized polymer A'), 5-(11-undecyl)-6-methyl-isocytosine (5.90 g, 20.0 mmol, compound F'), 1,6-hexanediol (4.72 g, 40.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (13.31 g, 79.2 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (20 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into excess methanol. It became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): M n= 14.0 kDa, Mw / Mn = 2.1.

[0174] Example 8: Preparation of Polymer 4 Telechelic hydroxy-terminated poly(tetramethylene ether) glycol with a molecular weight of 1000 Da (40.0 g, 40.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (6.76 g, 40.0 mmol, compound F'), 1,6-hexanediol (9.44 g, 80.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (26.61 g, 158.4 mmol, compound C') and 3 drops of catalytic tin dioctoate were dissolved in dry DMSO (60 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n = 16.5kDa, Mw / Mn = 1.9.

[0175] Example 9: Preparation of Polymer 5 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 1000 Da (20.0 g, 20.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (3.38 g, 20.0 mmol, compound F'), 1,4-butanediol (3.60 g, 40.0 mmol, dried in vacuum, compound B'), butylene diisocyanate (11.09 g, 79.2 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (30 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n = 14.0 kDa, Mw / Mn = 1.8.

[0176] Comparative Example 1: Preparation of Polymer C1 in which A':B':C':F' is 1:1:3:1 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 1000 Da (20.0 g, 20.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (3.38 g, 20.0 mmol, compound F'), 1,6-hexanediol (2.36 g, 20.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (10.69 g, 59.4 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (20 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n= 13.2 kDa, Mw / Mn = 2.1.

[0177] Comparative Example 2: Preparation of Polymer C2 in which A':B':C':F' is 1:2.5:4.5:1 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 1000 Da (20.0 g, 20.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (3.38 g, 20.0 mmol, compound F'), 1,6-hexanediol (5.90 g, 50.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (14.97 g, 89.1 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (40 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n = 18.4 kDa, Mw / Mn = 1.8.

[0178] Comparative Example 3: Polymer A' is M n Preparation of Polymer C3, a Polycarbonate with a Molar Mass of 3,000 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 3000 Da (30.0 g, 10.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (1.69 g, 10.0 mmol, compound F'), 1,6-hexanediol (2.36 g, 20.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (6.65 g, 39.6 mmol, compound C') and two drops of catalytic tin dioctoate were dissolved in dry DMSO (30 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): n = 15.1 kDa, Mw / Mn = 1.8.

[0179] Comparative Example 4: Polymer A' is M n Preparation of Polymer C4, a Polycarbonate with a Molar Mass of 500 Telechelic hydroxy-terminated poly(1,6-hexanediol) carbonate with a molecular weight of 500 Da (20.0 g, 40.0 mmol, dried in vacuum, functionalized polymer A'), isocytosine monomer from Example 1 (6.76 g, 40.0 mmol, compound F'), 1,6-hexanediol (9.44 g, 80.0 mmol, dried in vacuum, compound B'), hexamethylene diisocyanate (26.61 g, 158.4 mmol, compound C') and 3 drops of catalytic tin dioctoate were dissolved in dry DMSO (40 mL) and stirred at 80° C. The next day, the reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into an excess of methanol. This became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard):n = 16.2 kDa, Mw / Mn = 2.1.

[0180] Comparative Example 5: Polymer A' is M n Preparation of Polymer C5, a polycaprolactone having a molecular weight of 0.25g / g. Telechelic hydroxy-terminated polycaprolactone with a molecular weight of 2000 Da (20.4 g, 10.0 mmol, dried in vacuum, functionalized polymer A') and hexamethylene diisocyanate (6.85 g, 40 mmol, compound C') were stirred together in the presence of one drop of catalytic tin dioctoate at 80° C. for 2 hours. To this reaction mixture was subsequently added the isocytosine monomer obtained in Example 1 (1.72 g, 10.0 mmol, compound F'), dissolved in dry DMSO (120 mL) and stirred at 80° C. overnight. The next day, 1,6-hexanediol (2.34 g, 20.0 mmol, dried in vacuum, compound B') was added to the reaction mixture, followed by stirring at 80° C. for another 2 hours. The reaction mixture was cooled to 25° C., additional DMSO was added to reduce its viscosity, and the resulting mixture was added to an excess of water to precipitate the polymer. The polymer was recovered as an elastic white solid, redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated into excess methanol. It became a clear elastic solid after drying in vacuum at 50° C. SEC (DMF, 10 mM LiBr, PEO / PEG standard): M n = 20.3 kDa, Mw / Mn = 2.1.

[0181] Example 9: Thermal and Mechanical Properties The following table shows the superior thermal and mechanical properties of the polymers according to the invention when compared to the state of the art. All measurements were performed on films or film sections obtained from solvent casting and that showed no visible defects such as blisters. Moreover, all films were aged at room temperature for 2 weeks before testing.

[0182] [Table 1]

[0183] Thermal data was obtained using differential scanning calorimetry (DSC) at a heating rate of 20° C. / min and a heating range of −80° C. to 160° C. Data is based on the first heating run.

[0184] [Table 2]

[0185] Tensile tests were performed on dog-bone molds cut from the solvent-cast films according to ASTM D1708-96 standard at a temperature of 23±2° C. in air with an elongation rate of 20 mm / min and a preload of 0.02 N. Young's modulus was measured between 0.25% elongation and 2.50% elongation.

[0186] [Table 3]

[0187] Fatigue tests were performed on 5 × 25 mm solvent cast polymer film pieces with thickness between 0.2 mm and 0.5 mm at a temperature of 23 ± 2 °C in air using a uniaxial tensile testing machine with 10% elongation at a sample rate of 10 Hz, with fatigue failure defined as the cycle where the stress response is less than 10% of the stress response at the first cycle.

[0188] Example 10: Electrospinning Polymer 3 from Example 8 was dissolved in chloroform / hexafluoropropanol (80 / 20) at a concentration of 14 wt%. The resulting solution had a high enough viscosity to allow stable electrospinning of the solution with the desired fiber thickness. The resulting nonwoven mesh structure can be further used as a tissue engineering scaffold material. Electrospinning was performed at 12 kV, 0.025 mL / min, and a tip-tip distance of 15 cm. The fibers were deposited on a statically grounded current collecting plate covered with a polyethylene film to allow easy removal of the electrospun scaffold. The scaffold was subsequently dried in vacuum at 40° C. for 24 hours to remove any remaining solvent.

Claims

1. 1. A method for producing a biomedical supramolecular polymer having an ultimate tensile strength of at least 35 MPa, a Young's modulus between 40 MPa and 160 MPa, and an elongation at break of at least 350%, as determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min, comprising: 【Chemistry 1】 Compound F' according to Formula O=C=NR ３ Diisocyanate compound C' with -N=C=O, Formula P-(FG1) ｗ and a functionalized polymer A′ according to Formula FG2-R ４ Compound B' by -FG3 reacting with During the ceremony, X is O or S; k is 2 or an integer from 4 to 11; n is 0, R １ is a methyl group, R ２ is OH, FG1 is OH, FG2 and FG3 are OH and NH ２ is a functional group independently selected from w is in the range of 1.8 to 2; The functionalized polymer A' has a number average molecular weight M of 1000 to 2000 Da, as determined from its hydroxyl number. ｎ having the functionalized polymer A' is selected from polycarbonate functionalized with FG1, poly(tetramethylene glycol), and hydrogenated polybutadiene functionalized with FG1; P is a polymer with the proviso that it is not poly(ethylene glycol) or polycaprolactone; R ３ But linear C ４ ~C ２０ is an alkylene group, R ４ But linear C ２ ~C ２０ is an alkylene group, and the molar ratio of compounds A', B', C' and F', represented as A':B':C':F', is between 1:1.5:3.5:1 and 1:2:4:1; method.

2. 2. The method of claim 1, comprising reacting in one step a functionalized polymer A', a compound B', a diisocyanate compound C' and a compound F' according to formula (1).

3. The method according to claim 1 or 2, wherein compound B' is selected from the group consisting of 1,4-butanediol, 1,12-dodecyldiol and 1,6-hexanediol.

4. The process according to any one of claims 1 to 3, wherein the diisocyanate compound C' is selected from the group consisting of 1,4-diisocyanatobutane, 1,6-diisocyanatohexane (HDI) and 1,12-diisocyanatododecane.

5. Having an ultimate tensile strength of at least 35 MPa, a Young's modulus between 40 MPa and 160 MPa, and an elongation at break of at least 350%, as determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; A functionalized polymer A' according to formula P-(FG1) w , a compound B' according to formula FG2-R 4 -FG3, a diisocyanate compound C' according to formula O═C═N—R 3 -N═C═O, and a diisocyanate compound C' according to formula (1): 【Chemistry 2】 is the reaction product of compound F′ with During the ceremony, X is O or S; k is 2 or an integer from 4 to 11; n is 0, R 1 is a methyl group; R 2 is OH; FG1 is OH, FG2 and FG3 are functional groups independently selected from OH and NH 2 ; w is in the range of 1.8 to 2; the functionalized polymer A' has a number average molecular weight M n , determined from its hydroxyl number, of 1000 to 2000 Da; the functionalized polymer A' is selected from polycarbonate functionalized with FG1, poly(tetramethylene glycol), and hydrogenated polybutadiene functionalized with FG1; P is a polymer with the proviso that it is not poly(ethylene glycol) or polycaprolactone; R 3 is a linear C 4 -C 20 alkylene group; R 4 is a linear C 2 -C 20 alkylene group; and A biomedical supramolecular polymer represented by A':B':C':F', in which the molar ratio of compounds A', B', C' and F' is between 1:1.5:3.5:1 and 1:2:4:

1.

6. Number average molecular weights M of 3,000-150,000 Da as determined by size exclusion chromatography in DMF containing 10 mM LiBr at 50° C. using PEO / PEG standards. ｎ The supramolecular polymer for biomedical use according to claim 5, having the formula:

7. The following properties: i) a modulus at 100% elongation of at least 7 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; ii) an ultimate tensile strength of at least 40 MPa, determined by test method ASTM D 1708-96 at a crosshead speed of 20 mm / min; iii) fatigue resistance of at least 3 million cycles before fatigue, as determined using a uniaxial tensile tester with 10% elongation at a sample rate of 10 Hz on 5×25 mm polymer strips between 0.2 mm and 1 mm thick, with fatigue failure defined as the cycle where the stress response is less than 10% of the stress response at the first cycle; and iv) at least two thermal transitions selected from a glass transition and a melting point at temperatures between 50° C. and 125° C., and no thermal transitions between 0° C. and 45° C., as determined by differential scanning calorimetry at a heating rate of 20° C. / min. The biomedical supramolecular polymer according to claim 5 or 6, comprising at least one of the following:

8. A biomedical supramolecular polymer according to claim 7, having all of the above properties (i) to (iv).

9. A biomedical porous implant comprising a biomedical supramolecular polymer according to any one of claims 5 to 8.

10. A biomedical porous implant according to claim 9, having a non-woven mesh structure comprising the biomedical supramolecular polymer according to any one of claims 5 to 8.

11. A method for the manufacture of a biomedical porous implant having a non-woven mesh structure comprising a biomedical supramolecular polymer according to any one of claims 5 to 8, comprising: a) providing a supramolecular polymer for biomedical use according to any one of claims 5 to 8; b) dissolving the biomedical supramolecular polymer according to (a) in a solvent mixture; c) electrospinning the polymer solution according to (b) onto a target; d) isolating the biomedical porous implant from the target as a sheet, cylinder or 3D structure; A method comprising:

12. A biomedical porous implant according to claim 9 or 10, comprising 1 to 3 lobular structures.

13. 11. The biomedical porous implant of claim 9 or 10 in the form of a sheet with 0-6 arms or extensions for attachment to a structure at the implantation site.

14. 13. The biomedical porous implant of claim 9, 10 or 12 for use in the treatment of cardiovascular disease, said treatment comprising replacing a portion of an artery or vein, or a portion or all of a venous, pulmonary, mitral, tricuspid or aortic valve in a mammalian subject with said biomedical porous implant, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

15. 13. The biomedical porous implant of claim 9, 10 or 12 for use in the treatment of cardiovascular disease, said treatment comprising placing said biomedical porous implant at an intracardiac or intravascular site in a mammalian subject, said biomedical porous implant acting as a scaffold for the formation of new cardiovascular tissue.

16. 14. The biomedical porous implant of claim 9, 10 or 13 for use in the treatment of a condition requiring reconstructive surgery, support or augmentation selected from the group consisting of prolapse, pelvic organ prolapse, compartment syndrome, constrictive pericarditis, hemopneumothorax, hemothorax, dural injury, hernia and stress urinary incontinence, said treatment comprising surgical implantation of the biomedical porous implant at a site in a mammalian subject requiring reconstructive surgery, support or augmentation, said biomedical porous implant acting as a scaffold for the formation of new tissue.

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