UV polymerizable antimicrobial imidazolidinyl urea-based acrylate resin for 3D printing applications

Abstract

The present invention provides a polymeric chain made of acrylate-containing imidazolidinyl urea monomers and having antimicrobial properties, a UV polymerizable resin comprising said polymeric chain, and a product such as a medical device, obtained by 3D printing of said UV polymerizable resin.

Description

UV POLYMERIZABLE ANTIMICROBIAL IMIDAZOLIDINYL UREA-BASED ACRYLATE RESIN FOR 3D PRINTING APPLICATIONSTECHNICAL FIELD

[0001] The present invention provides a polymeric chain made of imidazolidinyl urea monomers and having antimicrobial properties; a photocurable resin comprising said polymeric chain; and a product such as a medical device, obtained by 3D printing of said photocurable resin.BACKGROUND ART

[0002] Three-dimensional (3D) photo printing provides immense flexibility in shaping polymeric objects with intricate geometries. However, the limited availability of photoactive resins for 3D printing poses numerous challenges in realizing the desired material properties. To encounter this, researchers consistently strive to develop new photoresins with multifunctional capabilities.

[0003] Photoactive methacrylate systems can readily undergo free radical polymerization during digital light processing (DLP) 3D printing. The system usually involves a photoinitiator and photoactive monomers / crosslinkers, and other additives such as photo stabilizers, photoabsorbers, photoinhibitors, and diluents may be added to enhance printability and modify resin properties. The mechanical properties of photocured polymers are closely related to the molecular structure of the crosslinked network, the ratio of monomers to crosslinkers, and other functional groups’ presence, which may take part in physical interaction (e.g., H-bonding, Van-Der Waals interaction, charge condensation, and supramolecular interaction). Acrylate-based systems are well-known for their fast-curing properties, and consequently, such systems usually result in highly crosslinked, inhomogeneous networks, which tend to have inferior mechanical properties (Guit et al., 2020). In this regard, methacrylate -based systems are less reactive than acrylate ones, and integrating methacrylate into photoactive resins resulted in polymers with enhanced mechanical behavior.

[0004] Imidazolidinyl urea (IU) is a well-known antimicrobial preservative frequently used in cosmetic products (Lehmann et al., 2006). Due to multiple urea bonds, IU can act as both hydrogen bond acceptor and donor, which can be used as a reinforced factor forconstructing hydrogen bonding networks (Yang et al., 2020). Furthermore, recently, it was discovered that IU can act as a multitargeted inhibitor for lung cancer, which suggests its potential use in biomedical applications (Ahmad et al. , 2023). In another recent study, Cheng and co-workers reported an IU -based hydrogel for diabetic wound healing applications, where IU is used as a reinforcing additive to improve the mechanical properties of the hydrogel (Yang et al., 2021). In addition to that, the presence of multiple modification sites in the IU offers an excellent platform for subsequent post-functionalization of IU -based polymers, thereby facilitating the incorporation of functional properties.SUMMARY OF INVENTION

[0005] In one aspect, disclosed herein is a polymeric chain of formula I:whereinX each independently is an imidazolidinyl urea of formula Xi or X2:Ri each independently is (Ci-C3)alkyl, preferably methyl, or H;R2, R3and R4each independently is H, -C(O)-CH=CH2, or -C(O)-C(CH3)=CH2; and n is an integer of at least 3,wherein said polymeric chain is optionally crosslinked to at least one additional such polymeric chain via one or more vinyl groups of the X groups thereof.

[0006] The polymeric chain disclosed may further be alkylated or dialkylated (wherein one or more of the nitrogen atoms in the X groups is alkylated or dialkylated, thereby forming a tertiary amine or quaternary ammonium group) and / or halogenated (wherein one or more of the nitrogen atoms in the X groups is halogenated, thereby forming a N-halogen bond). In addition, or alternatively, the polymeric chain may be conjugated to a drug, e.g., a small molecule drug, wherein the nitrogen atom in one or more of the -NH- groups and / or the oxygen atom in one or more of the -OH groups, when present, in the X groups, is substituted with said drug; or wherein said drug is non-covalently linked to said nitrogen or oxygen atom.

[0007] As shown herein, the polymeric chain disclosed, regardless of whether crosslinked, alkylated or dialkylated, and / or halogenated, has antimicrobial properties, and may thus be used both in vivo and in vitro, e.g., as an antibacterial material; a bioactive material for wound healing or for prevention of wound infections; a scaffold for tissue regeneration; an antimicrobial ingredient in cosmetics; a preservative material; a material for fabrication of a medical device or implant; or for removing heavy metals, i.e., as a chelation therapy.

[0008] In another aspect, disclosed herein is a process for the preparation of a polymeric chain of the formula I as defined above, said process comprising mixing, i.e., reacting, imidazolidinyl urea monomers each of the formula II:wherein R2, R3, R4 and R5 each independently is H, -C(O)-CH=CH2, or -C(O)- C(CH3)=CH2, provided that at least one of R2, R3, R4 and R5 is not H, in a solvent, optionally in the presence of a photoinitiator and optionally a photoinhibitor.

[0009] In a further aspect, disclosed herein is a photocurable resin comprising:(i) polymeric chains each of the formula I:wherein X each independently is an imidazolidinyl urea of formula Xi or X2:(ii) imidazolidinyl urea monomers each of formula II:wherein:Ri each independently is (Ci-C3)alkyl, preferably methyl, or H;R2, R3, R4, and R5 each independently is H, -C(0)-CH=CH2, or -C(O)-C(CH3)=CH2, provided that at least one of R2, R3, R4, and R5 when present, is not H; andn is an integer of at least 2, e.g., at least 5, 10, 15, 20, 25, 50, 60, 70, 80, 90, 100, 200, 500, or more, in a solvent, optionally comprising a photoinitiator and optionally a photoinhibitor.

[0010] In yet a further aspect, disclosed herein is product, e.g., a medical device such as an implant, scaffold, wound healing patch, and catheter, made by 3D printing of a photocurable resin as defined above. The product disclosed may be used as an antimicrobial, e.g. antibacterial, material; a bioactive material for wound healing or for prevention of wound infections; a scaffold for tissue regeneration; an antimicrobial ingredient in cosmetics; a preservative material; a material for fabrication of a medical device or implant; or for removing heavy metals (e.g., from the body, i.e., as a chelation therapy).BRIEF DESCRIPTION OF DRAWINGS

[0011] Figs. 1A-1B show (1A) FTIR of the IU, OSMCM and DSMCM; and (IB) 1H NMR of IU, OSMCM both in D2O and DSMCM in DMFD7.

[0012] Fig. 2 shows schematic illustration of flowchart-based approach for optimization of resin composition.

[0013] Figs. 3A-3F show the effect of different parameters on the resin for DLP 3D printing: (3A) working curve of DSMCM. (3B) semi-log working curve of DSMCM. (3C) the effect of the exposure time on layer thickness; and the effect of the (3D) photoinitiator (TPO), (3E) viscosity, and (3F) photoinhibitor (vitamin E) on the working curve penetration depth and critical energy.

[0014] Figs. 4A-4G show DLP 3D printing of the developed monomer and crosslinkers and different printed objects. (4A) 3D printing process in DLP printer. (4B) Different printed objects employing DSMCP, spanning from superficial to complex structures including circle, hexagon, star, cross and square of different sizes. (4C) Hollow cylinder (left panel) and layers of hollow cylinder (right panel). (4D) Microscopic image of cube (left panel) and layers of cube (right panel). (4E) Microscopic image of pyramid (left panel) and layers of pyramid (right panel). (4F) Letter “N” (left panel) and the Technion logo (right panel). (4G) Stent with circular hole (upper left panel), stent with low number of diamond holes (upper right panel), stent with high number of diamond holes (lower left panel), and 3D scaffold (lower right panel). Figs. 4F and 4G are on the same scale.

[0015] Figs. 5A-5D show physicochemical characterization of the printed object for different compositions. (5A) FTIR of DSMCM resin and subsequent DSMCP polymer. (5B) TGA profile (DTG onset). (5C) DSC of OSMCP, MSMCP, and DSMCP. (5D) Hydrolytic degradation profile of OSMCP, MSMCP, and DSMCP.

[0016] Figs. 6A-6H show compression profile of printed polymers with different compositions: (6A) Typical stress-strain curve of OSMCP, MSMCP, and DSMCP; (6B) Digital image of after compression test of OSMCP (left one) and DSMCP (right one); (6C) Compressive strength and strain of OSMCP, MSMCP, and DSMCP. The significant difference (p<0.01) between the compressive strength of the OSMCP, MSMCP, and DSMCP is denoted by asterisks; (6D) Stiffness and toughness of OSMCP, MSMCP, and DSMCP. The significant difference (p<0.05) between the stiffness and toughness of OSMCP, MSMCP, and DSMCP is denoted by an asterisk; (6E) Tensile cyclic loadingunloading and recovery curve (after 2 min) of OSMCP; (6F) Tensile cyclic loadingunloading and recovery curve (after 2 min) of MSMCP; (6G) Tensile cyclic loadingunloading and recovery curve (after 2 min) of DSMCP; (6H) Relative dissipated energy of OSMCP, MSMCP, and DSMCP recovered OSMCP, MSMCP and DSMCP after resting for 2 min.

[0017] Figs. 7A-7F show ten successive fatigue cycles of printed polymers with different compositions at 10% strain: (7A) Stress-strain curves for ten successive fatigue cycles of OSMCP. (7B) Relative dissipated energy and strength of ten fatigue cycles of OSMCP at 10% strain. (7C) Stress-strain curves for ten successive fatigue cycles of MSMCP. (7D) Relative dissipated energy and strength of ten fatigue cycles of MSMCP at 10% strain. (7E) Stress-strain curves for ten successive fatigue cycles of DSMCP. (7F) Relative dissipated energy and strength of ten fatigue cycles of DSMCP at 10% strain.

[0018] Figs. 8A-8C show an antibacterial study of printed polymers with different compositions against E. coli and B. subtilis. (8A) Colony formation assay for E. coli - control, and treated with OSMCP, MSMCP or DSMCP (upper panels); and for B. subtilis - control, and treated with OSMCP, MSMCP or DSMCP (lower panels). (8B) Live-dead fluorescence images for E. coli - control, and treated with OSMCP, MSMCP or DSMCP (upper panels); and for B. subtilis - control, and treated with OSMCP, MSMCP or DSMCP (lower panels). (8C) SEM images for E. coli - control, and treated with OSMCP, MSMCPor DSMCP (upper panels); and for B. subtilis - control, and treated with OSMCP, MSMCP or DSMCP (lower panels).

[0019] Figs. 9A-9C show cytocompatibility and blood compatibility study of cells treated with conditioned media of OSMCP, MSMCP, and DSMCP against control. (9A) Alamar blue cell viability assay. (9B) Blood compatibility. (9C) Fluorescent images of live / dead viability assay cells treated with conditioned media of OSMCP, MSMCP or DSMCP against TCPS control ab Day 1 and Day 3 (two upper lines); and cellular morphology of cells treated with conditioned media of OSMCP, MSMCP, and DSMCP against TCPS control at Day 1 and Day 3 (two lower lines).

[0020] Fig. 10 shows chlorine release profile of chlorinated OSMCP, MSMCP and DSMCP.DETAILED DESCRIPTION

[0021] In the present study, we have developed an lU-based methacrylate monomer named OSMCM as well as a crosslinker named DSMCM, and using these OSMCM and DSMCM, we have developed a series of photocurable resin compositions with tunable thermal, mechanical, and biodegradation properties, for high-resolution 3D printing. We have studied in-depth process parameters, including the effect of initiator, viscosity, photoinhibitor, and photoabsorber on the 3D printing process to achieve high-resolution printing. This thorough exploration allowed us to accomplish a notable z resolution of 10 pm under optimized conditions, surpassing the capabilities of most of the commercially available resins. Notably, an in-depth physicochemical characterization was performed later for three major compositions, where it was observed that thermal, mechanical, and biodegradation could be finetuned by simply varying the resin composition. More interestingly, the printed polymers exhibited excellent antimicrobial properties when tested against representative grampositive bacteria B. subtilis and gram-negative bacteria E. coli in a direct contact model without compromising cytocompatibility and blood compatibility. The newly developed IU- based resin reported herein emerges as a competitive alternative, addressing the growing demand for advanced photoresins with superior high-resolution 3D printing capabilities, particularly in biomedical applications. This groundbreaking achievement not only expands the possibilities of 3D printing technology but also presents a versatile solution with promising implications for various biomedical needs.

[0022] In one aspect, the present invention thus provides a polymeric chain of the formulaI:whereinX each independently is an imidazolidinyl urea of formula Xi or X2:Ri each independently is (Ci-C3)alkyl, preferably methyl, or H;R2, R3and R4each independently is H, -C(O)-CH=CH2, or -C(O)-C(CH3)=CH2; and n is an integer of at least 3, wherein said polymeric chain is optionally crosslinked to at least one additional such polymeric chain via one or more vinyl groups of the X groups thereof.

[0023] The term "alkyl" typically means a linear or branched hydrocarbyl, i.e., a univalent group derived from a saturated linear or branched aliphatic chain by removal of hydrogen atom from any of the carbon atoms, having, e.g., 1-16 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, neopentyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n- dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, and the like. Preferred are (Ci-C8)alkyls, more preferably (Ci-C4)alkyls, most preferably (Ci-C3)alkyls, i.e., methyl, ethyl, n-propyl, and isopropyl.

[0024] The term "halogen" as used herein refers to a halogen and includes fluoro, chloro, bromo, and iodo, but it is preferably fluoro or chloro.

[0025] The polymeric chain disclosed herein comprises a plurality of imidazolidinyl urea groups, each independently of the formula Xi or X2, linked to the polymer backbone via the nitrogen atom at position 1 or 3, respectively, of one of the two imidazolidine-2, 4-dione groups.

[0026] In certain embodiments, said polymeric chain comprises imidazolidinyl urea groups of the formula Xi only. In other embodiments, said polymeric chain comprises imidazolidinyl urea groups of the formula X2 only. In further embodiments, said polymeric chain comprises a mixture of imidazolidinyl urea groups each independently of the formula Xi or X2, wherein the ratio between the group of the formula Xi and the groups of the formula X2 is from about 1:100 to about 100:1, e.g., from about 1:95 to about 95:1, from about 1:90 to about 90:1, from about 1:85 to about 85:1, from about 1:80 to about 80:1, from about 1:75 to about 75:1, from about 1:70 to about 70:1, from about 1:65 to about 65:1, from about 1:60 to about 60:1, from about 1:55 to about 55:1, from about 1:50 to about 50:1, from about 1:45 to about 45:1, from about 1:40 to about 40:1, from about 1:35 to about 35:1, from about 1 :30 to about 30: 1 , from about 1 :25 to about 25:1, from about 1 :20 to about 20: 1 , from about 1:15 to about 15:1, from about 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1, respectively.

[0027] In certain embodiments, said polymeric chain comprises imidazolidinyl urea groups of the formula Xi only, wherein R2 and R4 each is H; and R3 each independently is H, -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2, e.g., wherein R2, R3 and R4 each is H; or wherein R2 and R4 each is H; and R3 is -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2. In particular such embodiments, the ratio between said imidazolidinyl urea of the formula Xi wherein R3 is H, and said imidazolidinyl urea of the formula Xi wherein R3 is -C(O)-CH=CH2 or -C(O)- C(CH3)=CH2, is from about 1:100 to about 100:1, e.g., from about 1:95 to about 95:1, from about 1:90 to about 90:1, from about 1:85 to about 85:1, from about 1:80 to about 80:1, from about 1:75 to about 75:1, from about 1:70 to about 70:1, from about 1:65 to about 65:1, from about 1:60 to about 60:1, from about 1:55 to about 55:1, from about 1:50 to about 50:1, fromabout 1:45 to about 45:1, from about 1:40 to about 40:1, from about 1:35 to about 35:1, from about 1:30 to about 30:1, from about 1:25 to about 25:1, from about 1:20 to about 20:1, from about 1:15 to about 15:1, from about 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1, respectively. In particular such embodiments, the ratio between said imidazolidinyl urea of the formula Xi wherein R3 is H, and said imidazolidinyl urea of the formula Xi wherein R3is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2, is about 1:1.

[0028] In other embodiments, said polymeric chain comprises imidazolidinyl urea groups of the formula X2only, wherein R3and R4 each is H; and R2each independently is H, -C(O)- CH=CH2or -C(O)-C(CH3)=CH2, e.g., wherein R2, R3and R4 each is H; or wherein R3and R4 each is H; and R2is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2. In particular such embodiments, the ratio between said imidazolidinyl urea of the formula X2wherein R2is H, and said imidazolidinyl urea of the formula X2wherein R2is -C(O)-CH=CH2or -C(O)- C(CH3)=CH2, is from about 1:100 to about 100:1, e.g., from about 1:95 to about 95:1, from about 1:90 to about 90:1, from about 1:85 to about 85:1, from about 1:80 to about 80:1, from about 1:75 to about 75:1, from about 1:70 to about 70:1, from about 1:65 to about 65:1, from about 1:60 to about 60:1, from about 1:55 to about 55:1, from about 1:50 to about 50:1, from about 1:45 to about 45:1, from about 1:40 to about 40:1, from about 1:35 to about 35:1, from about 1:30 to about 30:1, from about 1:25 to about 25:1, from about 1:20 to about 20:1, from about 1:15 to about 15:1, from about 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1, respectively. In particular such embodiments, the ratio between said imidazolidinyl urea of the formula X2wherein R2is H, and said imidazolidinyl urea of the formula X2wherein R2is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2, is about 1:1.

[0029] The polymeric chain of the formula I, as defined in any one of the embodiments above, comprises imidazolidinyl urea groups Xi and / or X2, each as defined above, wherein R2, R3and R4each independently is H, -C(O)-CH=CH2, or -C(O)-C(CH3)=CH2. Said copolymers, wherein at least one of the imidazolidinyl urea groups comprises one or more acrylate or metacrylate groups, i.e., wherein at least one of R2, R3and R4 of a particular Xi or X2group is not H, are thus capable of crosslinking via the vinyl groups of said one or more acrylate or metarcylate groups, i.e., forming a crosslinked polymeric chain. In certain embodiments, the polymeric chain disclosed, as defined in any one of the embodimentsabove, is thus crosslinked to at least one additional such polymeric chain via one or more vinyl groups of the imidazolidinyl urea groups thereof.

[0030] In certain embodiments, disclosed herein is a polymeric chain according to any one of the embodiments above, optionally crosslinked, wherein at least one of the nitrogen atoms in the groups Xi and / or X2 is alkylated or dialkylated, thereby forming a tertiary amine or quaternary ammonium group; and / or at least one of said nitrogen atoms is halogenated (e.g., chlorinated), thereby forming a N-halogen (e.g., N-Cl) bond. Particular such embodiments are those wherein at least one of the nitrogen atoms in the groups Xi and / or X2 is alkylated or dialkylated; and at least one of said nitrogen atoms is halogenated (e.g., chlorinated). The terms “alkylated” and “dialkylated” as used herein with respect to said copolymer mean that at least one of the nitrogen atoms, e.g., secondary nitrogen atoms, in the groups Xi and / or X2is substituted with one or two alkyl groups each independently selected from, e.g., (Ci- C16)alkyl, (C1-C8)alkyl, or (Ci-C4)alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, isobutyl, and tert-butyl, forming a tertiary amine or quaternary ammonium group. Such polymeric chains are referred to herein as “alkylated and / or halogenated polymeric chains” .

[0031] In certain embodiments, disclosed herein is a polymeric chain according to any one of the embodiments above, optionally crosslinked, and further optionally wherein at least one of the nitrogen atoms in the groups Xi and / or X2 is alkylated / dialkylated and / or at least one of said nitrogen atoms is halogenated, wherein the hydrogen atom of (i) at least one of the -NH- groups in the groups Xi and / or X2; or (ii) at least one of the -OH groups, when present, in the groups Xi and / or X2, is substituted with a drug covalently linked to the nitrogen atom of said -NH- group or to the oxygen atom of said -OH group; or wherein said drug is non-covalently linked to said nitrogen or oxygen atom, e.g., via ionic interactions. Such polymeric chains are referred to herein as “drug-conjugated polymeric chains” . The term “drug” as used herein refers in particular to a small molecule drug, which may optionally be functionalized (i.e., modified to include a functional group) so as to be able covalently or non-covalently linking to nitrogen or oxygen atom of -NH- / -NH2 or -OH group, respectively.

[0032] As shown herein, the polymeric chain disclosed herein, which is optionally crosslinked, alkylated and / or halogenated, and / or conjugated to a drug, has antimicrobial properties, and is thus useful both in vivo and in vitro, e.g., as an antimicrobial, e.g.,antibacterial, material; a bioactive material for wound healing or for prevention of wound infections; a scaffold for tissue regeneration; an antimicrobial ingredient in cosmetics; a preservative material; a material for fabrication of a medical device or implant; or for removing heavy metals (e.g., from the body, i.e., as a chelation therapy).

[0033] In certain embodiments thus disclosed herein is a polymeric chain according to any one of the embodiments above, optionally crosslinked, alkylated and / or halogenated, and / or conjugated to a drug, for use as an antimicrobial material; a bioactive material for wound healing or for prevention of wound infections; a scaffold for tissue regeneration, an antimicrobial ingredient in cosmetics; a preservative material; a material for fabrication of a medical device or implant, or for removing heavy metals, i.e., as a chelation therapy.

[0034] In another aspect, the present invention relates to a process (method) for the preparation of a polymeric chain of the formula I as defined in any one of the embodiments above (but excluding alkylated and / or halogenated polymeric chains as well as drug- conjugated polymeric chains), said process comprising mixing, i.e., reacting, imidazolidinyl urea monomers each of the formula II:wherein R2, R3, R4 and R5 each independently is H, -C(O)-CH=CH2, or -C(O)- C(CH3)=CH2, provided that at least one of R2, R3, R4 and R5 is not H, in a solvent, optionally in the presence of a photoinitiator and optionally a photoinhibitor.

[0035] In certain embodiments, the process disclosed comprises reacting imidazolidinyl urea monomers each of the formula II, wherein R2, Rs, and one of R3 and R4, each is H; and the other one of R3 and R4 is -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2. In other embodiments, said process comprises reacting imidazolidinyl urea monomers each of the formula II, wherein R2 and Rs each is H, and R3 and R4 each independently is -C(O)-CH=CH2 or -C(O)- C(CH3)=CH2. In further embodiments, said process comprises reacting imidazolidinyl ureamonomers each of the formula II, wherein R2 and R5 each is H; and either (i) R3 is H, and R4 is -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2; or (ii) both R3 and R4 each independently is - C(0)-CH=CH2 or -C(O)-C(CH3)=CH2. In particular such embodiments, the weight ratio between the two monomers reacted, i.e., between said monomers of the formula II wherein R3 is H, and said monomers of the formula II wherein R3 and R4 each independently is - C(O)-CH=CH2 or -C(O)-C(CH3)=CH2, is from about 1:100 to about 100:1, e.g., from about 1:95 to about 95:1, from about 1:90 to about 90:1, from about 1:85 to about 85:1, from about 1:80 to about 80:1, from about 1:75 to about 75:1, from about 1:70 to about 70:1, from about 1:65 to about 65:1, from about 1:60 to about 60:1, from about 1:55 to about 55:1, from about 1:50 to about 50:1, from about 1:45 to about 45:1, from about 1:40 to about 40:1, from about 1:35 to about 35:1, from about 1:30 to about 30:1, from about 1:25 to about 25:1, from about 1:20 to about 20:1, from about 1:15 to about 15:1, from about 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1, respectively. In more particular such embodiments, the weight ratio between the two monomers reacted is about 1:1.

[0036] In other embodiments, the process disclosed comprises reacting imidazolidinyl urea monomers each of the formula II, wherein R3, R4, and one of R2 and R5, each is H; and the other one of R2 and R5 is -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2. In other embodiments, said process comprises reacting imidazolidinyl urea monomers each of the formula II, wherein R3 and R4 each is H, and R2 and R5 each independently is -C(O)-CH=CH2 or -C(O)- C(CH3)=CH2. In further embodiments, said process comprises reacting imidazolidinyl urea monomers each of the formula II, wherein R3 and R4 each is H; and either (i) R2 is H, and R5 is -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2; or (ii) both R2 and R5 each independently is - C(O)-CH=CH2 or -C(O)-C(CH3)=CH2. In particular such embodiments, the weight ratio between the two monomers reacted, i.e., between said monomers of the formula II wherein R2 is H, and said monomers of the formula II wherein R2 and R5 each independently is - C(O)-CH=CH2 or -C(O)-C(CH3)=CH2, is from about 1:100 to about 100:1, e.g., from about 1:95 to about 95:1, from about 1:90 to about 90:1, from about 1:85 to about 85:1, from about 1:80 to about 80:1, from about 1:75 to about 75:1, from about 1:70 to about 70:1, from about 1:65 to about 65:1, from about 1:60 to about 60:1, from about 1:55 to about 55:1, from about 1:50 to about 50:1, from about 1:45 to about 45:1, from about 1:40 to about 40:1, from about 1:35 to about 35:1, from about 1:30 to about 30:1, from about 1:25 to about 25:1, from about1:20 to about 20:1, from about 1:15 to about 15:1, from about 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1, respectively. In more particular such embodiments, the weight ratio between the two monomers reacted is about 1:1.

[0037] The solvent in which the reaction disclosed herein is carried out may be any suitable inorganic solvent, organic solvent, or mixture thereof, in which the imidazolidinyl urea monomers are soluble. Examples of suitable inorganic solvents include water; nonlimiting examples of suitable organic solvents include dimethylformamide (DMF) and dimethyl sulfoxide (DMSO); and examples of suitable inorganic-organic solvent systems include, without being limited to, mixtures of water and DMF; water and ethanol; water and DMSO; water, DMF and ethanol; water, DMF and DMSO; water, ethanol and DMSO; and water, DMF, ethanol, and DMSO. ; and examples of suitable inorganic-organic solvent systems include, without being limited to,.

[0038] In certain cases, depending on the time period during which the imidazolidinyl urea monomers are mixed in the solvent, as well as the storage conditions of said mixture, polymerization of the imidazolidinyl urea monomers may occur even without a photoinitiator. Yet, in most cases, the process disclosed, according to any one of the embodiments above, is carried out in the presence of a photointiator and optionally a photoinhibitor.

[0039] The term “photoinitiator” as used herein refers to a molecule capable, upon irradiation with light (UV or visible), of absorbing photons and consequently forming reactive species out of the excited state (e.g., radicals, cations, or anions), which initiate consecutive reactions. The photoinitiator used in the process disclosed herein may be any photoinitiator soluble in the solvent utilized, e.g., a Norrish Type I photoinitiator, which is characterized by a cleavage reaction into two radical fragments of the original photoinitiator (the irradiation with UV-light leads to a homolytic bondage cleavage and generation of two highly reactive radical species), which then initiate the polymerization. Examples of Norrish Type I photoinitiators include, without being limited to, diphenyl (2,4,6-trimethylbenzoyl)- phosphine oxide (TPO), benzoyl peroxide (BPO), lithium phenyl-2,4,6- trimethylbenzoylphosphinate (FAP), 2-oxoglutaric acid, riboflavin (vitamin B2), phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO), and oligo [2-hydroxy-2- methyl-l-[4-(l-methylvinyl)phenyl] propanone] (Irgacure 2959).

[0040] In certain embodiments, the process disclosed, according to any one of the embodiments above, is carried out in the presence of a photointiator and optionally a photoinhibitor, wherein said photoinitiator constitutes up to about 10%, preferably from about 0.01%, 0.05% or 0.1% to about 6%, e.g., about 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5%, by weight, of the overall weight of said monomers, said photoinitiator, and said photoinhibitor when present.

[0041] The term “photoinhibitor” as used herein refers to a molecule capable of inhibiting, i.e., decreasing, the photochemical efficiency experienced in response to intense illumination due to radiation damages; and the presence of a photoinhibitor in the process disclosed herein will thus attenuate the polymerizatrion rate. Examples of suitable photoinhibitors for use according to the present invention include, without being limited to, vitamin E, hydroquinone, hydroxyquinone, 2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO), tetraethylthiuram disulfide (TETD), and bis[2-(o-chlorophenyl)-4,5-diphenylimidazole].

[0042] In certain embodiments, the process disclosed, according to any one of the embodiments above, is carried out in the presence of a photointiator and a photoinhibitor, wherein said photoinhibitor constitutes up to about 5%, preferably up to 2% or 3%, e.g., about 0.05%, 0.1%, 0.25%, 0.5%, 0.75%, or 1%, by weight, of the overall weight of said monomers, said photoinitiator, and said photoinhibitor.

[0043] In certain embodiments, the polymeric chain of the formula I is obtained by the process disclosed herein according to any one of the embodiments above, and is then alkylated and / or halogenated, thereby forming at least one tertiary amine or quaternary ammonium group, and / or at least one N-halogen (e.g., N-Cl) bond, thus obtaining an alkylated and / or halogenated copolymer. In particular such embodiments, the polymeric chain obtained is then both alkylated and halogenated.

[0044] In certain embodiments, the polymeric chain of the formula I is obtained by the process disclosed herein according to any one of the embodiments above, optionally alkylated and / or halogenated, and then reacted or complexed with a drug molecule (e.g., a small-molecule drug), thereby either covalently linking said drug molecule to a nitrogen atom or oxygen atom of said polymeric chain or alkylated and / or halogenated polymeric chain, by substituting an -NH- or -OH group in said polymeric chain or said alkylated and / or halogenated polymeric chain; or non-covalently linking said drug to said nitrogen atom or oxygen atom, e.g., via ionic interactions.

[0045] A composition comprising polymeric chains of the formula I according to any one of the embodiments above (e.g., oligomeric such chains, i.e., relatively short such polymeric chains), which are capable of further polymerized, i.e., wherein at least one of R2, R3 and R4 is not H; imidazolidinyl urea monomers of formula II as defined above; or both such polymeric chains and monomers at any ratio, may be provided as a photocurable resin for use, e.g., as a printing material in a 3D printing process, wherein said photocurable resin optionally further comprises a photoinitiator and optionally a photoinhibitor.

[0046] In a further aspect, the present invention thus provides a composition, more specifically a photocurable resin, comprising:(i) polymeric chains each of formula I:wherein X each independently is an imidazolidinyl urea of formula Xi or X2:(ii) imidazolidinyl urea monomers each of formula II:wherein:Ri each independently is (Ci-C3)alkyl, preferably methyl, or H;R2, R3, R4, and R5 each independently is H, -C(0)-CH=CH2, or -C(O)- C(CH3)=CH2, provided that at least one of R2, R3, R4, and R5 when present, is not H; and n is an integer of at least 2, e.g., at least 5, 10, 15, 20, 25, 50, 60, 70, 80, 90, 100, 200, 500, or more, in a solvent, optionally comprising a photoinitiator and optionally a photoinhibitor.

[0047] In certain embodiments, the photocurable resin disclosed comprises polymeric chains of the formula I, optionally together with a photoinitiator and optionally a photoinhibitor. In other embodiments, the photocurable resin disclosed comprises imidazolidinyl urea monomers of the formula II, optionally together with a photoinitiator and optionally a photoinhibitor. In further embodiments, said photocurable resin comprises both polymeric chains of the formula I and imidazolidinyl urea monomers of the formula II, at any ratio, optionally together with a photoinitiator and optionally a photoinhibitor.

[0048] In yet a further aspect, the present invention provides a product made by 3D printing of a photocurable resin as defined in any one of the embodiments above. Examples of such products include, without limiting, medical devices such as implants, scaffolds, wound healing patches, and catheters. The product disclosed herein may be used as an antimicrobial, e.g. an antibacterial, material; a bioactive material for wound healing or for prevention of wound infections; a scaffold for tissue regeneration; an antimicrobial ingredient in cosmetics; a preservative material; a material for fabrication of a medical device or implant; or for removing heavy metals (e.g., as a chelation therapy).

[0049] Unless otherwise indicated, all numbers expressing, e.g., ratios such as molar ratios or amounts, used in this specification, are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parametersset forth in this specification are approximations that may vary by up to plus or minus 10% depending upon the desired properties to be obtained by the present invention.

[0050] The invention will now be illustrated by the following non-limiting Examples.EXAMPLESStudy 1. Engineering multifunctional UV-polymerizable imidazolidinyl urea-based methacrylate resin for 3D printing: Synthesis, characterization, and antimicrobial propertiesMaterials and Methods

[0051] Materials. Imidazolidinyl urea, triethylamine, and sodium hypochlorite (11%), were supplied by Sigma-Aldrich. (±)-Alpha-tocopherol (vitamin E) was bought from Thermos Scientific. Methacryloyl chloride and trimethyl benzoyl phosphine oxide (TPO) were purchased from Angene. Dimethylformamide (DMF) was procured from Biolab. Deuterium oxide (D2O) and deuterated A,A-di methyl formamide (DMF-D7) were purchased from ARMAR I3sotopes. Luria broth, Dulbecco’s Modified Eagle Medium (DMEM) cell culture media, 4,6-diamidino-2-phenylindole (DAPI), and paraformaldehyde were purchased from Sigma Aldrich, E. coli (MG1566) was generously donated by Daniel lab at Technion, while B. subtilis (W168) was generously donated by Ruai lab at Technion. The live-dead bacterial viability kit (SYTO9 / PI kit), live / dead cell imaging kit, Alexa Fluor™ 488 Phalloidin, fetal bovine serum (FBS), penicillin / streptomycin solution, and alamar blue were procured from Thermofisher Scientific. All the other solvents used in this study were analytical grade and purchased from Sigma Aldrich.

[0052] Preparation of methacrylate imidazolidinyl urea (OSMCM) monomer. The mono methacrylate imidazolidinyl urea (OSMCM) was prepared by reacting IU with methacryloyl chloride (1:1 molar ratio) in the presence of triethylamine (TEA), as depicted in Scheme 1 (upper panel). Briefly, 15 g of IU was dissolved in 105 ml DMF and stirred for 10 min until all IU was completely dissolved. Subsequently, 8.07 ml of TEA was introduced into the reaction mixture and then incubated for 15 minutes. This was followed by a dropwise addition of 3.75 ml of methacryloyl chloride for 2 h at 0°C, and then the reaction was continued for another 3h under a nitrogen atmosphere.

[0053] After 3h, the reaction mixture was filtered using a Buchner funnel to remove the TEA salt, and then DMF was taken out with a rotary evaporator at 45 °C under reduced pressure (BUCHI Rotavapor™, R-300). A combi-flash chromatography (CombiFlash NextGen) was used to purify the OSMCM and to separate it from any trace of unreacted IU. The product yield is -70%.

[0054] Preparation of dimethacrylate imidazolidinyl urea (DSMCM) crosslinker. The dimethacrylate imidazolidinyl urea (DSMCM) was prepared by reacting IU with methacryloyl chloride (1:2 molar ratio) in the presence of TEA, as depicted in Scheme 1 (lower panel). Briefly, 15 g of IU was added to 105 ml DMF, and 10 min was allowed to dissolve all the IU. After that, 16.14 ml of TEA was added to the reaction mixture and rested for another 15 min. Subsequently, 7.5 ml of methacryloyl chloride was added dropwise for 2h at 0°C, and the reaction was continued for another 3h under a nitrogen atmosphere.Scheme 1. Preparation of OSMCM monomer and DSMCM crosslinker

[0055] After 3 hours, the reaction mixture was filtered using a Buchner funnel to remove the TEA salt; DMF was subsequently removed using a rotary evaporator under reduced pressure at 45°C. To purify DSMCM, deionized distilled water (DDW) was added to the reaction mixture since IU is highly soluble in DDW while DSMCM is insoluble in water.The obtained DSMCM is freeze-dried in lyophilizer (Christ Alpha 2-4 LSCbasic). The product yield is -80%.

[0056] FTIR. The FTIR spectra of IU, OSMCM, DSMCM, and final printed objects for different compositions were recorded using Nicolet iSlO Thermo Scientific Fourier transform infrared spectrometer. All spectra were recorded between 400-4000 cm'1over 16 scans with a resolution of 4 cm'1.

[0057] 1H-NMR and13C NMR. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) were performed using AVANCE II 500 MHz (Bruker, Germany) to confirm the structural modification of IU with the methacrylol chloride. D2O was used as a solvent to acquire the1H NMR spectra of IU and OSMCM while deuterated DMF-D7 was used to acquire1H NMR spectra of DSMCM. The13C NMR of the IU, OSMCM and DSMCM were obtained using DMF-D7 as solvent. Tetramethylsilane was used as an internal standard.1H NMR spectra for all the samples were measured at room temperature for at least 64 scans while13C NMR spectra for all the samples were recorded at room temperature for at least 256 scans.

[0058] Viscosity determination of printing resin. The viscosity of the printing resins was determined using a Brookfield Amtek DV2T viscometer. The measurements were performed at 25 °C, with a spindle size of 62 and a rotational speed of 70 rpm with accuracy ±4.3 centipoise (cP).

[0059] Preparation of photocurable IU resins. Different compositions of photocurable IU resins were prepared by mixing different amounts of OSMCM and DSMCM. DMF was used as a diluent, TPO was used as a photoinitiator, and vitamin E was employed as a photoinhibitor. Table 1 represents the different photocurable IU resin compositions. Each composition is prepared in weight ratio.

[0060] TGA. The thermal stability of IU, OSMCM, DSMCM, and final printed objects for different compositions were examined using Mettler Toledo TGA / DSC 3+. A standard aluminum pan was used to conduct experiments at a heating rate of 10°C / min from 25 to 500°C and under a nitrogen atmosphere flow rate of 50 ml / min.

[0061] DSC. Differential scanning calorimetry (DSC) of the final printed objects was done using Mettler Toledo DSC 3+. Like TGA, a standard aluminum pan was employed to conductthe experiments under a nitrogen atmosphere with a flow rate of 230 ml / min and a heating rate of 10°C / min. To erase the thermal memory of the material, a heating (25-100°C) -^cooling (100-0°C) — > heating (0-250°C) cycle was performed, and the last cycle data was collected to determine the glass transition temperature (Tg).Table 1. Different compositions of photocurable resin consist of OSMCM, DSMCM, TPO, and vitamin E. All the compositions were prepared in wt / wt%

[0062] 3D Printing. 3D objects were printed utilizing the DLP technique. Different resin compositions were prepared, as shown in Table 1, mixed, and then poured into the resin tank. Then, the resin was exposed to a UV laser of 385 nm and cured in a layer-by-layer fashion using the Asiga Max X printer. For DLP 3D printing of objects, the exposure time utilized was chosen using the working curve. The image of the 3D printed objects was captured using a digital camera, while the layer thickness of the printed objects was measured using an inverted EVOS microscope (Thermo Fisher Scientific M5000).

[0063] Preparation of working curve. The Jacobs working curves were established for the different compositions as described in Table 1. A model was designed using Solidworks software to calculate the working curve. The model contains 20 squares, each with a different height (thickness) that indicates different exposure times, as shown in Table 2. After polymerization, the uncured material was removed from the object by washing it with DMF. The thicknesses of the samples were measured with a caliper and plotted as a function of energy. The penetration depth and critical energy are two important characteristics of photocurable resins that can be determined from the Jacobs working curve (Bennett, 2017). The equation of Jacobs's working curve is represented by Equation 1.Where Ecdenotes the critical energy where the transition from liquid to solid takes place, Cd represents the cured depth, Emaxindicates the exposure on the surface, and Dpsignifies the penetration depth. The expression appears as a straight line on the semi-logarithmic plot, where Cd is plotted on the y-axis and Emaxon the x-axis. In the graph, Ecis designated by the point where the straight line intersects the x-axis, while the slope of the line denotes Dp.Table 2. Correlation between exposure time light intensity and dose for Jacobs working curve

[0064] Mechanical properties. The tensile properties of the 3D-printed polymers for different compositions shaped in strips featuring a height of 1 mm, a length of 40 mm, and a width of 10 mm were assessed using a universal testing machine (Shimadzu EZ LX UTM) at room temperature, equipped with a 50 N load cell.

[0065] The compressive properties of the 3D printed polymers with different compositions shaped in the form of cylinders featuring a height of 10 mm and a diameter of 7 mm were assessed using a universal testing machine (LLOYD 01 / LFLS / LXA / EU) at room temperature, equipped with a 1000 N load cell. At least three parallel samples for eachcomposition were tested. From the compressive stress-strain curve of different compositions, compressive strength and strain were obtained directly, whereas compressive stiffness and toughness were calculated from the linear elastic region, and toughness was the area under the curve. The anti-fatigue property and cyclic loading-unloading tests proceeded at 10 % strain for 10 cycles, and the dissipated energy was the loop area of each loadingunloading curve.

[0066] In vitro hydrolytic degradation . In vitro, hydrolytic degradation was employed to investigate the biodegradability of the printed OSMCP, MSMCP and DSMCP polymers in PBS buffer (pH 7.4) following the methodology outlined by Ghosal et al. (2022) with minor adaptations. For this process, 1 g of the dried printed polymer was precisely weighed, immersed in a 13 ml PBS solution, and placed in a shaker incubator at 37°C with a constant stirring of 50 rpm for one day. Before initiating the degradation process, the printed polymers underwent a meticulous washing procedure with diluent to ensure the complete removal of any residual monomers within the printed polymer, followed by thorough drying. After one day, the samples underwent lyophilization before being re-weighed. All degradation experiments were performed in triplicate and represented as mean ± standard deviation. The percentage of weight loss is determined using the following formula:where Wo designates the initial weight of the 3D-printed polymer samples, while Wt signifies the weight of 3D-printed polymers at different time points.

[0067] Antibacterial activity investigation by the direct contact test (DCT). The antibacterial activity assessment of the printed polymers, featuring different compositions, was performed according to Farah et al. with slight modifications (Farah et al., 2013). E. coli and B. subtilis bacterial strains were used as representative gram-negative and grampositive bacteria for the antibacterial study. Briefly, at first, 10 pl of fresh med-log phase bacterial culture (105CFU / ml) was added to the surface of each printed material in 96 well plates. Subsequently, the plate was incubated at 37°C for approximately Ih to allow the evaporation of the liquid of bacterial suspension, ensuring direct contact between the bacteria and the tested material. An empty well served as a negative control. Subsequently, 245 pl of fresh LB broth was added to the wells containing the tested samples, including the control. Then, the 96-well plates were incubated at 37°C under shaking conditions (180 rpm) for 4h, followed by seeding 10 pl from the wells containing the printed material in a fresh LB plate agar.

[0068] Bacterial live / dead assay. A live / dead bacterial staining assay was conducted using the L7012 BacLight bacterial viability kit (Molecular Probes, Invitrogen, United States). Briefly, a single colony from a fresh LB plate was incubated in 5 ml LB broth for 14 hr at 37°C and 180 rpm to obtain 108CFU / ml cells, followed by the dilution of 1:100 in fresh LB broth. Next, the printed polymers were submerged in 1 ml of bacterial suspension and incubated in the same conditions for 4 hr. Then, 1 ml suspension was transferred to a labeled microcentrifuge tube that was centrifuged at 8000 rpm for 10 min (4°C), followed by three washing steps with 0.85% saline solution. Then, the pellet was re-suspended in 500 pl of saline, and 1.5 pl of 1:1 dye mixture (SYTO9:PI) was added to each sample, following the manufacturer’s instructions, and incubated for 15 min under static and dark conditions. Subsequently, samples were washed from access dye, and 20 pl was drop cast on a glass slide and covered by the 18 mm coverslip. Images were taken using a fluorescence EVOS 5000 (Thermo Fisher Scientific) microscope.

[0069] Scanning Electron Microscopy (SEM) analysis of treated bacteria against control. SEM was utilized to determine the bacterial morphological changes after exposing the bacteria to the printed material. Briefly, a single colony from a fresh LB plate was incubated in 5 ml LB broth for 14 hr at 37°C and 180 rpm to obtain 108CFU / ml cells, followed by the dilution of 1: 100 in fresh LB broth. Next, the printed polymers were submerged in 1 ml of bacterial suspension and incubated in the same conditions for 4 hr. Afterwards, 1 ml suspension was transferred to a labeled microcentrifuge tube that was centrifuged at 8000 rpm for 10 min (4°C), followed by three washing steps with PBS. Next, the bacteria were fixed with 2.5% paraformaldehyde for 2 hr at 4°C. Subsequently, the fixed cells were serially dehydrated in ethanol gradient (30%, 50%, 70%, 90%, and 100%), each for 10 min, and incubated with 100% ethanol for Ihr. After that, 10 pl of the 100% ethanol- containing bacteria were drop cast on a sterile silicon wafer, thoroughly air-dried, followed by gold sputtering, which was subjected to SEM (Phenom ParticleX Battery Desktop SEM) imaging.

[0070] In vitro cytocompatibility study of the printed object. The in vitro cytocompatibility of the different compositions was accessed according to Ghosal et al.(2023) against NIH-3T3 mouse fibroblast cells. Briefly, the printed polymers with different compositions were cut into small pieces and sterilized in 70% ethanol, followed by drying and washing with DPBS thrice. After that, the small pieces of printed polymers (~1.5 mg) were placed within 10 ml of cell culture medium and placed in a CO2 incubator for one day under shaking conditions. The medium, composed of the degradation products of the polymer, was referred to hereafter as the conditioned medium, which was subsequently treated to the cells to evaluate the cytotoxicity of the polymers. Then, cells were seeded at a density of about 2.5xl04cells into 24-well plates, and each well was incubated for 1, 3 and 7 days to evaluate cell viability. For the study, cells treated with complete cell culture media without any degradation product were used as a control. The media is replaced with fresh media in 2-day intervals for the complete study. The cell viability study was conducted using alamar blue assay at predetermined time points. The treated cells were exposed to 1 mg / mL alamar blue dye for 4 h, and subsequently, the fluorescence intensity was recorded at a 560 / 590 nm (excitation / emission) wavelength with a Biotek Synergy H1F1 Plate reader. All measurements were performed in triplicate. The % cell viability was calculated according to Equation 3.

[0071] Live dead imaging study of cells. The cell viability of the conditioned media- treated cells against the control was also examined by semi-quantitative LIVE / DEAD imaging (Molecular probes, Invitrogen). Calcein dye in a concentration of 2 mM and ethidium homodimer with a concentration of 4 mM were used to stain live and dead cells simultaneously. The staining was performed in a CO2 incubator for 30 min maintained at 37°C and immediately imaged in a fluorescence microscope (EVOS 5000 Thermo Fisher Scientific).

[0072] Cell morphology analysis. To examine the effect of polymer degradation products on cellular morphology, cells were first fixed at predetermined time points with a 3.7% methanol-free paraformaldehyde solution for half an hour. After that, the paraformaldehyde solution was removed, and cells were washed with DPBS thrice. Subsequently, the cells were treated for 15 min with 0.1% Triton X-100 solution to permeabilize the cell membrane, followed by washing with DPBS thrice. Then, cells were stained with 10 pg / mL Alexa Fluor™ 488 Phalloidin dye for 30 min and washed with DPBS thrice. Thereafter, cells wereagain treated with 1 μg / mL of DAPI dye for 10 min, followed by washing with DPBS thrice. Right after, stained cells were imaged using a fluorescence microscope (EVOS 5000 Thermo Fisher Scientific).

[0073] Blood compatibility . The blood compatibility of the printed polymers (OSMCP, MSMCP and DSMCP) was assessed using fresh human blood. Each sample, weighing 10 mg, was prepared and immersed in 1 mL of physiological saline for a 30-minute incubation period at 37°C with gentle agitation at 50 rpm. Subsequently, fresh human blood was introduced, and the incubation continued for an additional 60 min. Following incubation, all of the samples with blood were subjected to centrifugation at 2000 rpm for 5 min. The absorbance of the supernatant was measured at 545 nm using a Biotek Synergy H1F1 plate reader. To establish baselines, human blood samples were treated with 1 mF of deionized water and physiological saline, serving as positive and negative controls, respectively.

[0074] The hemolysis ratio was determined using Equation 4, which quantitatively measures the printed polymers' impact on blood compatibility.where ODH, ODp and ODN are the absorbance values of the polymer group, positive control, and negative control, respectively.

[0075] Chlorination and chlorine release study. Printed OSMCP, MSMCP, and DSMCP were soaked inside the neutralized 11% sodium hypochlorite solution at room temperature for 24 hours for chlorination, respectively. Then, chlorinated objects were washed using DDW for 2 hours and started the chlorine release process. The release profiles were studied via soaking the chlorinated objects inside DDW at 37°C for different time points, and the released Cl was detected by a spectrophotometer (Lovibond MultiDirect, Germany). The Cl release profile was based on the object concentration of 1 mg / mE.

[0076] Statistical significance . All of the mechanical testing experiments and biological experiments were conducted in triplicate for reproducibility, and the data were represented in the form of the average value ± standard deviation (SD). To check the statistical significance, two-way ANOVA was performed in GraphPad Prism software, and *p values < 0.05 and **p values < 0.01 were used.Results and Discussion

[0077] The synthesis of lU-based monomer (OSMCM) and crosslinker (DSMCM) involved a nucleophilic substitution reaction, where methacrylol chloride (MC) reacted with IU in the presence of TEA (the reaction scheme for OSMCM and DSMCM is illustrated in Scheme 1). The detailed synthesis steps of the OSMCM and DSMCM were described in the materials and methods section. Integration of the methacrylate group into the IU structure enables the 3D printability of the IU. The structure of the OSMCM and DSMCM was confirmed by FTIR,1H-NMR and13C-NMR.

[0078] Fig. 1A represents the FTIR spectra of IU, OSMCM and DSMCM. From the FTIR, it was clear that there was a significant decrease in -OH peak (between 3500-3200 cm'1) intensity after the conjugation of methacrylate groups in the IU structure. However, the decrease in -OH peak intensity was notably more pronounced in DSMCM compared to OSMCM. This is because, in case of OSMCM, only one -OH group is consumed by methacrylol chloride, while for DSMCM, both -OH groups of IU are consumed. Additionally, a substantial increase in the characteristic C-H stretching (between 3000-2800 cm'1) was noticed for OSMCM and DSMCM, which was nearly negligible in IU. In contrast, a distinct C-C bond appeared at 1180 cm'1, indicating the successful incorporation of methacrylate groups into the IU structure via an ester bond. On the other side, in case of1H- NMR (Fig. IB), the generation of a new singlet peak was noticed around 1.8 ppm due to the methyl protons, while the peaks at 5.5 and 6 ppm assigned to protons attached with double bond. Similar type of observation is also noticed for DSMCM, however due to the solvent effect the peaks are shifted to downfield. For 1H spectra of DSMCM, the peak around 1.9 ppm was assigned to methyl protons, while the peaks at around 5.8 and 6.3 ppm were attributed to double -bonded protons. Additionally, traces of triethylamine manifested as peaks around 1.6 ppm in 1H NMR and at around 10 ppm in 13C NMR. For further structural confirmation of OSMCM and DSMCM we have performed 13C NMR (refer to Figure S2), where the peak for methyl carbon was observed around 20 ppm, while the peaks at approximately 125 ppm and 135 ppm were associated with double -bonded carbons, suggesting successful synthesis of OSMCM and DSMCM. After successfully synthesizing the monomer (OSMCM) and crosslinker (DSMCM), we proceeded with the DUP 3D printing.

[0079] Optimization of resin composition. A flowchart-based approach was employed to optimize resin properties in additive manufacturing processes, as shown in Fig. 2. The optimization process commences with selecting the desired layer thickness at the initial step.

[0080] Subsequently, the cure depth is measured after each modification step during the optimization process. If the measured cure depth (Cd) is smaller than the desired layer thickness and there is no occurrence of dark curing, the exposure time may need to be increased. However, in the presence of dark curing (which we have also observed in our case, data not shown), the addition of a photoinhibitor is recommended before adjusting the exposure time. Furthermore, whenever a dark cure depth is observed, the addition of a photoinhibitor is required. On the other hand, if the measured cure depth is larger than the desired layer thickness and no dark curing is observed, the exposure time should be reduced. Once the desired layer thickness is achieved without any dark curing, it is essential to examine over-curing issues. If there is any over curing, adding a photoabsorber (dye) to the resin is recommended to decrease the penetration depth of the light and mitigate the over- curing effects. This flowchart-based approach provides a systematic framework for resin optimization, facilitating improved control and enhancing additive manufacturing products' overall quality and performance.

[0081] Preparation of working curve for different resin compositions. Fig. 3A shows the working curve plot of composition 3, while Fig. 3B exhibits the semi-log plot of the same composition; the semi-log plot is a straight line as expected, where the intercept with the x- axis indicates the critical energy and the slope indicates the penetration depth of the resin. Fig. 3C depicts a schematic diagram illustrating the correlation between exposure time, object thickness, critical energy, and penetration depth.

[0082] Figs. 3D-3F show the effect of the photoinitiator, photoinhibitor, and viscosity on the working curve, cure depth, critical energy, and penetration depth. As clearly evident from Fig. 3D, with the increase in photoinitiator weight ratio, the value of the penetration depth decreased significantly from 0.85 mm to 0.17 mm, which indicates better z resolution. In addition, the value of critical energy decreased from 693 mJ / cm2to 256 mJ / cm2. Photoinitiators are responsible for absorbing light energy and initiating the polymerization process; therefore, when the concentration of photoinitiators is increased, they tend to absorb a significant amount of the exposed light. This can reduce the amount of light that can penetrate deeper into the material, as more of it is absorbed near the surface.

[0083] A low slope in the layer thickness / exposure energy plots indicates low Dpvalues. It can facilitate more precise adjustments to layer thickness during the 3D printing process, ultimately enhancing resolution in the Z-axis direction. Briefly, in the case of low Dpvalues, if an object cannot be printed successfully for a specific exposure energy per layer, a slight rise in exposure energy can result in a relatively small increase in layer thickness. Such a rise might be enough for a successful print with high resolution, without increasing the risk of additional UV light that can penetrate into adjacent layers. Similar to photoinitiators, viscosity also plays a critical role in the printing process. Fig. 3E represents the effect of the viscosity on the resin properties. It was observed that, with the increase in viscosity, the value of the penetration depth decreased from 0.88 mm to 0.32 mm. In addition, the value of critical energy decreased from 689 mJ / cm2to 160 mJ / cm2. This can be attributed to the higher resin viscosity, which reduces mobility and increases resistance to flow, consequently impeding the diffusion of chemicals, such as photoinitiators, into the resin. In addition to photoinitiator and viscosity, the effect of photoinhibitor concentration is also accessed for the printing of the resin. A photoinhibitor is usually used to improve the x / y resolution. Fig. 3F shows the impact of the photoinhibitor on the resin properties. As observed from Fig. 3F, with an increase in the photoinhibitor weight ratio in the resin, the value of the penetration depth increased from 0.33 mm to 0.49 mm. In addition, the value of critical energy decreased from 85 mJ / cm2to 389 mJ / cm2. The addition of a photoinhibitor enhanced the x / y resolution but also decreased the z resolution, which can be reached by increasing the penetration depth. The correlation between penetration depth and critical energy for different compositions was enlisted in Table 3.Table 3. Correlation between penetration depth and critical energy values for different compositions

[0084] 3D Printing. Following optimization and establishment of a working curve for various compositions, different 3D object samples were printed using the DLP technique. Initially, the resins were prepared according to Table 1, mixed, and then poured into the resin tank. Subsequently, the ink was exposed to a UV laser of 385 nm and cured in a layer- by-layer fashion by using the Asiga Max X printer, as shown in Fig. 4A. Scheme 2 depicts the UV polymerization step of DSMCM in the presence of TPO as the photoinitiator. The working curve was used to determine the exposure time for DLP 3D printing of items. The lU-based resin facilitated a range of high-resolution 3D-printed objects in all directions, starting from elementary shapes like the circle, hexagon, star, cross, and square (Fig. 4B) to more intricate designs such as the letter “N” and the Technion logo (Fig. 4F). We used two different resin compositions to print the objects. The high-resolution objects including cube (depicted in Fig. 4D), pyramid (illustrated in Fig. 4E), stents and 3D scaffold (Fig. 4G) were printed using resin composition 11, whereas other printed objects were fabricated using resin composition 3.Scheme 2. UV polymerization step of DSMCM in the presence of TPO

[0085] More evidently, it was observed that after optimizing the printing process and addition of the photoabsorber, the z-axis resolution was significantly improved from 188 pm to 50 pm to 10 pm. We have printed a hollow cylinder (Fig. 4C) with a layer thickness of 188 pm, a cube (Fig. 4D) with a layer thickness of 50 pm, and a pyramid (Fig. 4E) with a layer thickness of 10 pm which is itself a significant improvement over the currently available commercial resins. Typically, in DLP 3D printing, achieving a resolution of <100 pm is considered a high-resolution printing benchmark that most commercial resins aim for. In our particular case, we achieved a remarkable 10 pm layer thickness (z resolution), surpassing the performance of some of the commercially available resins. For greater significance, we have printed some of the medically important complex structures such as stents and 3D porous scaffold (Fig. 4G), which justify their versatile use case for different biomedical applications.

[0086] Physicochemical characterization and hydrolytic degradation profile of 3D printed object for different compositions. After the 3D printing of objects with different compositions, they were washed with excess diluent and then dried at 40°C. Subsequently, these printed objects are subjected to physicochemical characterization, such as FTIR, TGA and DSC. Fig. 5A illustrates the FTIR spectra of both the printed object formulated with DSMCP and the DSMCM resin itself. Where before printing, the presence of a peak at 942 cm'1in the DSMCM can be ascribed to the C=C bending, while after printing (UV polymerization), the peak is significantly reduced, indicating successful polymerization and crosslinking of the resin taking place during the printing process. Furthermore, a notable augmentation in the intensity of the hydrogen-bonded amide peak was observed. This increase in hydrogen bonding intensity can be attributed to the presence of multiple hydrogen bonds in the crosslinked network structure of the polymer, as the IU molecule contains multiple hydrogen bonding sites that can act as donors and acceptors. The increased amide peak indicates the establishment of robust hydrogen bonding networks within the printed objects. The FTIR findings provide valuable insights into printed polymers' chemical transformations and bonding characteristics, contributing to a better understanding of their structural properties. Furthermore, for a deeper understanding of the structure -property relationship of the printed polymer with different compositions, we have performed TGA and DSC analysis. The thermal stability of the printed objects for different compositions was examined using TGA, which was represented in Fig. 5B. For the rest of the study, we haveaccessed the physicochemical properties of the printed polymers for three different compositions, designated as OSMCP (Composition 1), MSMCP (Composition 2), and DSMCP (Composition 3). These three compositions were explicitly selected to facilitate a more comprehensive understanding of the structure -property relationship of OSMCM as well as DSMCM. Where OSMCP is composed of 98.5 wt% OSMCM, DSMCP is composed of 98.5 wt% DSMCM, while MSMCP consists of a balanced composition of 49.25 wt% OSMCM and 49.25% DSMCM. From the TGA thermogram, it is clear that all of the compositions show thermal stability up to ~90°C. Beyond this temperature, a gradual weight loss was observed for all of the compositions, reaching almost 20% of the initial weight by 500°C. Notably, the printed object with OSMCP experiences higher weight loss, while DSMCP shows less, with MSMCP falling in between. Intriguingly, thermal degradation occurs in four distinct stages: an initial 20% degradation occurs between 100-180°C, followed by a significant degradation of -40% between 200-280°C. The third stage, accounting for around 15% degradation, occurs between 290-350°C, and the final stage sees approximately 10% degradation between 360-460°C.

[0087] The superior thermal stability observed in the case of DSMCP is attributed to its highly crosslinked structure. In contrast, the printed object with MSMCP, which possesses both OSMCM and DSMCM, exhibits less crosslinking, leading to faster thermal degradation than DSMCP. Whereas in the case of OSMCP, which lacks chemical crosslinking, it experiences the highest thermal degradation. Furthermore, DSC thermograms are recorded for the printed objects with different compositions to gain more insight into structureproperty relationships (Fig. 5C). The printed object with OSMCP exhibited a glass transition temperature (Tg) of 119.5°C, which increased to 132.6°C for DSMCP. This trend aligns with the TGA data, indicating that the higher crosslinking in DSMCP requires more energy for polymer chain vibrations, resulting in an elevated Tg. Whereas in the case of the MSMCP Composition, incorporating both OSMCM and DSMCM, a Tgof 126.3°C was observed, positioned between the values for OSMCP and DSMCP, which is consistent with the TGA findings.

[0088] Biodegradability stands as a pivotal property in developing new polymers, particularly in biomedical applications; herein, we have examined the biodegradation behavior of the OSMCP, MSMCP and DSMCP in PBS at physiological pH. The in vitro hydrolytic degradation behavior of the printed polymers is represented in Fig. 5D. As clearlyshown in Fig. 5D, the printed polymers with different compositions are neither too fast for hydrolytic degradation nor too slow to degrade, making them suitable for regenerative medicine applications. Notably, OSMCP exhibited the highest degradation, with approximately 7% breakdown over 28 days, while DSMCP displayed a more protracted degradation, registering a 4% weight loss after 28 days. MSMCP, being a composite of 50% OSMCM and 50% DSMCM, occupied an intermediate position with a 4.5% degradation after 28 days. This degradation trend can be linked to the monomer-to-crosslinker ratio within the composition. OSMCP, devoid of crosslinker, facilitated faster water penetration in the polymeric backbone, leading to ester bond hydrolysis. In contrast, DSMCP, which was comprised entirely of crosslinkers, exhibited slower degradation due to reduced water permeation. Meanwhile, MSMCP, blending OSMCM and DSMCM, struck a balance, showcasing an adaptable degradation profile. Thus, the modulation of the monomer-to- crosslinker ratio emerges as a powerful tool for tailoring the polymer's degradation characteristics, offering versatility for diverse biomedical applications.

[0089] Mechanical properties of the printed object. Furthermore, we have also examined the mechanical properties of the printed polymer for different compositions under tensile and compressive deformations. OSMCP was able to reach a maximum tensile strength of 50 kPa, while DSMCP was able to reach a tensile strength of about 280 kPa. Conversely, MSMCP showed a tensile strength of around 150 kPa, which falls in between OSMCP and DSMCP (data not shown). It was observed that as the percentage of DSMCM increased, there was a corresponding increase in the tensile properties, evident from the enhancement in tensile stress, strain, Young’s modulus, and toughness values (data not shown). This improvement can be attributed to heightened crosslinking within the material. Similar observations were also noticed for compressive properties. Figs. 6A and 6B showcase a typical compressive stress-strain graph and a photographic image of the printed material after compression testing. While Figs. 6C and 6D represent compressive strength, strain, stiffness, and toughness for OSMCP, MSMCP, and DSMCP. As may be observed from Fig. 6A, all the printed objects exhibit typical stress-strain behavior, characterized by an initial gradual rise aligning with the materials’ stiffness at low strains, followed by a sharp increase in stress in the high-strain region. The excellent compressive strength of the printed polymers is due to the cooperative hydrogen bonds formed between the IU bonds along the polymeric backbone (Wang et al., 2022).

[0090] As clearly shown in Fig. 6C, all of the compositions can reach up to -33-42% compression strain with no significant difference in strain %. However, a significant difference was noticed in compressive strength, stiffness, and toughness. The augmentation in mechanical strength of the printed object was notably observed with an increase in DSMCM percentage. This can be attributed to the heightened crosslinking density associated with the elevated DSMCM percentage. For instance, in the case of OSMCP, where no DSMCM is present, the maximum compressive strength of 500 kPa was achieved, whereas DSMCP, featuring the highest percentage of DSMCM, attained a compressive strength of approximately 4 MPa. On the other hand, MSMCP displayed a compressive strength of -1.7 MPa, which is in between OSMCP and DSMCP. The significant difference (p value < 0.01) between the compressive strength of the OSMCP, MSMCP and DSMCP is denoted by asterisks. In a similar fashion, the stiffness and toughness are much higher for DSMCP with a value of 13.5 MPa and 9.5 MJ / m3, while for MSMCP and OSMCP, the value is only 8 MPa, 2 MJ / m3and 2.5 MPa, 1 MJ / m3, respectively. The significant difference (p value < 0.05) between the stiffness and toughness of OSMCP, MSMCP and DSMCP is denoted by asterisk. It is worth mentioning that all of the printed polymers fractured even after sustaining a good amount of compressive load. These printed polymers not only show higher compressive strengths than some of the state-of-the-art newly developed printed polymers reported in the literature but also, for the first time, allow us to avail a wide range of strengths by simply tuning the composition (Ge et al., 2021). These results indicate that, by simply adjusting the monomer: crosslinker ratio, we can access additive manufacturing objects with tailor-made mechanical properties that can be tuned according to the requirement of the specific application. Inspired by these fascinating mechanical properties of the printed polymers, we have further investigated the recovery behavior of the printed polymers after 2-minute intervals at 10% strain. The stress-strain graph for recovery of OSMCP, MSMCP and DSMCP after 2 min was demonstrated in Figs. 6E, 6F and 6G. Whereas Fig. 6H exhibits the extent of recovery % after 2 min. Interestingly, all of the printed polymers with distinct compositions showcased good recovery behavior, surpassing 80% recovery after a mere 2- minute rest period in all instances, indicating the presence of robust hydrogen bonding throughout the polymeric backbone. This notable self-recovery property of the printed polymers encouraged our curiosity, prompting a deeper exploration into their fatigue behavior. All of the printed polymers with the different compositions exhibited someresidual strain after the completion of the first cycle (Figs. 7A, 7C and 7E). The dissipated energy accounted for about 50-90% of the total work, indicating a significant role of the sacrificial associative H bond's physical cross-links as energy-dissipating motifs. Starting from the second cycle onwards, a considerable reduction in the area under the hysteresis curve was noticed. This substantial decrease can be attributed to internal damage inflicted during previous cycles, hindering the printed polymer’s ability to completely restore reversible bonds, exacerbated by the repetition of cycles without adequate rest periods (Figs. 6B, 6D and 6E). However, all the printed polymers recovered more than 90% of the original stress for all the compositions, suggesting the highly elastic nature of polymers. These results indicate robust fatigue resistance characteristics of this class of polymer under compressive loading.

[0091] Antibacterial performance of the printed material. As IU has been well- acknowledged as an antibacterial preservative for cosmetic products over the years, it is anticipated that polymers synthesized from IU monomers and crosslinkers will exhibit noteworthy antibacterial properties. The antimicrobial mechanism of IU is ascribed to the gradual release of formaldehyde through the degradation of IU molecules (Lehmann et al. , 2006). More specifically, the antimicrobial properties of imidazolidinyl urea compounds are based on their proposed mechanism of protein alkylation of sulfhdryl groups (Llabres and Ahearn, 1985). A direct contact method was employed for OSMCP, MSMCP, and DSMCP composition in the presence of gram-negative bacteria E. coli and gram-positive bacteria B. subtilis. Interestingly, it was observed that all of the compositions are highly effective in killing both the gram-negative and gram-positive bacteria.

[0092] Observations revealed that in the absence of the printed polymer, there was noticeable growth on the agar plates. However, upon direct contact with the printed polymer surface, no colonies were discernible on the plates, indicating the polymers' effective eradication of bacteria (Fig. 8A). These results were further supported by the live / dead fluorescence and scanning electron microscopy images. Fig. 8B represents the untreated bacteria stained green, showing their viable nature, whereas cells treated with the printed polymer- stained red represent death. Similarly, bacteria that were grown in the absence of printed material exhibited intact morphology with a smooth appearance, whereas those treated with the printed polymers showed damaged and deformed bacterial structures indicating prominent cell death (Fig. 8C). Therefore, these results strongly correlate with theantibacterial nature of the engineered printed polymer, thereby paving the way for potential applications of these materials as 3D-printed personalized antibacterial scaffolds.

[0093] In vitro cytocompatibility and blood compatibility study. In addition to antimicrobial properties, we have also investigated the cytocompatibility traits of the printed polymers on mouse fibroblast (NIH3T3) cells at the time points of 1 day and 3 days. Fig. 9A shows the cell viability data treated with conditioned media against control. It was observed that, after 1 day, almost 80% of the cells were viable in all the cases against control, while after 3 days, the cell numbers were less than -60% for OSMCP, indicating some toxicity of the degraded products. This may be attributed to the faster degradation of OSMCP in the absence of any crosslinkers. On the other hand, MSMCP and DSMCP exhibited over 90% cell viability after 3 days, suggesting the non-toxic nature of their degraded products. To further support these findings, we have also performed semi-quantitative fluorescence imaging of the treated cells at 1 day and 3 days. Fig. 9C illustrates minimal dead cells after 1 day, and a significant increase in dead cells after 3 days for OSMCP, which is consistent with the cell viability data. For the other two compositions, the number of viable cells is similar to the control, indicating the nontoxic nature of the degraded materials.

[0094] Moreover, our investigation extended to examining the impact of degraded products from the printed polymers on cellular morphology. This facet is of paramount importance, providing crucial insights into cell functionality and contributing to a comprehensive understanding of the implications of polymer degradation products on cellular behavior. To assess cellular morphology, we employed DAPI staining for the nucleus and Alexa Fluor Phalloidin for actin filaments. Fig. 9C further illustrates the cellular morphologies after treatment with conditioned media of OSMCP, MSMCP and DSMCP at various time points against the control (TCPS). Remarkably, in all cases, no significant morphological differences were discernible between cells treated with fresh medium and those treated with conditioned medium from the printed polymers.

[0095] The cells exhibited a healthy and consistently distributed pattern, indicating effective communication between neighboring cells through filopodial protrusions (Kutner et al., 2021). This observation aligns seamlessly with the cell viability data, reinforcing the notion of the excellent cytocompatibility of the printed polymers. Additionally, except OSMCP, the other compositions displayed a notable increase in cell numbers, corroborating findings from cell viability and live / dead data. This collective evidence underscores not onlythe biocompatibility but also the positive influence of printed polymers on cellular proliferation and overall cellular health.

[0096] In addition to in vitro cytocompatibility, we have also performed in vitro blood compatibility of the printed polymers (Fig. 9B). To perform the test, we have used normal deionized water and physiological saline as positive and negative controls, respectively. Promisingly, all the printed polymers exhibited a very low hemolysis index of less than 5%, which is considered safe to use.

[0097] Chlorine release study. Printed objects OSMCP, MSMCP, and DSMCP contain six active N-H groups for halogenation, resulting in N-halamines that have remarkable antimicrobial activities. In this work, N-Cl obtained via chlorination could slowly release Cl ion in the physiological microenvironment for enhancing antimicrobial performance. As shown in Fig. 10, all three chlorinated OSMCP, MSMCP, and DSMCP exhibit an increased Cl release over time. The DSMCP with higher crosslinking density gives minimal Cl release, while OSMCP with lower crosslinking degree exhibits significantly effective Cl release. These results strongly indicate that these objects have great potential as long-term bleaching materials for diverse uses.REFERENCESAhmad, S.; Singh, V.; Gautam, H.K.; Raza, K., Multisampling-based docking reveals imidazolidinyl urea as a multitargeted inhibitor for lung cancer: an optimisation followed multi- simulation and in-vitro study. Journal of Biomolecular Structure and Dynamics, 2023, 1-18Anindita, S.N.; Conti, R.; Zauchner, D.; Paunovi'c, N.; Qiu, W.; Buzhor, M.G.; Krivitsky, A.; Luo, Z.; Muller, R.; Griitzmacher, H.; Qin, X.H.; Leroux, J.C.; Bao, Y., Tough PEG-only hydrogels with complex 3D structure enabled by digital light processing of “all- PEG” resins, Aggregate, 2023, 4(6), e368Bennett, J., Measuring UV curing parameters of commercial photopolymers used in additive manufacturing. Addit. Manuf., 2017, 18, 203-212Farah, S.; Khan, W / ; Farber, I.; Kesler-Shvero, D.; Beyth, N.; Weiss, E.I.; Domb, A. J., Crosslinked QA-PEI nanoparticles: synthesis reproducibility, chemical modifications, and stability study. Polymers for Advanced Technologies, 2013, 24(5), 446Ge, Q.; Chen, Z.; Cheng, J.; Zhang, B.; Zhang, Y.F.; Li, H.; He, X.; Yuan, C.; Liu, J.; Magdassi, S.; Qu, S., 3D printing of highly stretchable hydrogel with diverse UV curable polymers, Science Advances, 2021, 7(2), eaba4261Ghosal, K.; Pal, S.; Ghosh, D.; Jana, K.; Sarkar, K., In vivo biocompatible shape memory polyester derived from recycled polycarbonate e-waste for biomedical application. Biomaterials Advances, 2022, 138, 212961Ghosal, K.; Sarkar, P.; Chakraborty, D.; Das, S.; Sarkar, K., Green synthesis of Nonisocyanate poly(ester urethanes) from renewable resources and recycled poly (ethylene terephthalate) waste for tissue engineering application. ACS Sustain. Chem. Eng, 2023, 11(37), 13688-13708Guit, J.; Tavares, M.B.L.; Hui, J.; Ye, C.; Loos, K.; Jager, J.; Folkersma, R.; Voet, V.S.D., Photopolymer resins with biobased methacrylates based on soybean oil for stereolithography. ACS Applied Polymer Materials, 2020, 2(2), 949-957Kutner, N.; Kunduru, K.R.; Rizik, L.; Farah, S., Recent advances for improving functionality, biocompatibility, and longevity of implantable medical devices and deliverable drug delivery systems, Adv. Funct. Mater., 2021, 31(44), 2010929Lehmann, S.V.; Hoeck, U.; Breinholdt, J.; Olsen, C.E.; Kreilgaard, B., Characterization and chemistry of imidazolidinyl urea and diazolidinyl urea. Contact Dermatitis, 2006, 54(1), 50-58Llabres, C.M.; Ahearn, D.G., Antimicrobial activities of N-chloramines and diazolidinyl urea, Appl. Environ. Microbiol., 1985, 49(2), 370-373Wang, R.; Chen, X.; Yang, Y.; Xu, Y.; Zhang, Q.; Zhang, Y.; Cheng, Y., Imidazolidinyl urea reinforced polyacrylamide hydrogels through the formation of multiple hydrogen bonds. React. Funct. Polym., 2022, 172, 105183Yang, Y.; Zhao, X.; Yu, J.; Chen, X.; Chen, X.; Cui, C.; Zhang, J.; Zhang, Q,; Zhang, Y.; Wang, S.; Cheng, Y., H-bonding supramolecular hydrogels with promising mechanical strength and shape memory properties for postoperative antiadhesion application, ACS Appl. Mater. Interfaces, 2020, 12(30), 34161-34169Yang, Y.; Zhao, X.; Yu, J.; Chen, X.; Wang, R.; Zhang, M.; Zhang, Q.; Zhang, Y.; Wang, S.; Cheng, Y., Bioactive skin-mimicking hydrogel band-aids for diabetic wound healing and infectious skin incision treatment. Bioactive Materials, 2021, 6, 3962-3975

Claims

CLAIMS1. A polymeric chain of formula I:whereinX each independently is an imidazolidinyl urea of formula Xi or X2:Ri each independently is (Ci-C3)alkyl, preferably methyl, or H;R2, R3and R4each independently is H, -C(O)-CH=CH2, or -C(O)-C(CH3)=CH2; and n is an integer of at least 3, wherein said polymeric chain is optionally crosslinked to at least one additional such polymeric chain via one or more vinyl groups of the X groups thereof.

2. The polymeric chain of claim 1, wherein said imidazolidinyl urea is a group of the formula Xi, wherein R2and R4each is H; and R3each independently is H, -C(O)-CH=CH2or -C(O)-C(CH3)=CH2.

3. The polymeric chain of claim 2, wherein said imidazolidinyl urea is a group of the formula Xi, wherein R2, R3and R4each is H.

4. The polymeric chain of claim 2, wherein said imidazolidinyl urea is a group of the formula Xi, wherein R2 and R4 each is H; and R3 is -C(0)-CH=CH2 or -C(O)-C(CH3)=CH2.

5. The polymeric chain of claim 2, wherein the ratio between said imidazolidinyl urea of the formula Xi wherein R3 is H, and said imidazolidinyl urea of the formula Xi wherein R3is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2, is from about 1:100 to about 100:1.

6. The polymeric chain of claim 5, wherein the ratio between said imidazolidinyl urea of the formula Xi wherein R3 is H, and said imidazolidinyl urea of the formula Xi wherein R3is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2, is about 1:1.

7. The polymeric chain of any one of claims 1-6, wherein at least one of the nitrogen atoms in the groups X is alkylated or dialkylated, thereby forming a tertiary amine or quaternary ammonium group; and / or at least one said nitrogen atoms is halogenated, thereby forming a N-halogen bond.

8. The polymeric chain of claim 7, wherein at least one of the nitrogen atoms in the groups X is alkylated or dialkylated; and at least one of said nitrogen atoms is halogenated.

9. The polymeric chain of any one of claims 1-8, wherein the hydrogen atom of (i) at least one of the -NH- groups in the groups X; or (ii) at least one of the -OH groups, when present, in the groups X, is substituted with a drug covalently linked to the nitrogen atom of said -NH- group or to the oxygen atom of said -OH group; or said drug is non-covalently linked to said nitrogen or oxygen atom.

10. The polymeric chain of any one of claims 1-9, for use as an antimicrobial; a bioactive material for wound healing or for prevention of wound infections; a scaffold for tissue regeneration; an antimicrobial ingredient in cosmetics; a preservative material; a material for fabrication of a medical device or implant; or for removing heavy metals.

11. A process for the preparation of a polymeric chain according to any one of claims 1- 6, comprising reacting imidazolidinyl urea monomers each of formula II:wherein R2, R3, R4 and R5 each independently is H, -C(0)-CH=CH2, or -C(O)- C(CH3)=CH2, provided that at least one of R2, R3, R4 and R5 is not H, in a solvent, optionally in the presence of a photoinitiator and optionally a photoinhibitor.

12. The process of claim 11, wherein said imidazolidinyl urea monomers each is a group of the formula II, wherein R2, Rs, and one of R3 and R4, each is H; and the other one of R3 and R4is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2.

13. The process of claim 11, wherein said imidazolidinyl urea monomers each is a group of the formula II, wherein R2 and Rs each is H; and R3 and R4 each independently is -C(O)- CH=CH2or -C(O)-C(CH3)=CH2.

14. The process of claim 11, wherein said imidazolidinyl urea monomers each is a group of the formula II, wherein R2 and Rs each is H; and either (i) R3 is H, and R4 is -C(O)- CH=CH2or -C(O)-C(CH3)=CH2; or (ii) R3and R4each independently is -C(O)-CH=CH2or -C(O)-C(CH3)=CH2.

15. The process of claim 14, wherein the weight ratio between said imidazolidinyl urea monomers wherein R3 is H, and said imidazolidinyl urea monomers wherein R3 and R4 each independently is -C(0)-CH=CH2 or -C(O)-C(CH3)=CH2, is from about 1:100 to about 100:1.

16. The process of claim 15, wherein the weight ratio between said imidazolidinyl urea monomers wherein R3 is H, and said imidazolidinyl urea monomers wherein R3 and R4 each independently is -C(O)-CH=CH2 or -C(O)-C(CH3)=CH2, is about 1:1.

17. The process of any one of claims 11-16, wherein said imidazolidinyl urea monomers are reacted in the presence of said photoinitiator and optionally said photoinhibitor.

18. The process of claim 17, wherein said photoinitiator is a type 1 photoinitiator such as diphenyl (2,4,6-trimethylbenzoyl)-phosphine oxide (TPO), benzoyl peroxide (BPO), lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), 2-oxoglutaric acid, riboflavin (vitamin B2), phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO), and oligo[2-hydroxy-2- methyl-l-[4-(l-methylvinyl)phenyl] propanone] (Irgacure 2959).

19. The process of claim 17 or 18, wherein the weight of said photoinitiator constitutes up to about 10%, preferably from about 0.1% to about 6%, of the overall weight of said monomers, said photoinitiator, and said photoinhibitor when present.

20. The process of any one of claims 11-19, wherein said photoinhibitor is selected from vitamin E, hydroquinone, hydroxy quinone, 2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO), tetraethylthiuram disulfide (TETD), and bis[2-(o-chlorophenyl)-4,5- diphenylimidazole] .

21. The process of any one of claim 17-20, wherein the weight of said photoinhibitor constitutes up to about 5%, preferably up to 2%, of the overall weight of said monomers, said photoinitiator, and said photoinhibitor.

22. The process of any one of claims 11-21, wherein the polymeric chain obtained is then alkylated and / or halogenated, thereby forming at least one tertiary amine or quaternary ammonium group, and / or at least one N-halogen bond.

23. The process of claim 22, wherein the polymeric chain obtained is then both alkylated and halogenated.

24. The process of any one of claims 11-23, wherein the polymeric chain obtained is then reacted or complexed with a drug molecule, thereby either covalently linking said drug molecule to a nitrogen atom or oxygen atom of said polymeric chain, by substituting an - NH- or -OH group in said polymeric chain; or non-covalently linking said drug to said nitrogen atom or oxygen atom.

25. A photocurable resin comprising:(i) polymeric chains each of formula I:wherein X each independently is an imidazolidinyl urea of formula Xi or X2:(ii) imidazolidinyl urea monomers each of formula II:wherein:Ri each independently is (Ci-C3)alkyl, preferably methyl, or H;R2, R3, R4, and R5each independently is H, -C(O)-CH=CH2, or -C(O)-C(CH3)=CH2, provided that at least one of R2, R3, R4, and R5when present, is not H; and n is an integer of at least 2, in a solvent, optionally comprising a photoinitiator and optionally a photoinhibitor.

26. A product made by 3-dimensional (3D) printing of a photocurable resin of claim 25.

27. The product of claim 26, wherein said product is a medical device such as an implant, scaffold, wound healing patch, or catheter.

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