Biodegradable polymers and uses thereof

Abstract

Provided herein is a composition comprising a polyacrylate crosslinked by a plurality of hydrolysable crosslinkers. Further, use of the composition for manufacturing of tissue markers detectable by X-ray, US and / or MRI is also provided.

Description

BIODEGRADABLE POLYMERS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of IL Patent Application No.318591 filed January 23, 2025. The contents of the above application are all incorporated by reference as if fully set forth herein in its entirety.FIELD OF THE INVENTION

[0002] The present invention, in some embodiments thereof, relates to biodegradable polymers, preparation and uses thereof as tissue markers.BACKGROUND OF THE INVENTION

[0003] Breast cancer is a major public health problem. It accounts for almost 30% of all female cancers. In 2020, it was the most frequently diagnosed women's cancer in the world, with an incidence of more than 2.26 million, or 11.7% of all cancer cases; it was responsible for more than 680,000 deaths.

[0004] When an anomaly / lesion is discovered during breast examination (mammography), several examinations must be carried out to complete the diagnostic work-up. Currently, the most common procedure for characterizing and classifying cancer and establishing its prognosis is a tissue biopsy. It is the anatomopathological examination of the tissue taken from the site of the abnormality that establishes the diagnosis of breast cancer. In the case of small lesions, a small 3 to 5 mm tissue marker called a ‘clip’ is placed on the site of the biopsy. The clips, which are generally made of titanium, stainless steel or nitinol (an alloy of nickel and titanium) or other non-degradable / nonabsorbable material, are used to mark the location of the biopsy or an area of pathological interest. The clip is commonly visualized by mammography (X-ray), ultrasound (US) and / or magnetic resonance imaging (MRI). If the surgeon needs to return to the biopsy site, the implanted clips serve as a marker and help to easily relocate the suspicious mass or the region in which it was located.

[0005] The visibility of biopsy markers under imaging is essential for the assessment of breast lesions. These markers are particularly useful in the follow-up of lesions that have not been confirmed as malignant. Women with multiple solid lesions are often followed up for months, and the clips (placed at the time of biopsy) can clearly indicate which lesions have been removed, avoiding the need for repeated biopsies (follow-up in other institutions, or different imaging modality).

[0006] The first markers developed were intended for mammography. They remain the most commonly used today and are all based on the same principle: they are radiopaque metallic markers, 3-5 mm in size, primarily composed of titanium or stainless steel.

[0007] In 80% of cases, the biopsy reveals a benign tumor, and follow-up is recommended for a period ranging from 6 months to 2 years. However, after this period, the clip remains permanently in place.

[0008] Therefore, there is a need for degradable materials (biomarkers) with controlled degradation time and which can be detected by X-Ray (and optionally by at least one of: MRI and US) inside the patients organism during the entire lifetime of the biomarker.SUMMARY OF THE INVENTION

[0009] In one aspect of the invention, there is provided a composition comprising a polyacrylate crosslinked by a plurality of crosslinkers; wherein:the polyacrylate comprises a first plurality of repeating units each independently represented by Formula 1 :, wherein R1 is H or comprises an optionally substituted alkyl, X comprises any one of O, S, NR’ and a linker; A comprises an aryl or a heteroaryl; and R2 represents at least one substituent comprising halo, or haloalkyl, and optionally at least one second substituent;each of said plurality of crosslinkers comprises an oligomer; andsaid oligomer comprises a plurality of oligomer units covalently bound to each other via a hydrolysable bond.

[0010] In one embodiment, the polyacrylate further comprises a second plurality of repeating units each independently represented by Formula 2:, wherein R1 is H or comprises an optionally substituted alkyl; X comprises any one of O, S, NR’ and the linker; and wherein R3 is absent or represents H or comprises an optionally substituted alkyl, alkoxy, alkylamine, mercaptoalkyl, a hydrophilic oligomer or an active agent.

[0011] In one embodiment, the hydrolysable bond is selected from ester, anhydride, thioester, ortho ester, carbonate and amide.

[0012] In one embodiment, the oligomer is characterized by an average Mw between 500 and 20000Da.

[0013] In one embodiment, the polyacrylate is in a form of a matrix comprising a plurality of polyacrylate chains; and wherein at least two of said polyacrylate chains within said matrix are crosslinked via at least two of said crosslinkers.

[0014] In one embodiment, each of said plurality of crosslinkers further comprises at least 2 attachment points to said at least two chains.

[0015] In one embodiment, each of the at least 2 attachment points is represented by Formula 3:, wherein R1 is independently H or comprises an optionally substituted alkyl, X is absent or comprises any one of: O, S, NR’, the linker and -O-linker-, and the dashed bond represent a bond to the plurality of oligomer units.

[0016] In one embodiment, the plurality of polymeric chains is characterized by an average Mw between 1000 and 50000Da.

[0017] In one embodiment, a mole portion of said plurality of crosslinkers relative to the polyacrylate chains is between 0.5 and 30mol%.

[0018] In one embodiment, the second plurality of repeating units each independently represented by Formula 2; and wherein a molar ratio between the first plurality of repeating units and the second plurality of repeating units is between 1:10 and 1:1.

[0019] In one embodiment, the hydrophilic oligomer comprises [C1-C10 alkyl-X]n, [C1-C10 heteroalkyl-X]n and A-Y-A; wherein each n is between 1 and 20, X is selected from O, S and NR’; each A is independently selected from [Cl -CIO heteroalkyl-X]n and [Cl -CIO alkyl -X]n, and Y is absent or is independently from -O-, -S-, -NR’-, -C(=O)-, -C(=NR’)-, -C(=S)-, -CONR’-, -C(NR’)NR’-, -C(NR’)O-, -C(NR’)S-, -S-S-, -S-C(=O), -CNNR’-, -CSNR’-, -NR’C(=O)O-, -NR’C(=S)O-, -NR’C(=S)NR’-, -SO2-, -SO-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)NR’-; and wherein each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted Cl -CIO alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof.

[0020] In one embodiment, the linker comprises an optionally substituted alkyl, [Cl-C10 alkyl-X]n, -O-, -S-, -NR’-, Y, or an optionally substituted alkyl -Y; wherein Y is selected from -O-, -S-, -NR’-, -C(=O)-, -C(=NR’)-, -C(=S)-, -CONR’-, -C(NR’)NR’-, -C(NR’)O-, -C(NR’)S-, -S-S-, -S-C(=O), -CNNR’-, -CSNR’-, -NR’C(=O)O-, -NR’C(=S)O-, -NR’C(=S)NR’-, -SO2-, -SO-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)NR’-.

[0021] In one embodiment, the second substituent comprises one or more substituents each independently selected from alkyl, -NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate, phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6alkyl), Ci-C6mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; and wherein X of Formulae 1, 2 and 3 is O.

[0022] In one embodiment, the oligomer is represented by Formula 4:, wherein:each n is an integer ranging between 0 and 10;m is an integer ranging between 0 and 5;each R is independently hydrogen, is absent or represents one or more substituents selected from: -OH, halogen, oxo, carbonyl, amino, imino, thioxo, phosphate, phosphonate, phosphine, phosphite, OR’, -NO2, -CN, -CONH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, - SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R’, -OCOR, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or any combination thereof;each Z is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, Y, [Cl -CIO alkyl -X]n, or any combination thereof; and each A is an ester oligomer.

[0023] In one embodiment, the ester oligomer comprises a plurality of C1-C10 alkylester monomers; and wherein each A is bound to said polyacrylate via the attachment point.

[0024] In one embodiment, the plurality of Cl -CIO alkyl -ester monomers is between 2 and 20 monomers, and wherein the attachment point is of Formula 3.

[0025] In one embodiment, each of the plurality of Cl -CIO alkyl-ester monomers comprises any one of caprolactone monomer, glycolate monomer, lactate monomer and hydroxyalkanoate monomer.

[0026] In one embodiment, at least one of:-said oligomer is selected fromand m is between 1 and 10; and wherein each * represents the attachment point;-said second plurality of repeating units comprises-said first plurality of repeating units comprises

[0027] In another aspect, there is provided an article comprising the composition of the invention.

[0028] In one embodiment, the article further comprises (i) a contrast agent selected from MRI, CT and US contrast agent, (ii) a therapeutically active agent, or both (i) and (ii).

[0029] In one embodiment, the article further comprises a hydrogel coating.

[0030] In one embodiment, the article is a tissue marker.

[0031] In one embodiment, the tissue marker is for implanting into a tissue a subject, and wherein said tissue marker is stable within said tissue for a time period of at least 2 m.

[0032] In one embodiment, the article is detectable within the subject by X-ray, and optionally by US, MRI or both.BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is an EDX spectrum showing distribution of iodine in an exemplary polymeric material sample (Table 1, #6). Iodine atom signal is presented in blue, oxygen atom signal is presented in pink, and carbon atom signal is presented in black.

[0034] Figures 2A-2B are SEM image and surface roughness analysis of the sample, respectively. The surface roughness profile is determined along the red line shown in Figure 2A.

[0035] Figure 3 is aFTIR spectrum of an exemplary polymeric material with 15 mol% of the crosslinker.

[0036] Figure 4 is an X-ray image of exemplary polymeric material samples implanted into pig’s tissue. The image presents various polymeric material samples with a concentration of the crosslinker ranging between 5 and 20mol%.

[0037] Figures 5A-5F are US images in a live rat showing exemplary polymeric material samples (markers 1-3) implanted subcutaneously at day 1 (5A-5C) and at day 15 (5D-5F) after implantation.

[0038] Figure 6 is an X-ray post-mortem image of a rat with the implanted markers (1-2 in the upper dorsal region and 3 in the lower dorsal region).DETAILED DESCRIPTION OF THE INVENTION

[0039] In one aspect, there is provided a polymeric material comprising a polyacrylate crosslinked by a plurality of crosslinkers; wherein the polyacrylate comprises a first plurality of repeating units each independently represented by Formula 1 :wherein R1 is H or comprises an optionally substituted alkyl, X comprises any one of O, S, NR’ and a linker; A comprises an aryl or a heteroaryl; and R2 represents at least one substituent comprising halo, or haloalkyl, and optionally at least one second substituent; each of the plurality of crosslinkers comprises an oligomer; and the oligomer comprises a plurality of oligomer units covalently bound to each othervia a hydrolysable bond. In some embodiments, R2 represents 1, 2, 3, 4, or 5 substituents, each of the substituent(s) is independently as described herein.

[0040] In some embodiments, the second substituent comprises one or more substituents each independently selected from alkyl, -NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate, phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -C0NH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=0)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl -SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6alkyl), Ci-Ce mercaptoalkyl, -CONH(Ci-Ce alkyl), -CON(Ci-Ce alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkylheteroaryl or a combination thereof; and wherein each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted Cl -CIO alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof.

[0041] In some embodiments, the linker comprises any moiety being a spacer between the carbonyl and A. The linker may be linear or branched and is between 1 and 100 single C-C bonds long. In some embodiments, the linker is between 1 and 30, between 1 and 100, between 1 and 10, between 1 and 50, between 1 and 70, between 1 and 30, between 1 and 20, between 1 and 5, between 5 and 10, between 5 and 15, between 5 and 25 single C-C bonds long, including any range in between. In some embodiments, the linker is characterized by a molecular weight between 30 and 10,000Da, between 30 and 5,000Da, between 30 and l,000Da, between 100 and l,500Da, between 300 and l,000Da, between 300 and 5,000Da, between 300 and 2000, between 300 and 3,000Da, between 300 and 10,000Da, including any range in between.

[0042] In some embodiments, the linker is or comprises an optionally substituted alkyl, [Cl -CIO alkyl-X]n, -O-, -S-, -NR’-, Y, or an optionally substituted alkyl -Y; wherein Y is selected from -O-, -S-, -NR’-, -C(=O)-, -C(=NR’)-, -C(=S)-, -CONR’-, -C(NR’)NR’-, -C(NR’)O-, -C(NR’)S-, -S-S-, -S-C(=O), -CNNR’-, -CSNR’-, -NR’C(=O)O-, -NR’C(=S)O-, -NR’C(=S)NR’-, -SO2-, -SO-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)NR’.

[0043] In some embodiments, the first plurality of repeating units comprises X-ray contrast agent. In some embodiments, the first plurality of repeating units each independently represented by Formula 1, wherein A and R2 are absent and X is further covalently bound to an X-ray contrast agent.

[0044] Examples of X-ray contrast agents include but are not limited to: Iodinated Contrast Agents (e.g. lohexol (Omnipaque), lopamidol (Isovue), lodixanol (Visipaque)); a transition metal complex, such as Barium complex and Gadolinium-complex (e.g. Gd-complex with a chelating agent such as DOTA or any other carboxybased chelating agent) or a transition metal / transition metal oxide) nanoparticle.

[0045] Examples of transition metal complexes / transition metal nanoparticles suitable as X-ray contrast agents include: Ba- sulfate complex (e.g. Ba / BaSO4-complex with a chelating agent such as DTP A, EDTA or any other carboxy-based chelating agent), gadolinium complex (Gd-DTPA, Gd-DOTA, Gadolinium -HP -DO3 A (Gadoteridol), Gadolinium-BOPTA (Gadobenate dimeglumine), Gadolinium-DTPA-BMA (Gadodiamide)), iron oxide nanoparticle (such as SPION). A metal nanoparticle (e.g. SPION) may be bound to X directly or via a linker, wherein the metal nanoparticle comprises a shell comprising chemical groups configured to form a covalent bond (such as hydroxy, amino, thiol, carboxy, or any of the substituents listed herein).

[0046] Additional transition metal complexes / transition metal nanoparticles may include any one of the following metals: Pt, Au, Ta, Bi, La, Y, Zr, Yb, Hf, W, and Re, including any combination and any oxide thereof.

[0047] In some embodiments, R2 represents two or more substituents, each independently comprising halo. In some embodiments, R2 represents two or more iodo substituents.

[0048] In some embodiments, R1 is H. In some embodiments, X is O. In some embodiments, R1 is H, X is O and R2 represents two, three or more iodo substituents.

[0049] In some embodiments, the first plurality of repeating units is or comprises

[0050] In some embodiments, the (i) polymeric material and / or (ii) the plurality of crosslinkers are degradable. In some embodiments, (i) and / or (ii) are at least partially biodegradable. In some embodiments, (i) and / or (ii) biocompatible. In some embodiments, (i) and / or (ii) are substantially biodegradable after a predetermined time period inside patient’s organism.

[0051] As used herein, the term “biocompatible” refers to a material which the skilled practitioner would expect the body to generally accept without significant toxicity, immune response and / or rejection, or excessive fibrosis. In some embodiments, a moderate degree of immune response and / or fibrosis may optionally be acceptable or desired.

[0052] As used herein, the term "biodegradable", is intended to describe materials comprising covalent bonds that are degraded in vivo, wherein the degradation of the covalent bond occurs via hydrolysis. The hydrolysis can involve a direct reaction with an aqueous medium or can be catalyzed chemically or enzymatically. "Aqueous medium" refers to water, aqueous solutions, physiological media or biological fluids (e.g., body fluids), and other pharmaceutically acceptable media. The term “biodegradable” as used in the context of the present invention, also encompasses the term “bioresorbable”, which describes a substance that decomposes under physiological conditions to break down to products that undergo bioresorption into the host-organism, namely, become metabolites of the biochemical systems of the host-organism.

[0053] The biodegradable polymeric material in context of the invention, encompasses inter alia in-vivo cleavage of the hydrolysable bonds (via a chemical and / or enzymatic reaction) and subsequent release of the corresponding polyacrylate, which is expected to be fully soluble in a biological liquid and may be removed from the patient’ s organism via kidney and / or liver secretion pathway.

[0054] In some embodiments, the polyacrylate comprise a plurality of polyacrylate chains; and wherein at least two of the polyacrylate chains are crosslinked via the crosslinkers disclosed herein. In some embodiments, each of the plurality of polyacrylate chains is a copolymer. In some embodiments, each of the plurality of polyacrylate chains is selected from a block-co-polymer, a random co-polymer and an alternating copolymer.

[0055] In some embodiments, each of the plurality of polyacrylate chains comprises a first plurality of repeating units and further comprises a second plurality of repeating units each independently represented by Formula 2:, wherein R1 is H or comprises an optionally substituted alkyl; X comprises any one of O, S, NR’ and the linker; and wherein R3 is absent or represents H or comprises an optionally substituted alkyl, alkoxy, alkylamine, mercaptoalkyl, a hydrophilic oligomer or an active agent.

[0056] The term “active agent” encompasses inter alia a therapeutic agent or a contrast agent (e.g. a fluorophore, an MRI contrast agent, etc.).

[0057] The therapeutic agent may be a macro-biomolecule (for example, protein, peptide, nucleic acid, etc.) or a small molecule therapeutics (i.e. small molecules with a molecular weight ranging between 100 and 1000 g / mol). The active agent may be of natural or synthetic origin.

[0058] Examples of therapeutically active agents may include antiproliferative drugs, including paclitaxel, sirolimus (rapamycin), farnesylthiosalicylate (FTS, salirasib), fluoro-FTS, everolimus, zotarolimus, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, anthracycline, mitomycin C, mitomycin A, 9-amino camptothecin, aminopertin, antinomy cin, N8-acetyl spermidine, l-(2-chloroethyl)-l,2-dimethanesulfonyl hydrazine, bleomycin, tallysomucin, etoposide, camptothecin, irinotecan, topotecan, 9-amino camptothecin, paclitaxel, docetaxel, esperamycin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-one, anguidine, morpholinodoxorubicin, vincristine, vinblastine and derivatives thereof.

[0059] Additional therapeutically active agents may include antibiotic agents. Nonlimiting examples of suitable antibiotic agents include gentamicin, ceftazidime, mafenide benzoyl peroxide, octopirox, erythromycin, zinc, silver, tetracyclin, triclosan, azelaic acid and its derivatives, phenoxyethanol and phenoxypropanol, ethyl acetate, clindamycin and meclocycline; sebostats such as flavinoids; alpha and beta hydroxy acids; polydiallyldimethylammonium chloride and bile salts such as scymnol sulfate and its derivatives, deoxycholate and cholate.

[0060] Additional therapeutically active agents may include analgesic agents, anaesthetic agents, pain-killers, pain-reducers and the like (including NSAIDs, such asIbuprofen; COX-2 inhibitors, K+ channel openers, opiates and morphinomimetics); and hemostatic agents and antihemorrhagic agents. Additional therapeutically active agents may include anti -angiogenic agents, such as bevacizumab, sunitinib, sorafenib, pazopanib, and thalidomide.

[0061] In some embodiments, the polymeric material is in a form of a matrix. In some embodiments, the polyacrylate is in a form of a matrix.

[0062] The term "matrix" refers to a continuous 3 -dimensional structure formed by the cross-linked polyacrylate chains. The crosslinking degree (mol% ratio of the crosslinkers) of the polyacrylate chains predetermines physical properties of the polymeric material (e.g. biodegradation rate, density and / or mechanical properties, such as modulus, tensile strength etc.).

[0063] In some embodiments, the hydrophilic oligomer comprises [C1-C10 alkyl-X]n, [C1-C10 heteroalkyl-X]n and A-Y-A; wherein each n is between 1 and 20, X is selected from O, S and NR’; each A is independently selected from [Cl -CIO heteroalkyl-X]n and [Cl -CIO alkyl -X]n, and Y is absent or is independently from -O-, -S-, -NR’-, -C(=O)-, -C(=NR’)-, -C(=S)-, -CONR’-, -C(NR’)NR’-, -C(NR’)O-, -C(NR’)S-, -S-S-, -S-C(=O), -CNNR’-, -CSNR’-, -NR’C(=O)O-, -NR’C(=S)O-, -NR’C(=S)NR’-, -SO2-, -SO-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)NR’-.

[0064] In some embodiments, the second plurality of repeating units is represented by Formula 2, wherein R1 is H. In some embodiments, the second plurality of repeating units is represented by Formula 2, wherein X is O. In some embodiments, the second plurality of repeating units is represented by Formula 2, wherein R1 is H and X is O. In some embodiments, the second plurality of repeating units is represented by Formula 2, wherein R1 is H and X is O; and wherein R3 is H, or the hydrophilic oligomer (e.g. [Cl-C10 alkyl-X]n, or PEG-oligomer). In some embodiments, the second plurality of repeating units is represented by Formula 2, wherein R1 is H and X is O; and wherein R3 is the active agent (i.e., a small molecule therapeutic agent).

[0065] In some embodiments, the second plurality of repeating units is or comprises:

[0066] In some embodiments, the polyacrylate chains within the polyacrylate are characterized by an average Mw below 40000Da, below 35000 Da, below 30000 Da,between 1000 and 50000Da, between 1000 and 40000Da, between 1000 and 35000Da, between 1000 and 30000Da, between 5000 and 30000Da, between 5000 and 25000Da, between 5000 and 20000Da, between 10000 and 30000Da, between 20000 and 25000Da, between 15000 and 25000Da, between 15000 and 30000Da, including any range between. The average Mw can be determined based on GPC or viscosity based.

[0067] In some embodiments, the polyacrylate chains are water-soluble (e.g. having water solubility of at least O.lg / L, at least Ig / L, at least lOg / L or at least 20g / L at a temperature 40°C).

[0068] In some embodiments, a mole portion of the plurality of crosslinkers relative to the polyacrylate chains within the polyacrylate of the invention is between 0.5 and 30mol%, between 1 and 30mol%, between 1 and 25mol%, between 1 and 20mol%, between 1 and 10mol%, between 0.5 and 10mol%, between 0.5 and 15mol%, between 1 and 15mol%, between 0.5 and 7mol%, between 0.5 and 8mol%, between 1 and 7mol%, between 2 and 10mol%, between 2 and 20mol%, between 3 and 30mol%, between 3 and 20mol%, between 3 and 25mol%, between 3 and 10mol%, between 3 and 15mol%, between 3 and 8mol%, between 4 and 10mol%, between 4 and 15mol%, between 4 and 20mol%, including any range between.

[0069] In some embodiments, a molar ratio between the first plurality of repeating units and the second plurality of repeating units within the polyacrylate chain is between 1:10 and 1:1, between 1 : 1 and 1:5, between 1 : 1 and 1 :3, between 1:1.5 and 1 :3, between 1:1.5 and 1:4, between 1:1.5 and 1:5, including any range between.

[0070] In some embodiments, a mole portion of the first plurality of repeating units relative to a combined ratio of the 1stand 2ndplurality of repeating units in the polyacrylate chain is between 5 and 40%, between 5 and 30%, between 5 and 25%, between 10 and 20% including any range between.

[0071] In some embodiments, a mole portion of the second plurality of repeating units relative to a combined ratio of the 1stand 2ndplurality of repeating units in the polyacrylate chain is between 50 and 90%, between 50 and 80%, between 60 and 90%, between 70 and 90% including any range between.

[0072] In some embodiments, each of the plurality of crosslinkers consists essentially of the oligomer disclosed herein. In some embodiments, the oligomer is or comprises a biodegradable material. In some embodiments, the oligomer comprises at least one degradable segment comprising a plurality of repeating units attached to each other via a hydrolysable bond. In some embodiments, the oligomer comprises or consistsessentially of between 2 and 30, between 2 and 20, between 2 and 15, between 4 and 20, between 5 and 20, between 7 and 20, between 10 and 30, between 10 and 20 repeating units, including any range between.

[0073] In some embodiments, the oligomer consists essentially of the degradable segment. In some embodiments, the oligomer comprises or consists essentially of at least two degradable segments, wherein the at least two degradable segments are joined together via a covalent bond (which is not the hydrolysable bond), a functional group (such as a Y, disclosed hereinbelow) or via a linker.

[0074] In some embodiments, the oligomer is a linear or a branched oligomer.

[0075] As used herein, the term “branched oligomer” is related to any of: a star oligomer, a dendrimer, a graft oligomer, and a hyperbranched oligomer or any combination thereof. The term “star oligomer” is well-known in the art and refers to a multi-arm oligomer, wherein each arm is or comprises the degradable segment and wherein the arms are covalently linked to a core. The core may be a branched core or a star-shaped core comprising a plurality of branches, wherein each of the plurality of branches is linked to the degradable segment. The core may comprise between 2 and 10, between 2 and 4, between 4 and 6, between 6 and 8, between 8 and 10 branches including any range therebetween. Non-limiting examples of cores include but are not limited to: pentaerythritol-, dipentaerythritol-, tripentaerythritol- and calyx[8]arene-based core. In some embodiments, the branched oligomer comprises or consists of between 2 and 10, between 3 and 10, between 3 and 5, between 5 and 7, between 7 and 8, or between 8 and 10 arms, including any range between.

[0076] In some embodiments, the oligomer is a homo-oligomer. In some embodiments, the oligomer is a co-oligomer comprising at least two chemically distinct repeating units. In some embodiments, the co-oligomer is selected from the group consisting of: block-, alternating-, periodic-, and random- co-oligomer.

[0077] In some embodiments, each of the degradable segment(s) in the oligomer is a homo-oligomer or a co-oligomer.

[0078] In some embodiments, the degradable segment(s) is / are fully biodegradable. In some embodiments, the degradable segment(s) is / are fully biocompatible. In some embodiments, the degradable segment(s) is / are biodegradable and biocompatible.

[0079] In some embodiments, the plurality of crosslinkers are characterized by an average molecular weight of between 500 and 20000Da, from 1000 Da to 10,000 Da, from 1000 Da to 2,000 Da, from 2000 Da to 5000 Da, from 5000 Da to 7000 Da, from7000 Da to 10,000 Da, from 2000 Da to 3000 Da, from 3000 Da to 4000 Da, from 4000 Da to 5000 Da, from 5000 Da to 6000 Da, from 6000 Da to 9000 Da, including any range or value therebetween.

[0080] The term “average molecular weight” encompasses weight average molecular weight (Mw) or number average molecular weight (Mn). As used herein, the term "weight average molecular weight" generally refers to a molecular weight measurement that depends on the contributions of oligomer molecules according to their sizes. As used herein, the term "number average molecular weight" generally refers to a molecular weight measurement that is calculated by dividing the total weight of all the oligomer molecules in a sample with the total number of oligomer molecules in the sample. These terms are known by those of ordinary skill in the art. The average molecular weight is determined by Gel permeation chromatography (GPC) or by MALDI.

[0081] In some embodiments, the plurality of crosslinkers are further characterized by a dispersity index (D) between 1.01 and 2, between 1.01 and 1.6, including any range between. As used herein, “dispersity index”, also termed in the art: "poly dispersity index" (denoted hereinthroughout as: “D”) refers to a measure of the distribution of molecular mass in a given oligomer sample. The dispersity index is calculated by dividing Mw by Mn and can be measured by GPC.

[0082] In some embodiments, the hydrolysable bond is selected from ester, anhydride, thioester, ortho ester, carbonate and amide. In some embodiments, the hydrolysable bond is ester.

[0083] In some embodiments, each of the plurality of crosslinkers is attached to the one or more polyacrylate chain. In some embodiments, each of the plurality of crosslinkers is attached to one or more polyacrylate chain via at least 2 attachment points. In some embodiments, each of the plurality of crosslinkers is attached to two or more of the polyacrylate chains via at least 2 attachment points.

[0084] In some embodiments, the polyacrylate chain attachment point to the crosslinker is represented by Formula 3:, wherein R1 is independently H or comprises an optionally substituted alkyl, X is absent or comprises any one of: O, S, NR’, the linker and -O-linker-, and the dashed bond represent a bond to the oligomer (or to at least one degradable segment of the oligomer).

[0085] Non-limiting examples of biodegradable oligomer include but are not limited to: ester oligomer (such as oligo-glycolide, oligo-lactate, oligo-caprolactone, oligohydroxybutyrate, oligo-hydroxyvalerate, oligo-dioxanone), oligo-orthoester, oligophosphoester, and oligo-amides (e.g. oligo-amino acids) including any co-oligomer or any combination thereof.

[0086] In some embodiments, the ester oligomer is or comprises any one of oligo-glycolide, oligo-lactide, oligo-caprolactone, oligo-hydroxyalkanoate, oligohydroxybutyrate, oligo-ethylene adipate, oligo-butylene succinate, oligo- (3-hydroxybutyrate-co-3 -hydroxy valerate), oligo-ethylene terephthalate, oligo-butylene terephthalate, including any co-oligomer or any combination thereof.

[0087] In some embodiments, the degradable segment(s) and / or the oligomer comprises or consists essentially of ester oligomer(s). In some embodiments, the ester oligomer comprises a plurality of Cl -CIO alkyl-ester monomers (also used herein as “repeating units”).

[0088] In some embodiments, the repeating unit or Cl -CIO alkyl-ester monomer is of Formula 5: -O-[Cl-C10 alkyl]-C(=O)-, wherein the C1-C10 alkyl is a linear, cyclic, or branched alkyl. In some embodiments, the C1-C10 alkyl is a C2-10 alkyl optionally comprising a substituent or a functional moiety Y within the alkyl backbone.

[0089] In some embodiments, the C1-C10 alkyl is a Cl-C3alkyl. In some embodiments, the Cl -CIO alkyl is a Cl-C6alkyl. In some embodiments, the Cl -CIO alkyl is a Cl-C5alkyl. In some embodiments, the C1-C10 alkyl is a Cl-C2alkyl. In some embodiments, the repeating unit or Cl -CIO alkyl-ester monomer is an alpha-hydroxy carboxylic acid-based repeating unit having the -O- residue in alpha position to C(=O).In some embodiments, the alpha-hydroxy carboxylic acid-based repeating unit is selected from oligo-glycolide and oligo-lactide.

[0090] In some embodiments, the ester oligomer is or comprises alpha-hydroxy carboxylic acid-based repeating units and wherein the mole portion of the plurality of crosslinkers relative to the polyacrylate chains within the polyacrylate of the invention is between 0.5 and 20mol%, between 0.5 and 15mol%, between 0.5 and 10mol%, between 1 and 20mol%, between 1 and 15mol%, between 1 and 10mol%, between 1 and 7mol%, between 2 and 10mol%, between 3 and 10mol%, between 3 and 7mol%, including any range between.

[0091] In some embodiments, the ester oligomer is or comprises the repeating unit of Formula 5, wherein the C1-C10 alkyl is a C3-C7alkyl, C4 alkyl, C5 alkyl or C6 alkyl and wherein the mole portion of the plurality of crosslinkers relative to the poly acrylate chains within the polyacrylate of the invention is between 0.5 and 30mol%, between 0.5 and 25mol%, between 1 and 30mol%, between 1 and 25mol%, between 2 and 30mol%, between 3 and 30mol%, between 4 and 30mol%, between 3 and 25mol%, between 3 and 20mol%, between 4 and 25mol%, including any range between.

[0092] In some embodiments, the plurality of Cl -CIO alkyl -ester monomers / repeating units is between 2 and 20, between 4 and 20, between 4 and 15, between 5 and 20, between 6 and 20, between 8 and 20, between 10 and 20 monomers / repeating units, including any range between.

[0093] In some embodiments, the C1-C10 alkyl-ester monomer comprises any one of caprolactone monomer, glycolate monomer, lactate monomer and hydroxyalkanoate monomer. In some embodiments, the oligomer or the degradable segment thereof is selected from caprolactone oligomer, glycolate oligomer, lactate oligomer and hydroxyalkanoate oligomer.

[0094] In some embodiments, the oligomer / the degradable segment consists of or comprises the plurality of Cl -CIO alkyl-ester monomers, wherein at least one of the terminal Cl -CIO alkyl-ester monomers is bound to the polyacrylate chain via the attachment point.

[0095] In some embodiments, the oligomer is represented by Formula 4:, wherein: each n is an integer ranging between 0 and 10 ; m is an integer ranging between 0 and 5; each R is independently hydrogen, is absent or represents one or more substituents selected from: -OH, halogen, oxo, carbonyl, amino, imino, thioxo, phosphate, phosphonate, phosphine, phosphite, OR’, -NO2, -CN, -CONH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R’, -OCOR, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or any combination thereof; each Z is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, Y, [Cl -CIO alkyl-X]n, or any combination thereof; and each A is an ester oligomer. In some embodiments, the ester oligomer is of Formula 5.

[0096] In some embodiments, the oligomer is represented by Formula 4, wherein each R is H. In some embodiments, the oligomer is represented by Formula 4, wherein m is 0. In some embodiments, the oligomer is represented by Formula 4, wherein m is 0, each R is H and n is between 0 and 2.

[0097] In some embodiments, the oligomer is represented by Formula 4A:, wherein A, Z, R and n are as disclosed above.

[0098] In some embodiments, the crosslinker is represented by Formula 4-4A, wherein each A is further attached to the polyacrylate chain via the attachment point. In some embodiments, the crosslinker is represented by Formula 4-4A, wherein the terminalmonomer of each A is attached to the polyacrylate chain via the attachment point of Formula 3. In some embodiments, the crosslinker is represented by Formula 4-4A, wherein the terminal monomer of each A is attached to the polyacrylate chain via the attachment point of Formula 3, and the ester oligomer is of Formula 5.

[0099] In some embodiments, the oligomer is represented by Formula 4-4A, wherein Z is Y, [C1-C10 alkyl-X]n, or Y-[Cl-C10 alkyl-X]n-Y, and wherein n is between 1 and 10. In some embodiments, the oligomer is represented by Formula 4-4A, wherein Z is O, S or NH. In some embodiments, the oligomer is represented by Formula 4-4A, wherein Z is O or PEG (e.g. comprising between 2 and 10 monomers); and wherein R is H.

[0100] In some embodiments, the oligomer is or comprises any one of:Formula 5:n is between 2 and 20, and wherein * represents the attachment point. In some embodiments, the oligomer is or comprises any of Formulae 5-5 A, wherein m is 5 and wherein n is between 2 and 10, or any of 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0101] In some embodiments, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% or between 90 and 100%, between 90 and 95%, between 90 and 99.5%, between 95 and 99.5% by dry weight of the polyacrylate consists of: (i) the first plurality of repeating units represented by Formula 1, (ii) the second plurality of repeating units being represented by Formula 2, wherein R3 is absent or is selected from H, alkyl and the hydrophilic oligomer (e.g. PEG-oligomer), (iii) a third plurality of repeating units being represented by Formula 2, wherein R3 is the active agent and (iv) the at least 2 attachment points covalently bound to at least 2 of the oligomers.

[0102] In some embodiments, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% or between80 and 100%, between 80 and 99.9%, between 80 and 99.5%, between 90 and 100%, between 90 and 95%, between 90 and 99.5%, between 95 and 99.5% by weight of the composition consists of the polyacrylate disclosed herein.

[0103] In some embodiments, the composition of the invention is characterized by a storage modulus between about 50 KPa and about 5MPa.

[0104] In some embodiments, the composition of the invention is substantially devoid of a solvent. In some embodiments, the composition of the invention comprises less than 5 0.1%, less than 0.05%, less than 0.01% w / w or less than 500 ppm, less than 100 ppm, less than 50 ppm of an organic solvent.

[0105] In some embodiments, the composition of the invention further comprises at least one additional ingredient (also referred to herein as “additive”) which imparts an additional functionality.

[0106] Except where indicated otherwise, an additional ingredient is considered herein as part of the matrix when present within the matrix, but not when present outside the matrix (e.g., on a surface or a portion of a surface of the matrix).

[0107] In some such embodiments, the additional ingredient(s) is in a form of at least one additional layer. The additional layer(s) is optionally on at least a portion of at least one surface of the polymeric matrix, and / or within the polymeric matrix.

[0108] Examples of additional functionalities which may be imparted by an additional ingredient include, without limitation, inhibition of formation of an adhesion to tissue, which may be optionally be provided by an additive characterized by reduced adhesion to tissue, and / or by an agent which inhibits cell growth; reduction of risk of infection, which may optionally be provided by an antimicrobial agent, such as an antibiotic, and / or by a film which inhibits penetration of pathogens; reduction of risk of tissue rejection and / or immune response, which may optionally be provided by an agent which modulates an immune system; and adhesion to tissue without suturing, which may optionally be provided by an adhesive (e.g., applied on a surface) and / or an agent and / or surface which promotes cell growth and / or attachment (e.g., growth factors, extracellular matrix proteins, and / or other proteins). Examples of layers which may be formed from additional ingredients which impart such functionalities include, without limitation, tissue-adhesive layers (i.e., layers characterized by enhanced adherence to cells, as compared with the core matrix without a tissue-adhesive layer), cell growthpromoting layers and anti-fouling layers (i.e., layers characterized by reduced adherence to cells, as compared with the core matrix without an anti-fouling layer).

[0109] Examples of additional ingredients which may be included in the composition-of-matter ingredient include, without limitation, adhesive materials, nonadhesive materials (e.g., materials characterize by particularly low adherence to tissue and / or other substrate), plasticizers, hydrophobic polymer particles, biological and / or bio-active materials, cellular components, growth factors and therapeutically active agents.

[0110] In some embodiments, the additional ingredient is a pharmaceutical, a diagnostic agent (e.g. US-imaging marker, MRI-imaging marker).

[0111] Examples of the pharmaceutical agents which may be used as additives include, but are not limited to anti -angiogenic agents, antibiotics, NSAIDs (Nonsteroidal Anti-Inflammatory Drugs), cytotoxics and chemotherapeutic agents.

[0112] In some embodiments, the composition of the invention is substantially homogenous. In some embodiments, the composition of the invention is substantially stable, wherein stable is refers to the ability of the composition to maintain its structural and / or functional properties (such as a biodegradability, etc.). In some embodiments, the composition of the invention retains it’s detectability via X-ray and optionally via an additional imaging techniques when located inside the patient for a time period of at least 1 month (m), at least 2m, at least 4m, at least 6m, at least 12m, at least 16m, between Im and 5y, between Im and 3y, between Im and 2y, including any range between.

[0113] In some embodiments, a stable composition maintains substantially its structure (e.g. devoid of phase separation, aggregation, etc.). In some embodiments, maintains substantially is over a time period of at least 1 day (d), at least 10 d, at least 20 d, at least 30 d, at least 50 d, at least 100 d, at least 200 d, at least 300 d, at least 1 year (y), at least 2 y, at least 3 y, including any range or value therebetween. In some embodiments, the composition is referred to as stable, if it remains structurally intact upon storage under ambient conditions (such as a temperature between 10 and 40°C and moisture content of between 0 and 10% including any value therebetween).

[0114] In some embodiments, the composition is referred to as stable, if it remains structurally intact under physiological conditions (e.g., is not degraded in vivo, and hence is non-biodegradable or non-biocleavable) for a tine period of at least 24h, 2 d, lOd, 15d, 20d, including any range or value therebetween. In some embodiments, the composition is referred to as stable, if it retains at least 80%, at least 90%, at least 95%,of its structural and or mechanical intactness under physiological conditions, for a time period as described herein.

[0115] In some embodiments, physiological conditions comprise conditions comprise any of: aqueous environment, exposure to enzymes, pH between 4 and 8, temperature between 30 and 40C, etc.). In some embodiments, physiological conditions comprises exposure to a soft tissue (e.g. breast tissue).

[0116] In some embodiments, the composition is substantially degradable in-vivo. In some embodiments, the composition is substantially degradable upon contacting thereof with a soft tissue of a subject for a time period of at least 1 month (m), at least 2m, at least 4m, at least 6m, at least 12m, at least 16m, between Im and 5y, between Im and 3y, between Im and 2y, including any range between.Use

[0117] In another aspect, there is provided an article comprising the composition of the invention. In some embodiments, the article is shaped from the composition. In some embodiments, the article comprises or consists essentially of the composition disclosed herein having a predetermined shape.

[0118] In some embodiments, the article has a predetermined 3-dimensional shape. In some embodiments, the article has at least one dimension ranging between 2 mm and 10cm.

[0119] The shape of the article may vary. It can be in the shape of a rod, a spring, a sheet. The rod may be linear, coiled, in the shape of a “O”, a "U", an "X", an "S", etc. The shape can be a closed shape or have holes or opening(s) along its walls. The article may have a hollow shape. The surface of the article can be smooth or have grooves of varying depths to form edges.

[0120] In some embodiments, the article is a layered article, comprising the composition of the invention in the core, and further comprising at least one coating layer bound to the surface of the core. In some embodiments, the coating layer is between 1pm and 1mm thick. In some embodiments, the coating layer comprises a polysaccharide (e.g. hyaluronic acid and / or alginate).

[0121] In some embodiments, the article of the invention is a tissue implant. In some embodiments, the article is for use as a tissue marker and can be detected via X-ray and optionally an additional imaging techniques, such as MRI and / or US.

[0122] In some embodiments, the article of the invention is a tissue marker.

[0123] In some embodiments, the article of the present invention can be used for local delivery or release of drug(s) or other therapeutic nutraceutical or bioactive material(s) into the tissue. In some embodiments, the tissue is a tissue of the subject. In some embodiments, the tissue is a soft tissue. Examples of "soft tissue" include breast tissue, muscle, fat, connective tissue, blood vessels, nerve tissue, lymphatic tissue, skin, fibrous tissue, synovial membranes, and mucous membranes. In some embodiments, the tissue is a breast tissue.

[0124] In some embodiments, the article of the invention is characterized by physico-mechanical properties (e.g. modulus, mechanical strength, non-stickiness, etc.) suitable for implanting thereof within a tissue / organ of a subject via a biopsy device.

[0125] In some embodiments, the article of the present invention can be used as a tissue scaffold. The article may further comprise an antimicrobial coating to reduce the risk of infection at the implantation site. This coating could include agents such as silver nanoparticles, antibiotics, or other antimicrobial substances.

[0126] The article may include a bioactive coating that promotes tissue integration and healing. This could involve the incorporation of growth factors, extracellular matrix proteins, or other bioactive molecules that encourage cell attachment and proliferation.Definitions

[0127] As used herein, the term “alkyl” describes an aliphatic hydrocarbon including straight chain and branched chain groups. The term “alkyl”, as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl. The term “alkyl” further encompasses a “heteroalkyl”, i.e. an alkyl including one or more heteroatoms (e.g. O, S, N, or NH) within the backbone of the alkyl chain.

[0128] The term “alkenyl” describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0129] The term “alkynyl”, as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0130] The term “cycloalkyl” describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl group may be substituted or unsubstituted, as indicated herein.

[0131] The term “aryl” describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted, as indicated herein.

[0132] The term “alkoxy” describes both an O-alkyl and an -O-cycloalkyl group, as defined herein. The term “aryloxy” describes an -O-aryl, as defined herein.

[0133] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0134] The term “halide”, “halogen” or “halo” describes fluorine, chlorine, bromine or iodine. The term “haloalkyl” describes an alkyl group as defined herein, further substituted by one or more halide(s). The term “haloalkoxy” describes an alkoxy group as defined herein, further substituted by one or more halide(s). The term “hydroxyl” or “hydroxy” describes a -OH group. The term “mercapto” or “thiol” describes a -SH group. The term “thioalkoxy” describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein. The term “thioaryloxy” describes both an -S-aryl and a -S-heteroaryl group, as defined herein. The term “amino” describes a -NR’R” group, or a salt thereof, with R’ and R’ ’ as described herein.

[0135] The term “heterocyclyl” describes a monocyclic or fused ring group having in the ring(s) one or more heteroatoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino and the like.

[0136] The term “heteroatom” describes O, S, N, NH, NH2, or N(R’)l-2 as allowed by valency.

[0137] The term “carboxy” describes a -C(O)OR’ group, or a carboxylate salt thereof, where R’ is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bondedthrough a ring carbon) or heterocyclyl (bonded through a ring carbon) as defined herein. Or “carboxylate”.

[0138] The term “carbonyl” describes a -C(O)R’ group, where R’ is as defined hereinabove. The above-terms also encompass thio-derivatives thereof (thiocarboxy and thiocarbonyl).

[0139] The term “thiocarbonyl” describes a -C(S)R’ group, where R’ is as defined hereinabove. A “thiocarboxy” group describes a -C(S)OR’ group, where R’ is as defined herein. A “sulfinyl” group describes an -S(O)R’ group, where R’ is as defined herein. A “sulfonyl” or “sulfonate” group describes an -S(O)2R’ group, where R’ is as defined herein.

[0140] A “carbamyl” or “carbamate” group describes an -OC(O)NR’R” group, where R’ is as defined herein and R” is as defined for R’. A “nitro” group refers to a -NO2 group. The term “amide” as used herein encompasses C-amide and N-amide. The term “C-amide” describes a -C(O)NR’R” end group or a -C(O)NR’ -linking group, as these phrases are defined hereinabove, where R’ and R” are as defined herein. The term “N-amide” describes a -NR”C(O)R’ end group or a -NR’C(O)- linking group, as these phrases are defined hereinabove, where R’ and R” are as defined herein.

[0141] A “cyano” or “nitrile” group refers to a -CN group. The term “azo” or “diazo” describes an -N=NR’ end group or an -N=N- linking group, as these phrases are defined hereinabove, with R’ as defined hereinabove. The term “guanidine” describes a -R’NC(N)NR”R”’ end group or a -R’NC(N) NR”- linking group, as these phrases are defined herein above, where R', R" and R” are as ’’defined herein. As used herein, the term “azide” refers to a -N3 group. The term “sulfonamide” refers to a -S(O)2NR’R” group, with R’ and R’ ’ as defined herein.

[0142] The term “phosphonyl” or “phosphonate” describes an -OP(O)-(OR’)2 group, with R’ as defined hereinabove. The term “phosphinyl” describes a -PR’R” group, with R’ and R’ ’ as defined hereinabove. The term “alkylaryl” describes an alkyl, as defined herein, which is substituted by an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0143] The term “heteroaryl” describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. As used herein, the term “heteroaryl” refers to an aromatic ring in which at least one atom forming the aromatic ring is a heteroatom.Heteroaryl rings can include three, four, five, six, seven, eight, nine and more than nine atoms. Heteroaryl groups can be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl is selected from among oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinal, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl.

[0144] In some embodiments, a heteroaryl group is selected from among pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1.2.4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl)pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodi oxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thi enothiophenyl, 1,8-naphthyridinyl, other naphthyridinyls, pteridinyl or phenothiazinyl. Where the heteroaryl group includes more than one ring, each additional ring is the saturated form (perhydro form) or the partially unsaturated form (e.g., the dihydro form or tetrahydro form) or the maximally unsaturated (nonaromatic) form. The term heteroaryl thus includes bicyclic radicals in which the two rings are aromatic and bicyclic radicals in which only one ring is aromatic. Such examples of heteroaryl are include 3H-indolinyl, 2(lH)-quinolinonyl, 4-oxo- 1 ,4-dihydroquinolinyl, 2H- 1 -oxoisoquinolyl, 1 ,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydro-isoquinolinyl, chromonyl, 3,4-dihydroiso-quinoxalinyl, 4-(3H)quinazolinonyl, 4H-chromenyl, 4-chromanonyl, oxindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1, 2,3,4-tetrahydro-quinolinyl, lH-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1.2.3.4-tetrahydrobenzo-[g]isoquinolinyl, l,2,3,4-tetrahydro-benzo[g]isoquinolinyl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzo-dioxanyl, 1, 2,3,4-tetrahydro-quinoxalinyl, 5,6-dihydro-quinolyl, 5,6-dihydroiso-quinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-lH-benzimidazolyl, 4,5-dihydro-benzoxazolyl, 1,4-naphthoquinolyl, 5,6,7,8-tetrahydro-quinolinyl, 5, 6, 7, 8-tetrahydro-isoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4.5.6.7-tetrahydro-lH-benzimidazolyl, 4,5,6,7-tetrahydro-benzoxazolyl, lH-4-oxa-l,5-diaza-naphthalen-2-onyl, l,3-dihydroimidizolo-[4,5]-pyridin-2-onyl, 2, 3 -dihydro- 1,4-dinaphtho-quinonyl, 2,3-dihydro-lH-pyrrol[3,4-b]quinolinyl, 1, 2,3,4-tetrahydrobenzo[b]-[l,7]naphthyridinyl, l,2,3,4-tetra-hydrobenz[b][l,6]-naphthyridinyl, l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, l,2,3,4-tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-lH-pyrrolo-[3,4-b]indolyl, 1 H-2, 3,4,5 -tetrahydro-azepino[3,4-b]indolyl, lH-2,3,4,5-tetrahydroazepino-[4,3-b]indolyl, 1H-2, 3,4,5-tetrahydro-azepino[4,5-b]indolyl, 5,6,7,8-tetrahydro[l,7]napthyridinyl, 1, 2,3,4-tetrahydro-[2,7]-naphthyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 2,3-dihydrof 1 ,4]-dioxino[2,3 -b]27escry27, 3 ,4-dihydro-2H- 1 -oxa[4,6]diazanaphthalenyl, 4.5.6.7-tetrahydro-3H-imidazo-[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, l,2,3,4-tetrahydro[l,5]-napthyridinyl, l,2,3,4-tetrahydro[l,6]napthyridinyl, 1, 2,3,4-tetrahydro[l,7]napthyridinyl, l,2,3,4-tetrahydro-[l,8]napthyridinyl or 1, 2,3,4-tetrahydro[2,6]napthyridinyl. In some embodiments, heteroaryl groups are optionally substituted. In one embodiment, the one or more substituents are each independently selected from among halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Cl-6-alkyl, Cl-6-haloalkyl, Cl-6-hydroxy alkyl, Cl-6-aminoalkyl, Cl-6-alkylamino, alkyl sulfenyl, alkylsulfinyl, alkyl sulfonyl, sulfamoyl, or trifluorom ethyl.

[0145] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotri azole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O — Cl-6-alkyl, Cl-6-alkyl, hydroxy-Cl-6-alkyl and amino-Cl-6-alkyl.

[0146] As used herein, the terms “halo” and “halide”, which are referred to herein interchangeably, describe an atom of a halogen, that is fluorine, chlorine, bromine or iodine, also referred to herein as fluoride, chloride, bromide and iodide.General:

[0147] As used herein the term “about” refers to ± 10 %.T1

[0148] The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

[0149] The term “consisting of means “including and limited to”.

[0150] The term "consisting essentially of means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0151] The word “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0152] The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict. The words "further" and "optionally" may be used interchangeably.

[0153] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0154] As used herein, the term “substantially” is at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, at least 99% by weight of the composition including any range or value therebetween.

[0155] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0156] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases“ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0157] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0158] As used herein, the term “treatment” or "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0159] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0160] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.EXAMPLES

[0161] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.Materials and MethodsSynthesis of the hydrolysable crosslinker:

[0162] Two types of hydrolysable crosslinkers have been synthesized: one from lactide, the other from caprolactone as described below.

[0163] Polylactide dimethacrylate (also used herein as “LLA oligomer”)

[0164] Step 1: Synthesis of poly(L-lactide) diolL-lactide Diethylene glycol Poly(L-lactide) diol

[0165] The ring-opening polymerization of L-lactide was performed in the presence of diethylene glycol as initiator and stannous octoate as catalyst. Briefly, L- lactide (6.0234 g, 0.0418 mole), diethylene glycol (900 pL, 0.00738 mole) and stannous octoate were placed in a Schlenk equipped with a magnetic stir bar. The reaction flask was kept under vacuum for 10 minutes and polymerization was carried out in an inert atmosphere by flushing the flask with argon gas for 12-24 hours at 80-160°C.

[0166] The polymer mass was dissolved in chloroform and then precipitated with excess ether / petroleum ether, collected by filtration and dried at room temperature under reduced pressure. The chemical composition of the oligomer has been determined based on13C-, and 'H-NMR spectra.

[0167] Step 2: Methacryl ati on of poly(L-lactide) diolPoly(L-lactide) diol Anhydride methacryliquePoly(L-lactide) dimethacrylate- Formula 6

[0168] PLLA oligomer was dissolved in ethyl acetate (1 :2 v / v), and placed in a schlenk flask in the presence of trimethylamine (4-8 eq). The mixture was stirred with a magnetic stirrer and methacrylic anhydride (4-8 eq) was added dropwise. The reaction mixture was maintained at room temperature under argon flow for 8-16 h.

[0169] After reaction, the mixture was added dropwise to petroleum ether and the precipitate was dried under vacuum at room temperature to yield an oil-like or waxlike product, depending on the molecular weight.

[0170] Different LLA oligomers have been synthesized with n being 5 or 7.

[0171] Polycaprolactone dimethacrylate (also used herein as “PCL oligomer”)

[0172] Step 1: Synthesis of polycaprolactone diol£-Caprolactone Diethylene glycol Polycaprolactone diol

[0173] Step 2: Methacryl ati on of poly caprolactone diolPolycaprolactone diol Anhydride methacrylicCaprolactone crosslinker- Formula 7

[0174] Different PCL oligomers have been synthesized with n being 2, 4 or 6.

[0175] Synthesis of the radiopaque monomer :

[0176] The 2-methacryloyloxyethyl-(2,3,5-triiodobenzoate) (MAOETIB) is synthesized as follows:

[0177] MAOETIB was characterized by3H NMR and13C NMR to confirm its identity and purity. The data obtained:3H NMR analysis (CDCE, 5, 300 MHz): 8.29 ppm (d, 'H, benzyl), 7.73 ppm (d, 'H, benzyl), 6.15 ppm (s, 'H, olefinic), 5.60 ppm (s, 'H, olefinic), 4.57 and 4.48 ppm (m, 4H, OCH2CH2O), 1.95 ppm (s, 3H, CH3).

[0178] 13C NMR analysis (CDCh, 8): 167 ppm, 166 ppm, 149 ppm, 141 ppm, 137 ppm, 136 ppm, 127 ppm, 114 ppm, 107 ppm, 94 ppm, 64 ppm, 62 ppm and 19 ppm.

[0179] Synthesis of an exemplary crosslinked polyacrylate of the invention [poly(2-methacryloyloxyethyl-(2,3,5-triiodobenzoate)-co-ethylene glycol methyl ether methacrylate],

[0180] 2-methacryloyloxyethyl-(2,3,5-triiodobenzoate) molar concentration [i.e., an exemplary first repeating unit precursor] was varied between 10-30 mol% while oligomer crosslinker molar concentration was varied between 5-20 mol% and ethylene glycol methyl ether methacrylate molar concentration [i.e. an exemplary second repeating unit precursor] was varied between 50-75 mol% (Table 1). The initiator (AIBN) concentration was kept constant at 1 mol %.

[0181] Into a Teflon mold, a solution of 2-methacryloyloxyethyl-(2,3,5-triiodobenzoate) (MAOETIB), oligomer crosslinker, ethylene glycol methyl ether methacrylate (EGMA) and initiator in toluene were added. The mold was placed in an oven and the polymerization was allowed to proceed overnight at 80°C. On the completion of the reaction, the product was washed in successive organic solvents and dried on Teflon surface.

[0182] The chemical structures of EGMA / PEGMA are as presented below:PEGMA EGMA

[0183] Additional exemplary crosslinked polyacrylate of the invention may include the following:

[0184] Synthesis of an exemplary crosslinked polyacrylate of the invention containing USPIOs can be performed as disclosed hereinabove, including the addition of USPIOs (1% of the total organic phase volume) together with other monomers during the solubilization step in toluene.

[0185] Synthesis of an exemplary crosslinked polyacrylate of the invention containing Ibuprofen can be performed as disclosed hereinabove, including the addition of Ibuprofen at a concentration of 25 mg / mL together with the other monomers during the solubilization step in toluene.

[0186] Synthesis of an exemplary crosslinked polyacrylate of the invention containing Sunitinib can be performed as disclosed hereinabove, including the addition of Sunitinib at a concentration of 0.5 mg / mL together with other monomers during the solubilization step in toluene.EXAMPLE 1Accelerated degradation

[0187] For accelerated degradation study, the test samples shaped as disclosed above (1 mm in diameter, 7-8 mm length) were transferred into tubes filled with 2 M KOH solution and incubated at 60°C to determine the relative degradation. Table 1 summarizes the different variations in feed compositions and the corresponding degradation time.

[0188] TABLE I:* Formula 6, n = 7; ** Formula 7, n = 5

[0189] The inventors further tested a control sample (a commercial product) having substantially the same shape and dimensions under the accelerated degradation conditions disclosed above. The control sample characterized by in-vitro degradation time of 3 months exhibited accelerated degradation time of about 1-2 days.

[0190] Accordingly, the inventors postulate that the samples #1 and #10 will have in-vitro degradation time of about 3-4 years.

[0191] Synthesis of an exemplary crosslinked polyacrylate of the invention [poly(2-methacryloyloxyethyl-(2,3,5-triiodobenzoate-co-poly(ethylene glycol methyl ether)methacrylate] .

[0192] Same protocol as above, however EGMA was replaced by PEGMA (Table 2).

[0193] Table 2:

[0194] The inventors have surprisingly observed that degradation time of the crosslinked polyacrylates was significantly reduced with increasing the amount of the oligomer crosslinker (see Table 1, # 1 & 3 and #10& 13). Accordingly, it is postulated that for a tissue marker which needs to have a prolonged retention time inside the tissue / organ of a subject, the amount of oligomers should not exceed 30mol%.

[0195] Some of the test samples from tables 1 and 2 were subjected to analysis by EDXto determine the Iodine distribution in the sample’s volume. The results (shown in Figure 1) demonstrate an uniform iodine concentration along the outer surface of the sample.

[0196] Exemplary SEM image of one of the test samples as well as surface roughness analysis are presented in Figures 2A-2B, respectively.

[0197] Exemplary test samples were implanted in pig’s tissue and visualized by X-Ray. As shown in Figure 4, the tested markers were easily detectable within the tissue by X-ray. Furthermore, specific samples (entries 15 and 12) showed US visibility in addition to X-ray visibility.

[0198] Furthermore, the samples (LLA and PCL-based) were tested ex-vivo to determine MRI visibility. MRI acquisitions were performed on a 1.5 T Siemens Altea system using T1 -weighted sequences (coronal T1 TSE and sagittal 3D T1 SPACE). Theresults of this experiment confirmed MRI visibility of both LLA and PCL-based samples ex-vivo.EXAMPLE 2

[0199] The inventors tested exemplary compositions of the invention (termed herein as “markers”) in-vivo. Three tested markers with different chemical compositions, corresponding to entries 3, 10 and 11 of Table 1, were implanted subcutaneously in female rats.

[0200] The in-vivo experiment was performed as described hereinbelow. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the ethics committee.

[0201] Female Sprague-Dawley rats (250 g) were acclimated for 7 days prior to the experiment. Markers were sterilized by autoclaving. The rats’ backs were shaved and disinfected with 5% iodine tincture.

[0202] Rats (n=10) were implanted subcutaneously using a 15G trocar. Three different markers were implanted into each animal: two in the upper dorsal region [Left: marker 1 containing 10 mol% of LLA oligomer crosslinker (Table 1, # 3), Right: marker 2 containing 10 mol% of PCI oligomer crosslinker (Table 1, # 11] and one in the lower dorsal region [marker 3 containing 5 mol% of PCI oligomer crosslinker (Table 1, # 10)]. The rats were imaged under isoflurane anesthesia using ultrasound at 24 h and 15 days to assess marker visibility (see Figures 5A-5F). Figures 5A-5F show a clear US visibility of all the tested markers at day 1 (5A-5C) and day 15 (5D-5F) after implantation.

[0203] Immediately after each imaging session, a caudal blood sample was collected while the animals remained anesthetized, for complete blood count (CBC) analysis and C-reactive protein (CRP) quantification. Rats were euthanized on day 1, day 7, or day 15, as indicated in Table 3, by intraperitoneal injection of Euthasol (180 mg / kg), followed by a macroscopic examination of the organs. Tissue samples from the implantation site and adjacent tissues were collected for histological and immunohistochemical analyses. Post-mortem X-ray imaging was performed at day 15 on one rat (Figure 6).

[0204] As shown in Figure 6, all three markers are clearly visualized in X-ray imaging. The numbers in Fig. 6 indicate the corresponding markers 1-3.

[0205] The results of this experiment are summarized in Table 3 below.Table 3

[0206] As indicated in Table 3, under US, all three markers were clearly visible at every time point from day 1 to day 15. Similarly, all markers exhibited excellent visibility on X-ray imaging at day 15.

[0207] Macroscopic examination revealed no signs of inflammation throughout the study. Blood analyses supported these observations, showing no changes in serum amyloid A levels, an inflammatory marker, compared with the non-implanted control group. After sacrifice, histological evaluation of the implantation sites revealed minimal tissue reaction, with only a few macrophages present, indicating that the marker did not generate an acute or intermediate foreign-body inflammatory response.

[0208] While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.

Claims

1. CLAIMS1. A composition comprising a polyacrylate crosslinked by a plurality of crosslinkers; wherein:said polyacrylate comprises a first plurality of repeating units each independently represented by Formula 1 :, wherein R1 is H or comprises an optionally substituted alkyl, X comprises any one of O, S, NR’ and a linker; A comprises an aryl or a heteroaryl; and R2 represents at least one substituent comprising halo, or haloalkyl, and optionally at least one second substituent;each of said plurality of crosslinkers comprises an oligomer; andsaid oligomer comprises a plurality of oligomer units covalently bound to each other via a hydrolysable bond.

2. The composition of claim 1, wherein said polyacrylate further comprises a second plurality of repeating units each independently represented by Formula 2:, wherein R1 is H or comprises an optionally substituted alkyl; X comprises any one of O, S, NR’ and the linker; and wherein R3 is absent or represents H or comprises an optionally substituted alkyl, alkoxy, alkylamine, mercaptoalkyl, a hydrophilic oligomer or an active agent.

3. The composition of claim 1 or 2, wherein the hydrolysable bond is selected from ester, anhydride, thioester, ortho ester, carbonate and amide.

4. The composition of any one of claims 1 to 3, wherein said oligomer is characterized by an average Mw between 500 and 20000Da, based on GPC.

5. The composition of any one of claims 1 to 4, wherein said polyacrylate is in a form of a matrix comprising a plurality of polyacrylate chains; and wherein at least two of said polyacrylate chains within said matrix are crosslinked via at least two of said crosslinkers.

6. The composition of claim 5, wherein each of said plurality of crosslinkers further comprises at least 2 attachment points to said at least two chains.

7. The composition of claim 6, wherein each of the at least 2 attachment points is represented by Formula 3:, wherein R1 is independently H or comprises an optionally substituted alkyl, X is absent or comprises any one of: O, S, NR’, the linker and -O-linker-, and the dashed bond represent a bond to the plurality of oligomer units.

8. The composition of any one of claims 5 to 7, wherein the plurality of polymeric chains is characterized by an average Mw between 1000 and 50000Da, based on GPC.

9. The composition of any one of claims 5 to 8, wherein a mole portion of said plurality of crosslinkers relative to the polyacrylate chains is between 0.5 and 30mol%.

10. The composition of any one of claims 2 to 9, wherein the second plurality of repeating units each independently represented by Formula 2; and wherein a molar ratio between the first plurality of repeating units and the second plurality of repeating units is between 1:10 and 1:1.

11. The composition of any one of claims 2 to 10, wherein the hydrophilic oligomer comprises [Cl -CIO alkyl -X]n, [Cl -CIO heteroalkyl -X]n and A-Y-A; wherein each n is between 1 and 20, X is selected from O, S and NR’; each A is independently selected from [Cl -CIO heteroalkyl -X]n and [Cl -CIO alkyl-X]n, and Y is absent or is independently from -O-, -S-, -NR’-, -C(=O)-, -C(=NR’)- , -C(=S)-, -CONR’-, -C(NR’)NR’-, -C(NR’)O-, -C(NR’)S-, -S-S-, -S-C(=O), -CNNR’-, -CSNR’-, -NR’C(=O)O-, -NR’C(=S)O-, -NR’C(=S)NR’-, -SO2-, - SO-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)NR’-; and wherein each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted Cl -CIO alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof.

12. The composition of any one of claims 1 to 11, wherein said linker comprises an optionally substituted alkyl, [Cl -CIO alkyl-X]n, -O-, -S-, -NR’-, Y, or an optionally substituted alkyl-Y; wherein Y is selected from -O-, -S-, -NR’-, - C(=O)-, -C(=NR’)-, -C(=S)-, -CONR’-, -C(NR’)NR’-, -C(NR’)O-, - C(NR’)S-, -S-S-, -S-C(=O), -CNNR’-, -CSNR’-, -NR’C(=O)O-, -NR’C(=S)O- , -NR’C(=S)NR’-, -SO2-, -SO-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and - OC(=S)NR’-.

13. The composition of any one of claims 1 to 12, wherein said second substituent comprises one or more substituents each independently selected from alkyl, - NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate, phosphonate, phosphine, phosphite, -CONR’ 2, -CNNR’ 2, - CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, - NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, - SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, Cl- C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, - CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, - OC(=S)NR’, amino(Ci-Ce alkyl), Ci-Ce mercaptoalkyl, -CONH(Ci-Ce alkyl),-CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, - OC(=S)OR, -OC(=S)NR, alkyl -aryl, alkyl -heteroaryl or a combination thereof; and wherein X of Formulae 1, 2 and 3 is O.

14. The composition of any one of claims 1 to 13, wherein said oligomer is represented by Formula 4:wherein:each n is an integer ranging between 0 and 10;m is an integer ranging between 0 and 5;each R is independently hydrogen, is absent or represents one or more substituents selected from: -OH, halogen, oxo, carbonyl, amino, imino, thioxo, phosphate, phosphonate, phosphine, phosphite, OR’, -NO2, -CN, -CONH2, - CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, - NHCSR’, -NHCNR, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, - CO2H, -CO2R’, -OCOR, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or any combination thereof;each Z is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, Y, [Cl -CIO alkyl -X]n, or any combination thereof; and each A is an ester oligomer.

15. The composition of claim 14, wherein the ester oligomer comprises a plurality of Cl -CIO alkyl-ester monomers; and wherein each A is bound to said polyacrylate via the attachment point.

16. The composition of claim 14, wherein said plurality of C1-C10 alkyl-ester monomers is between 2 and 20 monomers, and wherein the attachment point is of Formula 3.

17. The composition of claim 14 or 15, wherein each of the plurality of C1-C10 alkyl-ester monomers comprises any one of caprolactone monomer, glycolate monomer, lactate monomer and hydroxyalkanoate monomer.

18. The composition of any one of claims 1 to 17, wherein at least one of:-said oligomer is selected from, rein n is between 2 and 20 and m is between 1 and 10; and wherein each * represents the attachment point;-said second plurality of repeating units comprises, and-said first plurality of repeating units comprises19. An article comprising the composition of any one of claims 1 to 18.

20. The article of claim 19, further comprising (i) a contrast agent selected from MRI, CT and US contrast agent, (ii) a therapeutically active agent, or both (i) and (ii).

21. The article of claim 19 or 20, further comprising a hydrogel coating.

22. The article of any one of claims 19 to 21, being a tissue marker.

23. The article of claim 22, wherein said tissue marker is for implanting into a tissue a subject, and wherein said tissue marker is stable within said tissue for a time period of at least 2 m.

24. The article of any one of claims 19 to 23, being detectable within said subject by X-ray, and optionally by US, MRI or both.

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