A bioactive poly(lactic-co-glycolic acid) (PLGA) material comprising protrusions, related printed structure and related methods thereof

Abstract

There is provided material for preventing or reducing scar formation during wound healing, the material comprising: (i) a base poly(lactic-co-glycolic acid) (PLGA); and (ii) a bioactive poly(lactic-co-glycolic acid) (PLGA) copolymer, wherein at least part of the material is in the form of a plurality of protrusions extending from a surface. Also provided are a medical device comprising said material, medical uses of said material, and a method of preparing said material.

Description

[0001] A BIOACTIVE POLY(LACTIC-CO-GLYCOLIC ACID) (PLGA) MATERIAL COMPRISING PROTRUSIONS, RELATED PRINTED STRUCTURE AND RELATED METHODS THEREOF

[0002] TECHNICAL FIELD

[0003] The present disclosure relates broadly to a bioactive poly(lactic-co-glycolic acid) (PLGA) material and related printed structure. The present disclosure also relates to a method of preparing said bioactive PLGA material, and related methods and uses.

[0004] BACKGROUND

[0005] Surgical or incisional wounds are typically treated by the use of sutures, commonly referred to as first intention healing, where wound edges are brought and kept together. The goal in incisional wound healing is to have scars that are minimally perceptible, with colour matching that of surrounding skin. However, the process of healing through sutures can result in development / formation of visible scars, which is part of the natural healing process. To date, healing efficacy of sutured wounds is limited. For instance, chronic inflammation can occur due to infection, poor surgical technique, poor post-operative care or slow reepithelization, or delayed healing process, which consequently increases the risk of scar formation for e.g., hypertrophic scars and keloids may form.

[0006] Current gold standard for scar treatments includes topical silicone scar gel products (e.g., Dermatix) and silicone gel sheets (e.g., Cica-Care) that are primarily focused on managing the appearance of scars after the wound has healed. Their working mechanism involves providing dermal hydration at the scar site to prevent over production of collagen. This helps to flatten and reduce the discoloration of the scar tissue, so that it can better blend in with the surrounding skin. However, these products focus on treating the scar after the wound has healed rather than scar prevention and cannot be applied on sutured wounds.

[0007] Other alternative types of scar treatments include steroidal injections or drugs such as triamcinolone which are used in reduction of hypertrophic scars and keloid scars. However, such treatments also focus on scar reduction after they have formed, instead of preventing the formation of scars in the first place. For example, steroidal injections are administered on the hypertrophic scar in attempts to flatten them rather than prevent them from forming. In fact, steroid injections on keloids are non-permanent treatments and keloids can re-form after treatment has ended. Furthermore, steroids used in scar treatment have associated negative side effects that include insomnia, adrenal suppression, immunosuppression leading to secondary infections, depression, gastrointestinal disorder and fluid retention.

[0008] In view of the above, there is a need to address or at least ameliorate the above-mentioned problems. In particular, there is a need to provide a material that not only aid in wound healing but also prevent the formation of scars, particularly in surgical or incisional wounds.

[0009] SUMMARY

[0010] In one aspect, there is provided a material for preventing or reducing scar formation during wound healing, the material comprising:

[0011] (i) a base poly(lactic-co-glycolic acid) (PLGA); and

[0012] (ii) a bioactive poly(lactic-co-glycolic acid) (PLGA) copolymer, wherein at least part of the material is in the form of a plurality of protrusions extending from a surface.

[0013] In one embodiment, each protrusion comprises a structure having a base tapering to a tip. In one embodiment, each base has a diameter falling in the range of from 0.5 mm to 2.5 mm.

[0014] In one embodiment, each tip has a diameter falling in the range of from 0.05 mm to 0.25 mm.

[0015] In one embodiment, the distance between the base and the tip falls in the range of from 1 mm to 10 mm.

[0016] In one embodiment, the plurality of protrusions is arranged in one or more arrays, each array comprising at least 5 protrusions.

[0017] In one embodiment, the distance between the protrusions falls in the range of from 1 mm to 10 mm.

[0018] In one embodiment, the ratio of the (i) base PLGA to (ii) bioactive PLGA copolymer present in the material is 60.0 - 99.9 : 0.1 - 40.0.

[0019] In one embodiment, the material comprises from 60 wt% to 99.9 wt% of the base PLGA.

[0020] In one embodiment, the material comprises from 0.1 wt% to 40 wt% of the bioactive PLGA copolymer.

[0021] In one embodiment, the material is part of a three-dimensional (3D) printed structure.

[0022] In one embodiment, the bioactive PLGA copolymer comprises a bioactive PLGA copolymer with a poly(norbornene-dicarboximide) backbone having one or more repeating units represented by general formula (I) and one or more repeating units represented by general formula (II): wherein

[0023] R1is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl or optionally substituted alkylcarbonylalkyl;

[0024] R2is optionally substituted alkyl;

[0025] R3is selected from H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

[0026] L is heteroalkylene;

[0027] X comprises a bioactive moiety selected from the group consisting of proteins, peptides, oligopeptides, carbohydrates, oligosaccharides, sugar, collagen, hyaluronic acid, therapeutic / drug molecules and derivatives thereof;

[0028] Z1and Z2are each independently selected from CRaRb, O, NRC, SiRaRb, PRaor S, wherein Ra, Rband Rcare each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; p > 1 ; and q > 1. In one embodiment, X is selected from the group consisting of RGD, SRGDS, RGDS, A5G81 (AGQWHRVSVRWGC), SVVYGLR, (IRIK)2, (IKKI)s, heparin oligosaccharide DP8, DP10, DP12, DP14, DP16, DGEA, (PHypG)n type sequence, (PGHyp)n type sequence, (HypGP)n type sequence, (HypPG)n type sequence, (GHypP)n type sequence, (GPHyp)ntype sequence, hyaluronic acid and combinations thereof.

[0029] In another aspect, there is provided a method of preparing a material as disclosed herein, the method comprising:

[0030] (i) providing a bioactive PLGA filament comprising a base poly(lactic- co-glycolic acid) (PLGA) and a bioactive poly(lactic-co-glycolic acid) (PLGA) copolymer ; and

[0031] (ii) printing a bioactive PLGA material from the bioactive PLGA filament according to a design model to obtain a printed structure or part with a plurality of protrusions printed thereon.

[0032] In one embodiment, the step (i) of providing a bioactive PLGA filament comprises:

[0033] (i-a) providing a base PLGA powder and a bioactive PLGA copolymer;

[0034] (i-b) mixing the base PLGA powder with the bioactive PLGA copolymer to obtain a bioactive PLGA formulation; and

[0035] (i-c) extruding a bioactive PLGA filament from the formulation.

[0036] In one embodiment, the step (ii) of printing a bioactive PLGA material from the bioactive PLGA filament comprises:

[0037] (ii-a) feeding the bioactive PLGA filament into a printing apparatus;

[0038] (ii-b) applying heat to the bioactive PLGA filament to obtain a molten form of the bioactive PLGA; and

[0039] (ii-c) depositing the molten bioactive PLGA on a print bed to form a printed part or structure. In another aspect, there is provided a material as disclosed herein for use in medicine.

[0040] In another aspect, there is provided a material as disclosed herein for use in treatment of wounds.

[0041] In another aspect, there is provided a material as disclosed herein for use in preventing and / or reducing scar formation.

[0042] In another aspect, there is provided use of a material as disclosed herein in the manufacture of a medicament for treatment of wounds.

[0043] In another aspect, there is provided use of a material as disclosed herein in the manufacture of a medicament for preventing and / or reducing scar formation.

[0044] In another aspect, there is provided a method of treating a wound, the method comprising applying the material as disclosed herein to a wound of a subject in need thereof.

[0045] In another aspect, there is provided a method of preventing and / or reducing scar formation in a subject in need thereof, the method comprising applying the material as disclosed herein to a body part of the subject in need thereof.

[0046] In one embodiment, the wound is selected from the group consisting of incisions, excisions, surgical wound, caesarean wound, laceration wound, sutured wound, and combinations thereof.

[0047] In another aspect, there is provided a medical device comprising the material as disclosed herein. In one embodiment, the medical device is selected from the group consisting of skin patch, dermal template, skin scaffold, wound care product, wound dressing, personal care product, beauty product and combinations thereof.

[0048] DEFINITIONS

[0049] The term “bioactive” as used herein broadly refers to the property of having a biological effect, preferably a desirable or positive biological effect on a living organism, tissue, or cell.

[0050] The term “biocompatible” as used herein broadly refers to a property of being compatible with biological systems or parts of the biological systems without substantially or significantly eliciting an adverse physiological response such as a toxic reaction, an immune reaction, an injury or the like. Such biological systems or parts include blood, cells, tissues, organs or the like.

[0051] The term "polymer" as used herein refers to a chemical compound comprising repeating units and is created through a process of polymerization. The units composing the polymer are typically derived from monomers and / or macromonomers. A polymer typically comprises repetition of a number of constitutional units.

[0052] The terms “monomer” or “macromonomer” as used herein refer to a chemical entity that may be covalently linked to one or more of such entities to form a polymer.

[0053] The term "bond" refers to a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.

[0054] In the definitions of a number of substituents below, it is stated that “the group may be a terminal group or a bridging group”. This is intended to signify that the use of the term is intended to encompass the situation where the group is a terminal group / moiety as well as the situation where the group is a linker between two other portions of the molecule. Using the term “alkyl” having 1 carbon atom as an example, it will be appreciated that when existing as a terminal group, the term “alkyl” having 1 carbon atom may mean -CH3 and when existing as a bridging group, the term “alkyl” having 1 carbon atom may mean -CH2- or the like.

[0055] The term "alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Examples of suitable straight and branched alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, hexyl, amyl, 1 ,2-dimethylpropyl, 1 ,1 - dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2- dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-trimethylpropyl, 1 ,1 ,2-trimethylpropyl, 2- ethylpentyl, 3-ethylpentyl, heptyl, 1 -methylhexyl, 2,2-dimethylpentyl, 3,3- dimethylpentyl, 4,4-dimethylpentyl, 1 ,2-dimethylpentyl, 1 ,3-dimethylpentyl, 1 ,4- dimethylpentyl, 1 ,2,3-trimethylbutyl, 1 ,1 ,2-trimethylbutyl, 1 ,1 ,3-trimethylbutyl, 5- methylheptyl, 1 -methylheptyl, octyl, nonyl, decyl and the like. The group may be a terminal group or a bridging group.

[0056] The term "alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched having 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms in the chain. The group may contain a plurality of double bonds and the orientation about each double bond is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, vinyl, allyl, 1 - methylvinyl, 1 -propenyl, 2-propenyl, 2-methyl-1 -propenyl, 2-methyl-1 -propenyl, 1 -butenyl, 2-butenyl, 3-butentyl, 1 ,3-butadienyl, 1 -pentenyl, 2-pententyl, 3- pentenyl, 4-pentenyl, 1 ,3-pentadienyl, 2,4-pentadienyl, 1 ,4-pentadienyl, 3- methyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1 ,3-hexadienyl, 1 ,4- hexadienyl, 2-methylpentenyl, 1 -heptenyl, 2-heptentyl, 3-heptenyl, 1 -octenyl, 2- octenyl, 3-octenyl, 1 -nonenyl, 2-nonenyl, 3-nonenyl, 1 -decenyl, 2-decenyl, 3- decenyl and the like. The group may be a terminal group or a bridging group.

[0057] The term "alkynyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched having 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms in the chain. The group may contain a plurality of triple bonds. Exemplary alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1 - butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3-methyl-1 -butynyl, 4- pentynyl, 1 -hexynyl, 2-hexynyl, 5-hexynyl, 1 -heptynyl, 2-heptynyl, 6-heptynyl, 1 - octynyl, 2-octynyl, 7-octynyl, 1 -nonynyl, 2-nonynyl, 8-nonynyl, 1 -decynyl, 2- decynyl, 9-decynyl and the like. The group may be a terminal group or a bridging group.

[0058] The term "heteroalkylene" as used herein refers to alkylene having one or more -CH2- replaced with a heteroatom selected from O, NR, Si, P or S, where R is hydrogen or alkyl as defined herein. The term "heteroalkylene" can be linear, branched or cyclic and containing up to 500 carbon atoms.

[0059] The term "alkoxy" as used herein refers to straight chain or branched alkyloxy groups. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, tertbutoxy, and the like.

[0060] The term "alkoxyalkyl" as used herein is intended to broadly refer to a group containing -R-O-R’, where R and R’ are alkyl as defined herein. The group may be a terminal group or a bridging group. The term "alkylcarbonyl" as used herein is intended to broadly refer to a group containing -R-C(=O)-, where R is alkyl as defined herein. The group may be a terminal group or a bridging group.

[0061] The term "alkylcarbonylalkyl" as used herein is intended to broadly refer to a group containing -R-C(=O)-R’, where R and R’ are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0062] The term "carboxylalkyl" as used herein is intended to broadly refer to a group containing -C(=O)-O-R, where R is alkyl as defined herein. The group may be a terminal group or a bridging group.

[0063] The term "oxycarbonylalkyl" as used herein is intended to broadly refer to a group containing -O-C(=O)-R, where R is alkyl as defined herein. The group may be a terminal group or a bridging group.

[0064] The term "alkylcarboxylalkyl" as used herein is intended to broadly refer to a group containing -R-C(=O)-O-R’, where R and R’ are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0065] The term "alkoxycarbonylalkyl" as used herein is intended to broadly refer to a group containing -R-O-C(=O)-R’, where R and R’ are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0066] The term "oxy" as used herein is intended to broadly refer to a group containing -O-.

[0067] The term "carbonyl" as used herein is intended to broadly refer to a group containing -C(=O)-.

[0068] The term "oxycarbonyl" as used herein is intended to broadly refer to a group containing -O-C(=O)-. The term "carboxyl" as used herein is intended to broadly refer to a group containing -C(=O)-O-R, where R is hydrogen or an organic group.

[0069] The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.

[0070] The term "amine group" or the like is intended to broadly refer to a group containing -NR2, where R is independently a hydrogen or an organic group. The group may be a terminal group or a bridging group.

[0071] The term "amide group" or the like is intended to broadly refer to a group containing -C(=O)NR2, where R is independently a hydrogen or an organic group. The group may be a terminal group or a bridging group.

[0072] The term “optionally substituted,” when used to describe a chemical structure or moiety, refers to the chemical structure or moiety wherein one or more of its hydrogen atoms is optionally substituted with a chemical moiety or functional group such as alcohol, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or -alkylNHC(O)alkyl), amine (such as alkylamino, arylamino, arylalkylamino), aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (e.g., CONH2, as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carboxyl, carboxylic acid, cyano, ester, ether (e.g., methoxy, ethoxy), halo, haloalkyl (e.g., -CCb, -CF3, -C(CFs)3), heteroalkyl, isocyanate, isothiocyanate, nitrile, nitro, phosphodiester, sulfide, sulfonamido (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl, thioether) or urea (-NHCONH-alkyl-).

[0073] The term “particle” as used herein broadly refers to a discrete entity or a discrete body. The particle described herein can include an organic, an inorganic, a composite particle or a biological particle. The particle used described herein may also be a macro-particle that is formed by an aggregate of a plurality of subparticles or a fragment of a small object. The particle of the present disclosure may be spherical, substantially spherical, or non-spherical, such as irregularly shaped particles or ellipsoidally shaped particles. The term “size” when used to refer to the particle broadly refers to the largest dimension of the particle. For example, the term “size” when used in the context of nanoparticle can refer to the diameter of the nanoparticle although it is not limited as such. In various embodiments, when the particle is substantially spherical, the term “size” can refer to the diameter of the particle; or when the particle is substantially non- spherical, the term “size” can refer to the largest length of the particle.

[0074] The term "nano" as used herein is to be interpreted broadly to include dimensions in a nanoscale, i.e., less than about 1000 nm, about 1 nm to less than about 1000 nm, about 1 nm to about 900 nm, about 1 nm to about 800 nm, about 1 nm to about 700 nm, about 1 nm to about 600 nm, about 1 nm to about 500 nm, about 1 nm to about 400 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, or from about 1 nm to about 100 nm. Accordingly, the term “nanostructures”, “nanoparticles”, “nanomaterials” and the like as used herein may include structures that have at least one dimension in the range of no more than said range. The term “nanostructures”, “nanoparticles”, “nanomaterials” and the like as used herein may include structures that have at least one dimension that is no more than about 100 nm, no more than about 90 nm, no more than about 80 nm, no more than about 70 nm, no more than about 60 nm, no more than about 50 nm, no more than about 40 nm, no more than about 30 nm, no more than about 20 nm, or no more than about 10 nm.

[0075] The term "micro" as used herein is to be interpreted broadly to include dimensions from about 1 micron to about 1000 microns, about 1 micron to less than about 1000 microns, about 1 micron to about 900 microns, about 1 micron to about 800 microns, about 1 micron to about 700 microns, about 1 micron to about 600 microns, about 1 micron to about 500 microns, about 1 micron to about 400 microns, about 1 micron to about 300 microns, about 1 micron to about 200 microns, or from about 1 micron to about 100 microns.

[0076] The term “array” as used herein is to be interpreted to refer to an ordered arrangement as opposed to a random arrangement.

[0077] The term “treatment", "treat" and “therapy”, and synonyms thereof as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) a medical condition, which includes but is not limited to diseases, symptoms and disorders. A medical condition also includes a body’s response to a disease or disorder, e.g., inflammation. Those in need of such treatment include those already with a medical condition as well as those prone to getting the medical condition or those in whom a medical condition is to be prevented.

[0078] As used herein, the term "therapeutically effective amount" of a compound is intended to refer to an amount that is sufficient or capable of preventing or at least slowing down (lessening) a medical condition, such as wounds or infections / inflammations arising from wounds (e.g., incisions, excisions, surgical wound, caesarean wound, laceration wound, sutured wound, or the like). Dosages and administration of compounds, compositions and formulations of the present disclosure may be determined by one of ordinary skill in the art of clinical pharmacology or pharmacokinetics. An effective amount of the active agent of the present disclosure to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.

[0079] The term “subject” is intended to broadly refer to any animal, such as a mammal, and including humans. Exemplary subjects include but are not limited to humans and non-human primates. The term “subject” as used herein also includes patients and non-patients. The term “patient” refers to individuals suffering or are likely to suffer from a medical condition such as wounds (e.g., incisions, excisions, surgical wound, caesarean wound, laceration wound, sutured wound, or the like), while “non-patients” refer to individuals not suffering and are likely to not suffer from the medical condition. “Non-patients” include healthy individuals, non-diseased individuals and / or an individual free from the medical condition. As used herein, the term "mammal" includes vertebrate such as a human or a large veterinary mammal (e.g., horses, cattle, deer, sheep, llamas, goats, pigs).

[0080] The terms "coupled" or "connected" as used in this description are intended to cover both directly connected or connected through one or more intermediate means, unless otherwise stated.

[0081] The term "associated with", used herein when referring to two elements refers to a broad relationship between the two elements. The relationship includes, but is not limited to a physical, a chemical or a biological relationship. For example, when element A is associated with element B, elements A and B may be directly or indirectly attached to each other or element A may contain element B or vice versa.

[0082] The term "adjacent" used herein when referring to two elements refers to one element being in close proximity to another element and may be but is not limited to the elements contacting each other or may further include the elements being separated by one or more further elements disposed therebetween.

[0083] The term "and / or", e.g., "X and / or Y" is understood to mean either "X and Y" or "X or Y" and should be taken to provide explicit support for both meanings or for either meaning.

[0084] Further, in the description herein, the word “substantially” whenever used is understood to include, but not restricted to, "entirely" or “completely” and the like. In addition, terms such as "comprising", "comprise", and the like whenever used, are intended to be non-restricting descriptive language in that they broadly include elements / components recited after such terms, in addition to other components not explicitly recited. For example, when “comprising” is used, reference to a “one” feature is also intended to be a reference to “at least one” of that feature. Terms such as “consisting”, “consist”, and the like, may in the appropriate context, be considered as a subset of terms such as "comprising", "comprise", and the like. Therefore, in embodiments disclosed herein using the terms such as "comprising", "comprise", and the like, it will be appreciated that these embodiments provide teaching for corresponding embodiments using terms such as “consisting”, “consist”, and the like. Further, terms such as "about", "approximately" and the like whenever used, typically means a reasonable variation, for example a variation of + / - 5% of the disclosed value, or a variance of 4% of the disclosed value, or a variance of 3% of the disclosed value, a variance of 2% of the disclosed value or a variance of 1% of the disclosed value.

[0085] Furthermore, in the description herein, certain values may be disclosed in a range. The values showing the end points of a range are intended to illustrate a preferred range. Whenever a range has been described, it is intended that the range covers and teaches all possible sub-ranges as well as individual numerical values within that range. That is, the end points of a range should not be interpreted as inflexible limitations. For example, a description of a range of 1% to 5% is intended to have specifically disclosed sub-ranges 1% to 2%, 1 % to 3%, 1 % to 4%, 2% to 3% etc., as well as individually, values within that range such as 1%, 2%, 3%, 4% and 5%. It is to be appreciated that the individual numerical values within the range also include integers, fractions and decimals. Furthermore, whenever a range has been described, it is also intended that the range covers and teaches values of up to 2 additional decimal places or significant figures (where appropriate) from the shown numerical end points. For example, a description of a range of 1% to 5% is intended to have specifically disclosed the ranges 1.00% to 5.00% and also 1.0% to 5.0% and all their intermediate values (such as 1.01 %, 1.02% ... 4.98%, 4.99%, 5.00% and 1.1 %, 1 .2% ... 4.8%, 4.9%, 5.0% etc.,) spanning the ranges. The intention of the above specific disclosure is applicable to any depth / breadth of a range.

[0086] Additionally, when describing some embodiments, the disclosure may have disclosed a method and / or process as a particular sequence of steps. However, unless otherwise required, it will be appreciated that the method or process should not be limited to the particular sequence of steps disclosed. Other sequences of steps may be possible. The particular order of the steps disclosed herein should not be construed as undue limitations. Unless otherwise required, a method and / or process disclosed herein should not be limited to the steps being carried out in the order written. The sequence of steps may be varied and still remain within the scope of the disclosure.

[0087] Furthermore, it will be appreciated that while the present disclosure provides embodiments having one or more of the features / characteristics discussed herein, one or more of these features / characteristics may also be disclaimed in other alternative embodiments and the present disclosure provides support for such disclaimers and these associated alternative embodiments.

[0088] It will also be appreciated that where priority is claimed to an earlier application, the full contents of the earlier application is also taken to form part of the present disclosure and may serve as support for embodiments disclosed herein.

[0089] DESCRIPTION OF EMBODIMENTS

[0090] Exemplary, non-limiting embodiments of a regenerative material, a bioactive poly(lactic-co-glycolic acid) (PLGA) material, related printed structure, a method of preparing said regenerative material and / or bioactive PLGA material and related methods / uses thereto are disclosed hereinafter. Bioactive Polvdactic-co-glycolic acid) (PLGA) Material

[0091] There is provided a bioactive poly(lactic-co-glycolic acid) (PLGA) material. Advantageously, in various embodiments, the material is suitable for preventing and / or reducing scar formation or scarring during wound healing. Advantageously, in various embodiments, the material is also suitable for the prophylaxis or treatment of an incisional wound such as surgical wound, caesarean wound or the like. In various embodiments, the material overcomes or at least ameliorates one or more of the inherent issues of conventional scar treatment products as described above.

[0092] In various embodiments, the material comprises a bioactive poly(lactic-co- glycolic acid) (PLGA) copolymer. In various embodiments, the material further comprises a base polymer. In various embodiments, the base polymer is a synthetic polymer. In various embodiments, the base polymer is a medical grade polymer. In various embodiments, the base polymer is biodegradable, allowing the material to be broken down naturally. In various embodiments, the base polymer comprises PLGA. The bioactive PLGA copolymer may be blended / mixed with the base PLGA.

[0093] In various embodiments, the bioactive PLGA material comprises / consists essentially of / consists of:

[0094] (i) a base poly(lactic-co-glycolic acid) (PLGA); and

[0095] (ii) a bioactive poly(lactic-co-glycolic acid) (PLGA) copolymer.

[0096] In various embodiments, the term “poly(lactic-co-glycolic acid)” comprises and / or may be used interchangeably with the terms “poly(lactide-co-glycolide)”, “poly(D-lactide-co-glycolide)”, ‘poly(L-lactide-co-glycolide)”, “poly(D,L-lactide-co- glycolide)” or the like. In various embodiments, PLGA comprises medical grade PLGA. In various embodiments, at least part of the material is in the form of a plurality of (or one or more) protrusions extending from a surface. In various embodiments, each protrusion comprises a structure having a base and a tip (e.g., a sharp tip). The structure may be a tapering structure that tapers from a larger base (e.g. larger diameter) to a smaller tip (e.g. smaller diameter). In various embodiments, each protrusion comprises a structure having a base tapering to a tip. In various embodiments, each protrusion comprises a needle- like / needle-shaped or pin-like / pin-shaped structure.

[0097] In various embodiments, the material comprises protrusions / needles / pins / needle-like / needle-shaped or pin-like / pin-shaped structures extending from a surface of said material. In various embodiments, the material comprises one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or twenty or more protrusions / needles / pins / needle-like / needle-shaped or pin-like / pin-shaped structures extending from a surface of said material. Advantageously, due to the presence of protrusions / needles / pins, embodiments of the material possess good / high permeability / transdermal permeability, allowing the material to penetrate skin (e.g., outer layer of skin or outer skin barrier) in a non-invasive manner without breaking / damaging / breaching the epidermis. In various embodiments, due to the presence of protrusions / needles / pins, embodiments of the material are capable of penetrating the outer layer of the skin without reaching / damaging / breaching deeper tissue layers (e.g., epidermis and / or dermis). Advantageously, in various embodiments, the protrusions / needles / pins can be inserted / introduced / pressed / lodged into the skin (e.g., via an incision opening) to allow active ingredient / substance(s) or bioactive(s) contained in / within the material to be in contact with the dermis without causing injury / trauma. In various embodiments, the protrusion / needle / pin design of the bioactive PLGA material allows for non-invasive penetration of active ingredient / substance(s) or bioactive(s), thereby making the material suitable for use in preventing and / or reducing risk of scar formation / scarring.

[0098] In various embodiments, each tip of the protrusion / needle / pin has a diameter falling in the range of from about 0.05 mm to about 0.25 mm. In various embodiments, each tip has a diameter falling in the range of from about 0.05 mm to about 0.25 mm, from about 0.06 mm to about 0.24 mm, from about 0.07 mm to about 0.23 mm, from about 0.08 mm to about 0.22 mm, from about 0.09 mm to about 0.21 mm, from about 0.10 mm to about 0.20 mm, from about 0.11 mm to about 0.19 mm, from about 0.12 mm to about 0.18 mm, from about 0.13 mm to about 0.17 mm, from about 0.14 mm to about 0.16 mm, or about 0.15 mm.

[0099] In various embodiments, each base of the protrusion / needle / pin has a diameter falling in the range of from about 0.50 mm to about 2.50 mm. In various embodiments, each base has a diameter falling in the range of from about 0.50 mm to about 2.50 mm, from about 0.55 mm to about 2.45 mm, from about 0.60 mm to about 2.40 mm, from about 0.65 mm to about 2.35 mm, from about 0.70 mm to about 2.30 mm, from about 0.75 mm to about 2.25 mm, from about 0.80 mm to about 2.20 mm, from about 0.85 mm to about 2.15 mm, from about 0.90 mm to about 2.10 mm, from about 0.95 mm to about 2.05 mm, from about 1.00 mm to about 2.00 mm, from about 1 .05 mm to about 1 .95 mm, from about 1.10 mm to about 1.90 mm, from about 1.15 mm to about 1.85 mm, from about 1.20 mm to about 1 .80 mm, from about 1 .25 mm to about 1 .75 mm, from about 1 .30 mm to about 1 .70 mm, from about 1 .35 mm to about 1 .65 mm, from about 1 .40 mm to about 1 .60 mm, from about 1 .45 mm to about 1 .55 mm, or about 1 .50 mm.

[0100] In various embodiments, each protrusion / needle / pin has a height / depth (e.g., distance between the base and the tip) falling in the range of from about 1.0 mm to about 10.0 mm. In various embodiments, the distance between the base and the tip falls in the range of from about 1 .0 mm to about 10.0 mm, from about 1 .5 mm to about 9.5 mm, from about 2.0 mm to about 9.0 mm, from about 2.5 mm to about 8.5 mm, from about 3.0 mm to about 8.0 mm, from about 3.5 mm to about 7.5 mm, from about 4.0 mm to about 7.0 mm, from about 4.5 mm to about 6.5 mm, from about 5.0 mm to about 6.0 mm, or about 5.5 mm. In various embodiments, each protrusion / needle / pin is designed to be sufficiently long to reach the deeper layer of a skin (e.g., dermis layer of a skin), thereby allowing the active ingredient / substance(s) or bioactive(s) contained in / within the material to be in contact with skin cells for skin repair, and / or with immune cells for immunomodulation, without causing injury / trauma.

[0101] In various embodiments, the plurality of protrusions is arranged in one or more arrays. In various embodiments, the plurality of protrusions is arranged in one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty- one or more, twenty-two or more, twenty-three or more, twenty-four or more, or twenty-five or more arrays. For example, the plurality of protrusions may be arranged in 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 arrays.

[0102] In various embodiments, each array comprises from about 1 to about 50 protrusions. In various embodiments, each array comprises at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, or at least 15 protrusions. Each array may comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 protrusions.

[0103] In various embodiments, the plurality of protrusions is arranged in an orderly manner / arrangement, for e.g., in a linear arrangement / row / line / pattern. In various embodiments, each protrusion is uniformly / evenly / regularly spaced apart from another protrusion. In various embodiments, the distance between the protrusions falls in the range of from about 1.0 mm to about 10.0 mm. The distance between the protrusions may be falling in the range of from about 1.0 mm to about 10.0 mm, from about 1 .5 mm to about 9.5 mm, from about 2.0 mm to about 9.0 mm, from about 2.5 mm to about 8.5 mm, from about 3.0 mm to about 8.0 mm, from about 3.5 mm to about 7.5 mm, from about 4.0 mm to about 7.0 mm, from about 4.5 mm to about 6.5 mm, from about 5.0 mm to about 6.0 mm, or about 5.5 mm.

[0104] In various embodiments, the plurality of protrusions is extended from substantially centre / middle of the surface. In various embodiments, the material comprises a zone / area surrounding the plurality of protrusions. In various embodiments, the zone / area is substantially devoid of protrusions and / or has substantially lesser protrusions than the area of the material it surrounds.

[0105] In various embodiments, the protrusions extend substantially vertically from the surface of the material, that is, the protrusions extend from the surface of the material at an angle of about 90efrom the surface of the m terial / substrate base. In various embodiments, the protrusions have substantially no lean e.g. a lean of no more than about 5s, no more than about 4a, no more than about 3e, no more than about 2s, no more than about 1e, or no more than about 0.5sfrom a normal or perpendicular line extending from the surface of the material / substrate base. Advantageously, with little or no lean, the protrusion is able to effectively penetrate or reach the intended dermis layer of the skin.

[0106] In various embodiments, the material has a thickness / height / depth falling in the range of from about 0.05 mm to about 0.50 mm. The material may have a thickness / height / depth falling in the range of from about 0.05 mm to about 0.50 mm, from about 0.06 mm to about 0.49 mm, from about 0.07 mm to about 0.48 mm, from about 0.08 mm to about 0.47 mm, from about 0.09 mm to about 0.46 mm, from about 0.10 mm to about 0.45 mm, from about 0.11 mm to about 0.44 mm, from about 0.12 mm to about 0.43 mm, from about 0.13 mm to about 0.42 mm, from about 0.14 mm to about 0.41 mm, from about 0.15 mm to about 0.40 mm, from about 0.16 mm to about 0.39 mm, from about 0.17 mm to about 0.38 mm, from about 0.18 mm to about 0.37 mm, from about 0.19 mm to about 0.36 mm, from about 0.20 mm to about 0.35 mm, from about 0.21 mm to about 0.34 mm, from about 0.22 mm to about 0.33 mm, from about 0.23 mm to about 0.32 mm, from about 0.24 mm to about 0.31 mm, from about 0.25 mm to about 0.30 mm, from about 0.26 mm to about 0.29 r im, or from about 0.27 mm to about 0.28 mm.

[0107] In various embodiments, the material is part of a structure that has a length falling in the range of from about 10.0 mm to about 200.0 mm. The material may be part of a structure that has a length falling in the range of from about 10.0 mm to about 200.0 mm, from about 15.0 mm to about 195.0 mm, from about 20.0 mm to about 190.0 mm, from about 25.0 mm to about 185.0 mm, from about 30.0 mm to about 180.0 mm, from about 35.0 mm to about 175.0 mm, from about 40.0 mm to about 170.0 mm, from about 45.0 mm to about 165.0 mm, from about 50.0 mm to about 160.0 mm, from about 55.0 mm to about 155.0 mm, from about 60.0 mm to about 150.0 mm, from about 65.0 mm to about 145.0 mm, from about 70.0 mm to about 140.0 mm, from about 75.0 mm to about 135.0 mm, from about 80.0 mm to about 130.0 mm, from about 85.0 mm to about 125.0 mm, from about 90.0 mm to about 120.0 mm, from about 95.0 mm to about 115.0 mm, from about 100.0 mm to about 110.0 mm, or about 105.0 mm.

[0108] In various embodiments, the material is part of a structure that has a width falling in the range of from about 5.0 mm to about 150.0 mm. The material may be part of a structure that has a width falling in the range of from about 5.0 mm to about 150.0 mm, from about 10.0 mm to about 145.0 mm, from about 15.0 mm to about 140.0 mm, from about 20.0 mm to about 135.0 mm, from about 25.0 mm to about 130.0 mm, from about 30.0 mm to about 125.0 mm, from about 35.0 mm to about 120.0 mm, from about 40.0 mm to about 115.0 mm, from about 45.0 mm to about 110.0 mm, from about 50.0 mm to about 105.0 mm, from about 55.0 mm to about 100.0 mm, from about 60.0 mm to about 95.0 mm, from about 65.0 mm to about 90.0 mm, from about 70.0 mm to about 85.0 mm, or from about 75.0 mm to about 80.0 mm.

[0109] In various embodiments, the material has an infill density falling in the range of from about 70.0% to about 100.0%, from about 71 .0% to about 99.9%, from about 72.0% to about 99.8%, from about 73.0% to about 99.7%, from about 74.0% to about 99.6%, from about 75.0% to about 99.5%, from about 76.0% to about 99.0%, from about 77.0% to about 98.0%, from about 78.0% to about 97.0%, from about 79.0% to about 96.0%, from about 80.0% to about 95.0%, from about 81 .0% to about 94.0%, from about 82.0% to about 93.0%, from about 83.0% to about 92.0%, from about 84.0% to about 91 .0%, from about 85.0% to about 90.0%, from about 86.0% to about 89.0%, or from about 87.0% to about 88.0%.

[0110] In various embodiments, the ratio of the base PLGA to bioactive PLGA copolymer present in the material is about 60 - 99.9 : 0.1 - 40. The ratio of the base PLGA to bioactive PLGA copolymer present in the material may be about 60 - 99.9 : 0.1 - 40, about 70 - 99 : 1 - 30, about 80 - 95 : 5 - 20, or about 80 - 90 : 10 - 20.

[0111] In various embodiments, the material comprises from about 60.0 wt% to about 99.9 wt%, from about 61 .0 wt% to about 99.8 wt%, from about 62.0 wt% to about 99.7 wt%, from about 63.0 wt% to about 99.6 wt%, from about 64.0 wt% to about 99.5 wt%, from about 65.0 wt% to about 99.0 wt%, from about 66.0 wt% to about 98.5 wt%, from about 67.0 wt% to about 98.0 wt%, from about 68.0 wt% to about 97.0 wt%, from about 69.0 wt% to about 96.0 wt%, from about 70.0 wt% to about 95.0 wt%, from about 71.0 wt% to about 94.0 wt%, from about 72.0 wt% to about 93.0 wt%, from about 73.0 wt% to about 92.0 wt%, from about 74.0 wt% to about 91 .0 wt%, from about 75.0 wt% to about 90.0 wt%, from about 76.0 wt% to about 89.0 wt%, from about 77.0 wt% to about 88.0 wt%, from about 78.0 wt% to about 87.0 wt%, from about 79.0 wt% to about 86.0 wt%, from about 80.0 wt% to about 85.0 wt%, from about 81 .0 wt% to about 84.0 wt%, or from about 82.0 wt% to about 83.0 wt% of the base PLGA.

[0112] In various embodiments, the material comprises from about 0.1 wt% to about 40.0 wt%, from about 0.2 wt% to about 39.0 wt%, from about 0.3 wt% to about 38.0 wt%, from about 0.4 wt% to about 37.0 wt%, from about 0.5 wt% to about 36.0 wt%, from about 1 .0 wt% to about 35.0 wt%, from about 1 .5 wt% to about 34.0 wt%, from about 2.0 wt% to about 33.0 wt%, from about 3.0 wt% to about 32.0 wt%, from about 4.0 wt% to about 31 .0 wt%, from about 5.0 wt% to about 30.0 wt%, from about 6.0 wt% to about 29.0 wt%, from about 7.0 wt% to about 28.0 wt%, from about 8.0 wt% to about 27.0 wt%, from about 9.0 wt% to about 26.0 wt%, from about 10.0 wt% to about 25.0 wt%, from about 11 .0 wt% to about 24.0 wt%, from about 12.0 wt% to about 23.0 wt%, from about 13.0 wt% to about 22.0 wt%, from about 14.0 wt% to about 21 .0 wt%, from about 15.0 wt% to about 20.0 wt%, from about 16.0 wt% to about 19.0 wt%, or from about 17.0 wt% to about 18.0 wt% of the bioactive PLGA copolymer.

[0113] In various embodiments, the material is part of a printed structure. In various embodiments, the printed structure is a three-dimensional (3D) printed structure or part. In various embodiments, the material comprises a printed structure or part. For example, the printed structure or part may be a three- dimensional (3D) printed structure or part. In various embodiments therefore, there is provided a poly(lactic-co-glycolic acid) (PLGA) three-dimensional printed structure.

[0114] In various embodiments, the material is printed (e.g., three-dimensional printed) via fused filament fabrication (FFF), fused deposition modelling (FDM) or the like. In various embodiments, the material is obtained via FFF-based or FDM- based 3D printing. Advantageously, in various embodiments, that filament extrusion and 3DP by fused filament fabrication methods do not denature the biomolecules present in the material. In various embodiments, the material is suitable for use in preventing / reducing or lowering risk of scarring / scar formation of a wound. In various embodiments, the wound is an incisional wound such as surgical wound, caesarean wound or the like. Advantageously, in various embodiments, the material is capable of preventing / reducing scarring / scar formation of a wound without substantially causing breakage in or injury to the skin.

[0115] In various embodiments, the material is suitable for use in promoting / stimulating wound healing / regeneration / regrowth / repair / closure / treatment. In various embodiments, the wound is an incisional wound such as surgical wound, caesarean wound or the like.

[0116] In various embodiments, the material is suitable for use as a skin patch, dermal regeneration template, dermal substitute, skin scaffold, tissue scaffold, wound care, personal care and / or beauty product.

[0117] In various embodiments, there is provided a medical device comprising the bioactive PLGA material / printed structure or part as disclosed herein. In various embodiments, there is provided a skin patch or wound dressing comprising the bioactive PLGA material / printed structure or part as disclosed herein.

[0118] In various embodiments, the material / printed structure is substantially devoid of a drug (e.g., extraneous drug such as anti-inflammatory drug e.g., steroidal drugs) or a pharmaceutically active ingredient e.g. that is releasable to the human or animal body.

[0119] In various embodiments, the material / printed structure has one or more of the following properties: oxygen permeable; moisture / fluid / water permeable; flexible (i.e. capable of conforming to surface / site that it is applied to / on); thermally stable (i.e. capable of undergoing high temperatures e.g., melt processing); mechanically stable (i.e. does not warp and / or thin substantially); biodegradable; bioresorbable; and / or biocompatible. In various embodiments, the material / printed structure is biocompatible, i.e. the material is compatible with biological systems or parts of the biological systems without substantially or significantly eliciting an adverse physiological response such as a toxic reaction / response, an immune reaction / response, an injury or the like when used on the human or animal body. In various embodiments, the material is substantially devoid of substances that elicit an adverse physiological response.

[0120] Bioactive Poly(lactic-co-qlycolic acid) (PLGA) Copolymer

[0121] In various embodiments, the bioactive PLGA material comprises / consists essentially of / consists of a bioactive PLGA copolymer with a poly(norbornene- dicarboximide) backbone having one or more repeating units represented by general formula (I) and one or more repeating units represented by general formula (II): wherein

[0122] R1is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl or optionally substituted alkylcarbonylalkyl;

[0123] R2is optionally substituted alkyl; R3is selected from H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

[0124] L is heteroalkylene;

[0125] X comprises a bioactive moiety selected from the group consisting of proteins, peptides, oligopeptides, carbohydrates, oligosaccharides, sugar, collagen, hyaluronic acid, therapeutic / drug molecules and derivatives thereof;

[0126] Z1and Z2are each independently selected from CRaRb, O, NRC, SiRaRb, PRaor S, wherein Ra, Rband Rcare each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; p > 1; and q > 1.

[0127] In various embodiments, the repeating unit(s) represented by general formula (I) possess good mechanical strength / hardness. In various embodiments, the repeating unit(s) represented by general formula (II) and / or moiety X possess bioactivity, biocompatibility and / or biodegradability. In various embodiments, the repeating unit represented by general formula (I) has a higher mechanical strength than the repeating unit represented by general formula (II) and / or moiety X. Advantageously, the presence of repeating units represented by general formulae (I) and (II) in the bioactive PLGA copolymer imparts both bioactivity and mechanical strength to the copolymer, leading to a mechanically strong bioactive copolymer. In various embodiments, the copolymer may also be biocompatible and / or biodegradable. Accordingly, in various embodiments, the copolymer is capable of being classified as a biomaterial. Advantageously, due to the presence of synthetic and bioactive side chains, the bioactive PLGA copolymer may also have a high thermal stability than conventional biomolecules such as peptides, proteins, carbohydrates or glycosaminoglycans. Even more advantageously, the thermal stability of the bioactive peptide or oligosaccharide- based synthetic copolymer allows for embodiments of the copolymer to be suitable for processing at high temperatures or even harsh material processing such as melt processing / extrusion >100 °C, making the copolymer ideal / attractive for use in applications such as biomedical devices. In various embodiments, the repeating unit(s) represented by general formula (I) is substantially or completely non-bioactive, or at least less bioactive than the repeating unit(s) represented by general formula (II) and / or bioactive moiety X.

[0128] In various embodiments, L is a polymeric linker that links the bioactive moiety X to the poly(norbornene) backbone. Advantageously, L is designed to be adjustable and / or customizable based on the size of the bioactive moiety X and the size of the synthetic polymer (i.e. PLGA). The molecular weight and / or length of the polymeric linker L may be customized to suit the molecular weight and / or length of the bioactive moiety X and the synthetic polymer (i.e. PLGA), depending on the application the copolymer is to be used for. In various embodiments, physical properties of the copolymer can be changed / tuned / customized depending on the length of L (e.g., PEG chain). For example, depending on the rate of biodegradation required for the skin patch and its needle protrusions, L can be adjusted for quicker degradation.

[0129] In various embodiments, the molecular weight and / or length of the polymeric linker L is selected such that the overall molecular size of the repeating unit represented by general formula (I) is similar / comparable to the molecular size of the repeating unit represented by general formula (II). For example, if PLGA having a molecular weight of 4,000 is selected and a peptide having a molecular weight of from about 400 to about 500 is selected as the choice of bioactive moiety X, then L may be designed to comprise a molecular weight of about 3,400. It will be appreciated that in various embodiments, it is the length of L that gets adjusted to match the molecular weight of general formula (I) to molecular weight of general formula (II).

[0130] In various embodiments, the molecular weight of general formula (I) is comparable / substantially similar with / to the molecular weight of general formula (II). In various embodiments, the molecular weight of general formula (I) does not differ from the molecular weight of general formula (II) by more than 30% of the molecular weight of general formula (II) or vice versa. For example, the molecular weight of general formula (I) may be at most about 30% more or at most 30% less than the molecular weight of general formula (II) or vice versa. The molecular weight of general formula (I) may not differ from the molecular weight of general formula (II) by more than about 30%, more than about 25%, more than about 20%, more than about 15%, more about 10%, more than about 5%, more than about 4%, more than about 3%, more than about 2%, or more than about 1% of the molecular weight of general formula (II) or vice versa. In various embodiments, the molecular weight of general formula (I) does not differ from the molecular weight of general formula (II) by more than about 20% of the molecular weight of general formula (II) or vice versa. For example, the molecular weight of general formula (I) may be at most about 20% more or at most 20% less than the molecular weight of general formula (II) or vice versa. Advantageously, as the bioactive moiety bearing repeating unit has a molecular size / weight / length that is similar to that of the synthetic polymer (i.e. PLGA) bearing repeating unit, the length of the bioactive moiety X is extended, thereby allowing X to be “visible”, available for binding to cells or accessible to its targeted physiological site for desired bioactivity, i.e. not buried in a sea / matrix of synthetic polymers (i.e. PLGA).

[0131] In various embodiments, the molecular weight of general formula (I) is from about 100 to about 15,000, from about 200 to about 14,000, from about 300 to about 13,000, from about 400 to about 12,000, from about 500 to about 11 ,000, from about 1 ,000 to about 10,000, from about 1 ,500 to about 9,500, from about 2,000 to about 9,000, from about 2,500 to about 8,500, from about 3,000 to about 8,000, from about 3,500 to about 7,500, from about 4,000 to about 7,000, from about 4,500 to about 6,500, from about 5,000 to about 6,000 or about 5,500.

[0132] In various embodiments, the molecular weight of general formula (II) is about 15,000, about 14,000, about 13,000 or at least about 12,000. In various embodiments, the molecular weight of general formula (II) is from about 100 to about 15,000, from about 200 to about 14,000, from about 300 to about 13,000, from about 400 to about 12,000, from about 500 to about 11 ,000, from about 1 ,000 to about 10,000, from about 1 ,500 to about 9,500, from about 2,000 to about 9,000, from about 2,500 to about 8,500, from about 3,000 to about 8,000, from about 3,500 to about 7,500, from about 4,000 to about 7,000, from about 4,500 to about 6,500, from about 5,000 to about 6,000 or about 5,500.

[0133] In various embodiments, the total molecular weight of general formula (I) and general formula (II) is kept to about 300,000, no more than about 300,000, no more than about 200,000, no more than about 100,000, no more than about 90,000, no more than about 80,000, no more than about 70,000, no more than about 60,000, no more than about 50,000, no more than about 45,000, no more than about 40,000, no more than about 35,000, no more than about 30,000, no more than about 25,000, no more than about 20,000, or no more than about 15,000 to facilitate copolymerisation.

[0134] In various embodiments, the ratio of the number of repeating units represented by general formula (I) to the number of repeating units represented by general formula (II) in the bioactive PLGA copolymer is from about 1 :1 to about 1 :100, from about 1 :2 to about 1 :99, from about 1 :3 to about 1 :98, from about 1 :4 to about 1 :97, from about 1 :5 to about 1 :96, from about 1 :6 to about 1 :95, from about 1 :7 to about 1 :90, from about 1 :8 to about 1 :85, from about 1 :9 to about 1 :80, from about 1 :10 to about 1 :75, from about 1 :15 to about 1 :70, from about 1 :20 to about 1 :65, from about 1 :25 to about 1 :60, from about 1 :30 to about 1 :55, from about 1 :35 to about 1 :50, or from about 1 :40 to about 1 :45.

[0135] In various embodiments, the number of repeating units represented by general formula (I) in the bioactive PLGA copolymer is from about 10 to about 1 ,000. For example, the number of repeating units represented by general formula (I) in the bioactive PLGA copolymer may be from about 10 to about 1 ,000, from about 50 to about 950, from about 100 to about 900, from about 150 to about 850, from about 200 to about 800, from about 250 to about 750, from about 300 to about 700, from about 350 to about 650, from about 400 to about 600, from about 450 to about 550, or about 500.

[0136] In various embodiments, the number of repeating units represented by general formula (II) in the bioactive PLGA copolymer is from about 10 to about 1 ,000. For example, the number of repeating units represented by general formula (II) in the bioactive PLGA copolymer may be from about 10 to about 1 ,000, from about 50 to about 950, from about 100 to about 900, from about 150 to about 850, from about 200 to about 800, from about 250 to about 750, from about 300 to about 700, from about 350 to about 650, from about 400 to about 600, from about 450 to about 550, or about 500.

[0137] In various embodiments, L is hydrophilic. As L is adjustable, the hydrophilicity of the repeating unit represented by general formula (II) and also the overall hydrophilicity of the bioactive PLGA copolymer may be adjusted as desired. Advantageously, the presence of L increases the hydrophilicity of the repeating unit represented by general formula (II) and also the overall hydrophilicity of the bioactive synthetic copolymer. Even more advantageously, the presence of L increases the hydrophilicity of the bioactive synthetic copolymer, therefore softening the synthetic polymeric chains which are hydrophobic, making the copolymer less stiff after processing. It will be appreciated by a person skilled in the art that, bioactive moieties and synthetic polymers are typically mutually incompatible as the individual bioactive moiety is generally hydrophilic while synthetic polymer is generally hydrophobic. Advantageously, L in repeating unit represented by general formula (II) is also used to extend the chain length of the bioactive moiety X attached at the end of L.

[0138] In various embodiments, L is amorphous. Advantageously, the presence of L increases the amorphousness and / or decreases the crystallinity of the bioactive synthetic copolymer, making the copolymer useful for crafting softer, flexible or less stiff plastics. In various embodiments, L is a heteroalkylene having at least 20 carbon atoms, at least 30 carbon atoms, at least 40 carbon atoms, at least 50 carbon atoms, at least 60 carbon atoms, at least 70 carbon atoms, at least 80 carbon atoms, at least 90 carbon atoms, at least 100 carbon atoms, at least 150 carbon atoms, at least 200 carbon atoms, at least 250 carbon atoms or at least 300 carbon atoms. In various embodiments, L is C20-C300 heteroalkylene or a heteroalkylene having from 20 carbon atoms to 300 carbon atoms.

[0139] In various embodiments, L has a number average molecular weight of between about 500 and about 7,000. L may have a number average molecular weight of about 600, about 700, about 800, about 900, about 1 ,000, about 1 ,500, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, about 5,000, about 5,500, about 6,000, about 6,500 or about 7,000. In various embodiments, when X comprises a small bioactive moiety, the molecular weight of L may be adjusted to about 7,000 so that the total molecular weight of general formula (I) and general formula (II) is kept to no more than about 10,000. In various embodiments, the number average molecular weight of L is from about 1 ,000 to about 6,000.

[0140] In various embodiments, the heteroatom in L is O. In various embodiments, L is polyalkylene glycol, e.g., poly(C2-C4 alkylene glycol). L may be selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), polybutylene glycol (PBG) and the like, and combinations thereof. Advantageously, the use of a polyalkylene glycol such as PEG can increase hydrophilicity of the copolymer. In various embodiments, polyalkylene glycol such as PEG are used as spacers, linkers or linking groups in the overall polymers, instead of as terminal groups.

[0141] In various embodiments, L is polyalkylene glycol having at least about 10 repeating units, at least about 15 repeating units, at least about 20 repeating units, at least about 21 repeating units, at least about 22 repeating units, at least about 23 repeating units, at least about 24 repeating units, at least about 25 repeating units, at least about 30 repeating units, at least about 40 repeating units, at least about 50 repeating units, at least about 60 repeating units, at least about 70 repeating units, at least about 80 repeating units, at least about 90 repeating units, at least about 100 repeating units, at least about 150 repeating units, at least about 200 repeating units, or at least about 250 repeating units. In various embodiments, L comprises from about 10 monomers / repeating units to about 250 monomers / repeating units. Unlike conventional polymers which uses a short PEG chain, embodiments of the bioactive synthetic copolymer disclosed herein incorporate a long polyalkylene glycol chain of at least 21 repeating units at L.

[0142] In various embodiments, L comprises from about 10 monomers / repeating units to about 250 monomers / repeating units. For example, L is selected from the group consisting of PEGsoo, PEGeoo, PEG / oo, PEGsoo, PEGsoo, PEGwoo, PEGnoo, PEG1200, PEGnoo, PEG1400, PEGnoo, PEG2000, PEG2500, PEG3000, PEG3500, PEG4000, PEG4500, PEG5000, PEG5500, PEGeooo, PEGeeoo and mixtures thereof.

[0143] In various embodiments, X is coupled to the poly(norbornene dicarboximide) backbone through a carboxylic acid functionality in the following arrangement: -R1-L-NR3-C(=O)-X. Advantageously, by linking X through a carboxylic acid functionality, amine terminal group(s) in X is / are free up for delivering its bioactivity, therefore ensuring the bioavailability of X. It will be appreciated that as amine group(s) confer bioactivity, exhausting up amine groups in bioactive moieties for polymer binding may be undesirable.

[0144] In various embodiments, X is coupled to the polyfnorbornene dicarboximide) backbone via peptide / amide linkage, i.e. -NR3-C(=O)-. Advantageously, the bioactive PLGA copolymer disclosed herein is considerably stronger and / or stable than conventional polymers that contain ester linkages. Without being bound by theory, it is believed that amide linkages are stronger than ester linkages because ester linkages are more prone to hydrolysis, which may release bioactive moieties into the bloodstream, leading to a premature metabolism of bioactive moieties. Advantageously, the presence of an amide linkage prevents the bioactive moieties from breaking off from the polymer chain, therefore ensuring the bioavailability of the bioactive moieties. It will be appreciated that the active site for bioactivity (e.g, cell binding) is at bioactive moieties in general formula (II).

[0145] In various embodiments, one or more of H atoms in alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylcarbonyl and alkylcarbonylalkyl is / are optionally replaced by hydroxy, hydroxyalkyl, halogen, haloalkyl, cyano, cyanoalkyl and nitro.

[0146] In various embodiments, R1is selected from C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 alkoxyalkyl, C2-C20 alkylcarbonyl or C3-C20 alkylcarbonylalkyl. The C1-C20 alkyl substituents may be straight or branched substituents selected from methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hexyl, amyl, 1 ,2-dimethylpropyl, 1 ,1 -dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl,

[0147] 1 .3-dimethylbutyl, 1 ,2,2-trimethylpropyl, 1 ,1 ,2-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1 -methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,

[0148] 4.4-dimethylpentyl, 1 ,2-dimethylpentyl, 1 ,3-dimethylpentyl, 1 ,4-dimethylpentyl,

[0149] 1 .2.3-trimethylbutyl, 1 ,1 ,2-trimethylbutyl, 1 ,1 ,3-trimethylbutyl, 5-methylheptyl, 1 -methylheptyl, octyl, nonyl, decyl, the like or combinations thereof.

[0150] In various embodiments, R2is selected from straight or branched C1-C20 alkyl. The C1-C20 alkyl substituents may be straight or branched substituents selected from methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, hexyl, amyl, 1 ,2-dimethylpropyl, 1 ,1 -dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl,

[0151] 1 .3-dimethylbutyl, 1 ,2,2-trimethylpropyl, 1 ,1 ,2-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1 -methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,

[0152] 4.4-dimethylpentyl, 1 ,2-dimethylpentyl, 1 ,3-dimethylpentyl, 1 ,4-dimethylpentyl, 1 ,2,3-trimethylbutyl, 1 ,1 ,2-trimethylbutyl, 1 ,1 ,3-trimethylbutyl, 5-methylheptyl, 1 -methylheptyl, octyl, nonyl, decyl, the like or combinations thereof. R2may be straight or branched C1-C4 alkyl substituents. In various embodiments, the length of R2is the same as the length of a repeating unit in L. For example, if L is polyfbutylene glycol), then R2is butyl. In another example, if L is polyethylene glycol), then R2is ethyl. It will be appreciated that in various embodiments, R2is carefully designed to match L.

[0153] In various embodiments, R3is selected from H, C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl.

[0154] In various embodiments, Z1and Z2are each independently selected from CH2, O, NH, SiRaRb, PRaor S. The poly(norbornene) backbone may be selected from the group consisting of poly(norbornene-imide), poly(norbornene- dicarboximide), poly(5-norbornene-2,3-dicarboximide), poly(7-oxanorbornene), poly(oxanorbornene-imide), poly(oxanorbornene-dicarboximide) and the like. In various embodiments, Z1and Z2are each independently selected from CRaRb, O, NRC, SiRaRb, PRaor S, wherein Ra, Rb, and Rcare each independently selected from the group consisting of H, C1-C20 alkyl, C1-C20 alkenyl and C1-C20 alkynyl. In various embodiments, Z1is CH2. In various embodiments, Z2is CH2.

[0155] In various embodiments, X comprises a bioactive moiety selected from proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof. In various embodiments, proteins, peptides, carbohydrates or therapeutic / drug molecules derivatives thereof include proteins, peptides, carbohydrates or therapeutic / drug molecules that are or have been optionally modified to contain one carboxylic acid terminal group. In some embodiments, the bioactive moiety contains only one carboxylic acid terminal group.

[0156] In various embodiments, the bioactive moiety comprises a monocarboxylic acid. Advantageously, in some embodiments, the use of a bioactive moiety having a monocarboxylic acid terminal group may reduce / avoid the possibility of an undesirable crosslinking as compared to the case of using more than one carboxylic acid. In some embodiments therefore, the bioactive moiety X is substantially devoid of more than one carboxylic acid terminal group, for e.g., a dicarboxylic acid or tricarboxylic acid.

[0157] In various embodiments, X comprises protein or peptide. X may be a peptide sequence, laminin-derived peptide, integrin binding peptide, cellpenetrating peptide, collagen mimics or collagen fragments. In various embodiments, X comprises from 2 to 50 amino acid residues, from 2 to 40 amino acid residues or from 2 to 20 amino acid residues in any sequence. In various embodiments, X comprises 50 amino acid residues, 40 amino acid residues, 30 amino acid residues, 25 amino acid residues, 20 amino acid residues, 15 amino acid residues, 10 amino acid residues, 9 amino acid residues, 8 amino acid residues, 7 amino acid residues, 6 amino acid residues, 5 amino acid residues, 4 amino acid residues or 3 amino acid residues in any sequence. The amino acid residues may be selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, asparagine, glutamine, glycine, serine, threonine, serine, asparagine, glutamine, tyrosine, cysteine, lysine, arginine, histidine, aspartic acid and glutamic acid. In various embodiments, X is a peptide sequence comprising 3 to 20 natural amino acids. X may be integrin binding peptide selected from the group consisting of arginineglycine-aspartic acid (RGD), SRGDS and RGDS; laminin-derived peptide A5G81 (AGQWHRVSVRWGC); osteopontin derived peptides SVVYGLR; and cell- penetrating / antimicrobial peptide selected from (IRIK)2 or (IKKI)s. In various embodiments, X is a collagen sequence comprising 3 to 20 units of glycine (G), proline (P) and hydroxyproline (Hyp) in any sequence or permutation. X may be collagen fragment having a (PHypG)n type sequence, (PGHyp)n type sequence, (HypGP)n type sequence, (HypPG)n type sequence, (GHypP)ntype sequence, (GPHyp)n type sequence or collagen mimic DGEA.

[0158] In various embodiments, X comprises carbohydrate or sugar. In various embodiments, X comprises monosaccharide, disaccharide, oligosaccharide or polysaccharide. In various embodiments, X comprises from 2 to 50 saccharide units, from 2 to 40 saccharide units, from 2 to 20 saccharide units or from 10 to 14 saccharide units. In various embodiments, X comprises 50 saccharide units, 40 saccharide units, 30 saccharide units, 25 saccharide units, 20 saccharide units, 15 saccharide units, 14 saccharide units, 13 saccharide units, 12 saccharide units, 11 saccharide units, 10 saccharide units, 9 saccharide units, 8 saccharide units, 7 saccharide units, 6 saccharide units, 5 saccharide units, 4 saccharide units or 3 saccharide units or 2 saccharide units. X may be heparin sulfate (HS) or glycosaminoglycans (GAGs). In various embodiments, X is heparin sulfate / oligosaccharide selected from the group consisting of DP8, DP10, DP12, DP14 and DP16. In various embodiments, X is hyaluronic acid which is the simplest form of glycosaminoglycan (GAG). For example, X may be hyaluronic acid comprising from 8 to 20 saccharide units, from 8 to 13 saccharide units, about 8 saccharide units, about 9 saccharide units, about 10 saccharide units, about 11 saccharide units, about 12 saccharide units, about 13 saccharide units, about 14 saccharide units, about 15 saccharide units, about 16 saccharide units, about 17 saccharide units, about 18 saccharide units, about 19 saccharide units, or about 20 saccharide units.

[0159] In various embodiments, the term “hyaluronic acid” comprises and / or may be used interchangeably with the term “hyaluronic acid and / or derivatives thereof”, “hyaluronic acid”, “hyaluronan”, “derivatives of hyaluronic acid”, “conjugate base of hyaluronic acid” and ’’“hyaluronate”.

[0160] In various embodiments, X is chemically coupled to the rest of general formula (II) via its hydroxy group. For example, when X is carbohydrate / saccharide, oxidation and / or reductive amination reactions may be performed on the carbohydrate’s hydroxy for linking X to general formula (II). -CH2OH on the saccharide may be oxidised to -C(=O)H, which subsequently undergoes reductive amination using the -NH2 terminal on L to create a peptide linkage. In various embodiments, X comprises a carbohydrate / saccharide that contained or has been modified to contain one carboxylic acid terminal group. Modification by one or more chemical reaction(s) such as oxidation may be performed on the carbohydrate / saccharide to create a carboxylic acid group. In various embodiments, modification is performed on a hydroxyl group that is originally present in the carbohydrate / saccharide. In various embodiments, -CH2OH on the carbohydrate / saccharide is oxidized completely to -C(=O)OH, which subsequently reacts with a -NH2 terminal on L to create a peptide linkage that links the carbohydrate / saccharide to the rest of general formula (II): X-C(=O)-NH-L- It will be appreciated, however, that no modification to the carbohydrate / saccharide may be required / necessary if a carboxylic acid is naturally present in the carbohydrate / saccharide.

[0161] In various embodiments, X comprises therapeutic / drug molecule. In various embodiments, X comprises antibiotic, antimicrobial, antibacterial, blood thinning agents or anti-inflammatory agents. X may be penicillin, amoxicillin, amphotericin, ciprofloxacin (GIF), atorvastatin, aspirin or aminoglycoside-based molecules selected from streptomycin, ribostamycin or gentamycin. It will be appreciated that X may be any therapeutic or drug molecule that contains a carboxylic acid group.

[0162] In various embodiments, X is chemically coupled to the rest of general formula (II) via one of its chemical moiety selected from the group consisting of -COOH, -CH2OH, -CH2NH2 and =CHNH2. For example, -CH2NH2 or =CHNH2on the drug molecule may be coupled to a small dicarboxylic acid before reacting with a -NH2 terminal on L to create a peptide linkage that links the drug molecule to the rest of general formula (II): X-C(=O)-NH-L-.

[0163] In various embodiments, X comprises a therapeutic / drug molecule that contained or has been modified to contain one carboxylic acid terminal group. Modification by one or more chemical reaction(s) such as oxidation may be performed on the therapeutic / drug molecule to create a carboxylic acid group. In various embodiments, modification is performed on a hydroxyl group that is originally present in the therapeutic / drug molecule. For example, in various embodiments when X is ribostamycin or gentamycin, -CH2OH on the drug molecule is oxidized completely to -C(=O)OH, which subsequently reacts with a -NH2 terminal on L to create a peptide linkage that links the drug molecule to the rest of general formula (II): X-C(=O)-NH-L- It will be appreciated, however, that no modification to the therapeutic / drug molecule may be required / necessary if a carboxylic acid is already present in the therapeutic / drug molecule.

[0164] In various embodiments, the bioactive moiety is or has been modified to contain one carboxylic acid terminal group. For example, if a carboxylic acid terminal group is absent in a carbohydrate or therapeutic / drug molecule, the carbohydrate or therapeutic / drug molecule may be modified to add a carboxylic acid at one of the carbohydrate or therapeutic / drug molecule terminals. The modification may comprise oxidation reaction(s) to convert a hydroxy group in the carbohydrate to carboxylic acid.

[0165] In various embodiments, p > 1. In various embodiments, p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49,

[0166] 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70,

[0167] 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 ,

[0168] 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109,

[0169] 110, 111 , 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149 or 150. In various embodiments, q > 1. In various embodiments, q is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17,

[0170] 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38,

[0171] 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59,

[0172] 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

[0173] 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 , 112, 113, 114, 115, 1 16, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149 or 150.

[0174] In various embodiments, the total molecular weight of general formula (I) is kept to no more than about 15,000 or no more than about 10,000. It will be appreciated that copolymerisation may become inefficient when the total molecular weight of general formula (I) and (II) is too high. In various embodiments, when the bioactive PLGA copolymer is used for applications which require fast biodegradation, the molecular weight of general formula (I) is kept low by adjusting the value of p and / or q.

[0175] In various embodiments, the repeating unit represented by general formula (II) is in an amount of from about 1 molar % to about 100 molar %, from about 2 molar % to about 99 molar %, from about 3 molar % to about 98 molar %, from about 4 molar % to about 97 molar %, from about 5 molar % to about 96 molar %, from about 10 molar % to about 95 molar %, from about 15 molar % to about 90 molar %, from about 20 molar % to about 85 molar %, from about 25 molar % to about 80 molar %, from about 30 molar % to about 75 molar %, from about 35 molar % to about 70 molar %, from about 40 molar % to about 65 molar %, from about 45 molar % to about 60 molar %, or from about 50 molar % to about 55 molar % relative to the copolymer. In various embodiments, the repeating unit represented by general formula (II) is in an amount of from about 1 molar % to about 10 molar % relative to the copolymer. In various embodiments, the bioactive moiety is about 2 molar %, about 3 molar %, about 4 molar %, about 5 molar %, about 6 molar %, about 7 molar %, about 8 molar %, about 9 molar % or about 10 molar % of the bioactive PLGA copolymer.

[0176] In various embodiments, the bioactive PLGA copolymer has a number average molecular weight (Mn) falling in the range of from about 1 ,000 to about 300,000, from about 2,000 to about 250,000, from about 3,000 to about 200,000, from about 4,000 to about 150,000, from about 5,000 to about 100,000, from about 10,000 to about 90,000, from about 20,000 to about 80,000, from about 30,000 to about 70,000, from about 40,000 to about 60,000, or about 50,000.

[0177] In various embodiments, the bioactive PLGA copolymer has a polydispersity index (PDI) falling in the range of from about 1.0 to about 10.0. In various embodiments, PDI of the bioactive PLGA copolymer is about 1.0, about 1 .5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5 or about 10.0. In various embodiments, the bioactive PLGA copolymer has a polydispersity index (PDI) falling in the range of from about 1 .0 to about 3.0, from about 1.05 to about 2.95, from about 1.1 to about 2.9, from about 1 .2 to about 2.8, from about 1 .4 to about 2.6, from about 1 .6 to about 2.4, from about 1 .8 to about 2.2 or about 2.0. In various embodiments, the PDI of the bioactive PLGA copolymer is no more than 1 .50.

[0178] In various embodiments, the one or more repeating units represented by general formula (I) and the one or more repeating units represented by general formula (II) are designed to link to the poly(norbornene) backbone via at least covalent interactions. In various embodiments, each repeating unit represented by general formula (I) is covalently bonded to the poly(norbornene) backbone and / or each repeating unit represented by general formula (II) is covalently bonded to the poly(norbornene) backbone. Advantageously, as bioactive moieties (in general formula (II)) are covalently bonded to the bioactive PLGA copolymer, bioactivity is localized. In various embodiments, the bioactive moieties do not leach out from the polymer, therefore preventing undesirable / unwanted side effects caused by biomolecules entering the circulatory system and / or reaching unintended parts of the body system. Embodiments of the bioactive synthetic copolymer therefore overcome problems faced by conventional biomolecules that are administered as drugs which may metabolized prematurely before therapeutic effects are achieved. In various embodiments, the bioactive moieties such as drug molecules do not leach out into media which can escape into the environment in the event that disposal is improperly managed.

[0179] It will be appreciated that other interactions such as Van der Waals interactions may also be present within the copolymer.

[0180] In various embodiments, the bioactive PLGA copolymer comprises a brush, bottlebrush, block, comb or graft-copolymer structure. In various embodiments, the repeating units may be randomly distributed / arranged within the polymer.

[0181] In various embodiments, the one or more repeating units represented by general formula (II) comprises two or more different types of bioactive moiety X. In various embodiments, the one or more repeating units represented by general formula (II) comprises 2, 3, 4, 5, 6, 7 or 8 different types of bioactive moiety X. For example, within a bioactive PLGA copolymer, there may be repeating units represented by general formula (II) comprising peptide as X and repeating units represented by general formula (II) comprising carbohydrate as X. Advantageously, in various embodiments, the bioactive PLGA copolymer imparts two or more different types of bioactivities.

[0182] In various embodiments, the bioactive PLGA copolymer is a random polymer or a block copolymer. In some embodiments, the block polymer is a diblock or a triblock polymer. For example, the copolymer may have or is made up of two or three different polymer blocks. In some embodiments, the multi-block copolymer comprises more than three polymeric blocks. The blocks may be randomly distributed / arranged within the polymer.

[0183] In various embodiments, the bioactive PLGA copolymer is selected from one of the following: PLGA-RGD copolymer comprising RGD in general formula (II) (Scheme 1 ); and PLGA-HA copolymer comprising HA in general formula (II) (Scheme 2).

[0184]

[0185] Scheme 1 . Chemical structure of an example of PLGA-RGD copolymer

[0186]

[0187] Scheme 2. Chemical structure of an example of PLGA-HA copolymer

[0188] In various embodiments, x > 1. In various embodiments, x is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28,

[0189] 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49,

[0190] 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70,

[0191] 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 ,

[0192] 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 , 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125,

[0193] 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 ,

[0194] 142, 143, 144, 145, 146, 147, 148, 149 or 150. In various embodiments, y > 1 . In various embodiments, y is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17,

[0195] 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59,

[0196] 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

[0197] 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 , 112, 113, 114, 115, 1 16, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149 or 150. In various embodiments, n > 1. In various embodiments, n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49,

[0198] 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70,

[0199] 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 ,

[0200] 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109,

[0201] 110, 111 , 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149 or 150.

[0202] Advantageously, the bioactive PLGA copolymer disclosed herein is highly customizable. Depending on the application that the bioactive PLGA copolymer is intended, X with the desired biological activity may be selected to match the synthetic polymer PLGA, to eventually obtain the bioactive PLGA copolymer with the desired repeating units represented by general formulae (I) and (II).

[0203] It will be appreciated that the bioactive PLGA copolymer disclosed herein may be obtained by ROMP such as that disclosed in PCT application no. PCT / SG2020 / 050621 and PCT / SG2023 / 050288, which are fully incorporated in its entirety by reference.

[0204] Method of Preparing Bioactive PLGA Material

[0205] There is provided a method of preparing a bioactive PLGA material / printed structure or part as disclosed herein, the method comprising:

[0206] (i) providing / producing a bioactive PLGA filament; and

[0207] (ii) printing a bioactive PLGA material from the bioactive PLGA filament according to a design model to obtain a printed structure or part with a plurality of protrusions printed thereon. In various embodiments, there is also provided a bioactive polymer filament obtained from the filament production method disclosed herein. Advantageously, the bioactive polymer filament is a feedstock designed for use in fused filament fabrication (FFF) or fused deposition modelling (FDM) method of manufacturing which consists of thermally stable biological molecules that improves bioactivity with adequate mechanical properties. The bioactive polymer filament may comprise / consist essentially of / consist of the base polymer and bioactive copolymer disclosed herein. In various embodiments, the bioactive polymer filament is substantially free from or devoid of other additives such as lubricants.

[0208] In various embodiments, the bioactive polymer filament is substantially free from or devoid of other non-medically approved ingredients. In various embodiments, the bioactive polymer filament is a monofilament.

[0209] In various embodiments, the step (i) of providing / producing a bioactive PLGA filament comprises:

[0210] (i-a) providing a base PLGA powder and a bioactive PLGA copolymer;

[0211] (i-b) mixing / blending the base PLGA powder with the bioactive PLGA copolymer to obtain a bioactive PLGA formulation / mixture / blend; and

[0212] (i-c) extruding a bioactive PLGA filament from the formulation / mixture / blend.

[0213] In various embodiments, the step (ii) of printing a bioactive PLGA material from the bioactive PLGA filament comprises:

[0214] (ii-a) feeding the bioactive PLGA filament into a printing apparatus;

[0215] (ii-b) applying heat to the bioactive PLGA filament to obtain a molten form of the bioactive PLGA; and

[0216] (ii-c) depositing the molten bioactive PLGA on a print bed to form a printed part or structure. In various embodiments, the printing apparatus comprises a three- dimensional (3D) printing apparatus (e.g., FFF-based or FDM-based 3D printing apparatus). In various embodiments, the printed part or structure comprises a printed three-dimensional part or structure.

[0217] Accordingly, there is also provided a fused filament fabrication (FFF) or fused deposition modelling (FDM) based three-dimensional printing method using the bioactive polymer filament disclosed herein as a feedstock. In various embodiments, the method comprises feeding a bioactive polymer filament disclosed herein into a FFF or FDM based three-dimensional printing apparatus (e.g. fed to the print head of the apparatus); applying heat to bioactive polymer filament to obtain a molten / melted form of the bioactive polymer; and depositing the molten / melted bioactive polymer on a print bed to form a printed three- dimensional part or structure. Advantageously, FFF or FDM 3D printing / printers have great advantages such as low cost, shortened time to market and part customisation which are significantly beneficial for medical technology.

[0218] In various embodiments, the extruding step (i-c) is performed using an extruder having one or more rotating screws. The extruder may have one or more, or two or more rotating screws. For example, the extruder may be a single screw extruder. Advantageously, as opposed to a single screw extruder, an extruder with two or more rotating screws may achieve good and uniform mixing / blending of the base polymer and bioactive copolymer. In one example, the extruder is a twin screw extruder (TSE). In another example, the extruder is a multi-screw extruder. The twin screw and / or multi-screw extruder may be intermeshing or non-intermeshing and co-rotating or counter-rotating. Each screw may be made of multiple screw elements to support either feeding, mixing or discharging. In various embodiments, the mixing elements along each screw offers a unique advantage as it kneads the molten blended materials to achieve homogeneity. For example, in various embodiments, these elements form at three different segments along each screw, granting a thorough mixing process. In various embodiments, the extruder comprises a melt pump for building pressure and for ensuring constant output. The nozzle size of the extruder or melt pump of the extruder may have a diameter that allows for a filament diameter falling in the range of from about 1.0 mm to about 6.0 mm to be produced. The extruder or melt pump of the extruder may have a nozzle diameter that falls in the range of from about 1 .00 mm to about 6.00 mm, from about 1.10 mm to about

[0219] 5.90 mm, from about 1 .20 mm to about 5.80 mm, from about 1 .30 mm to about

[0220] 5.70 mm, from about 1 .40 mm to about 5.60 mm, from about 1 .50 mm to about

[0221] 5.50 mm, from about 1 .60 mm to about 5.40 mm, from about 1 .70 mm to about

[0222] 5.30 mm, from about 1 .80 mm to about 5.20 mm, from about 1 .90 mm to about

[0223] 5.10 mm, from about 2.00 mm to about 5.00 mm, from about 2.10 mm to about

[0224] 4.90 mm, from about 2.20 mm to about 4.80 mm, from about 2.30 mm to about

[0225] 4.70 mm, from about 2.40 mm to about 4.60 mm, from about 2.50 mm to about

[0226] 4.50 mm, from about 2.60 mm to about 4.40 mm, from about 2.70 mm to about

[0227] 4.30 mm, from about 2.80 mm to about 4.20 mm, from about 2.90 mm to about

[0228] 4.10 mm, from about 3.00 mm to about 4.00 mm, from about 3.10 mm to about

[0229] 3.90 mm, from about 3.20 mm to about 3.80 mm, from about 3.30 mm to about

[0230] 3.70 mm, from about 3.40 mm to about 3.60 mm, or about 3.50 mm.

[0231] In various embodiments, the formulation / mixture of base PLGA polymer and bioactive PLGA copolymer comprises from about 60.0 wt% to about 99.9 wt%, from about 61 .0 wt% to about 99.8 wt%, from about 62.0 wt% to about 99.7 wt%, from about 63.0 wt% to about 99.6 wt%, from about 64.0 wt% to about 99.5 wt%, from about 65.0 wt% to about 99.0 wt%, from about 66.0 wt% to about 98.5 wt%, from about 67.0 wt% to about 98.0 wt%, from about 68.0 wt% to about 97.0 wt%, from about 69.0 wt% to about 96.0 wt%, from about 70.0 wt% to about 95.0 wt%, from about 71 .0 wt% to about 94.0 wt%, from about 72.0 wt% to about 93.0 wt%, from about 73.0 wt% to about 92.0 wt%, from about 74.0 wt% to about 91 .0 wt%, from about 75.0 wt% to about 90.0 wt%, from about 76.0 wt% to about 89.0 wt%, from about 77.0 wt% to about 88.0 wt%, from about 78.0 wt% to about 87.0 wt%, from about 79.0 wt% to about 86.0 wt%, from about 80.0 wt% to about 85.0 wt%, from about 81 .0 wt% to about 84.0 wt%, or from about 82.0 wt% to about 83.0 wt% of the base PLGA polymer.

[0232] In various embodiments, the formulation / mixture of base PLGA polymer and bioactive PLGA copolymer comprises from about 0.1 wt% to about 40.0 wt%, from about 0.1 wt% to about 39.0 wt%, from about 0.2 wt% to about 38.0 wt%, from about 0.3 wt% to about 37.0 wt%, from about 0.4 wt% to about 36.0 wt%, from about 0.5 wt% to about 35.0 wt%, from about 1 .0 wt% to about 34.0 wt%, from about 1 .5 wt% to about 33.0 wt%, from about 2.0 wt% to about 32.0 wt%, from about 3.0 wt% to about 31 .0 wt%, from about 4.0 wt% to about 30.0 wt%, from about 5.0 wt% to about 29.0 wt%, from about 6.0 wt% to about 28.0 wt%, from about 7.0 wt% to about 27.0 wt%, from about 8.0 wt% to about 26.0 wt%, from about 9.0 wt% to about 25.0 wt%, from about 10.0 wt% to about 24.0 wt%, from about 11 .0 wt% to about 23.0 wt%, from about 12.0 wt% to about 22.0 wt%, from about 13.0 wt% to about 21 .0 wt%, from about 14.0 wt% to about 20.0 wt%, from about 15.0 wt% to about 19.0 wt%, from about 16.0 wt% to about 18.0 wt%, or about 17.0 wt% of the bioactive PLGA copolymer.

[0233] In various embodiments, the method further comprises, prior to the step (ii) of printing, digitally modelling / designing a geometry / structure (e.g., 3D geometry / structure) using a digital software. In various embodiments, the FFF or FDM based three-dimensional printing is according to a design model to obtain a structure with the desired design. The bioactive PLGA material may be printed in any shape and size as desired in order to suit a particular application.

[0234] In various embodiments, each protrusion is digitally modelled / designed to comprise a convex structure having a base and a tip (e.g., a sharp tip). In various embodiments, each protrusion is digitally modelled / designed to comprise a tapering structure that tapers from a larger base (e.g. larger diameter) to a smaller tip (e.g. smaller diameter). In various embodiments, each protrusion is digitally modelled / designed to comprise a structure having a base tapering to a tip. In various embodiments, each protrusion is digitally modelled / designed to comprise a needle-like / needle-shaped or pin-like / pin-shaped structure.

[0235] In various embodiments, each base of the protrusion is digitally modelled / designed to have a diameter of from about 0.50 mm to about 2.50 mm, from about 0.55 mm to about 2.45 mm, from about 0.60 mm to about 2.40 mm, from about 0.65 mm to about 2.35 mm, from about 0.70 mm to about 2.30 mm, from about 0.75 mm to about 2.25 mm, from about 0.80 mm to about 2.20 mm, from about 0.85 mm to about 2.15 mm, from about 0.90 mm to about 2.10 mm, from about 0.95 mm to about 2.05 mm, from about 1.00 mm to about 2.00 mm, from about 1 .05 mm to about 1 .95 mm, from about 1.10 mm to about 1 .90 mm, from about 1.15 mm to about 1 .85 mm, from about 1 .20 mm to about 1 .80 mm, from about 1 .25 mm to about 1 .75 mm, from about 1 .30 mm to about 1 .70 mm, from about 1 .35 mm to about 1 .65 mm, from about 1 .40 mm to about 1 .60 mm, from about 1 .45 mm to about 1 .55 mm, or about 1 .50 mm.

[0236] In various embodiments, each tip of the protrusion is digitally modelled / designed to have a diameter of from about 0.05 mm to about 0.25 mm, from about 0.06 mm to about 0.24 mm, from about 0.07 mm to about 0.23 mm, from about 0.08 mm to about 0.22 mm, from about 0.09 mm to about 0.21 mm, from about 0.10 mm to about 0.20 mm, from about 0.11 mm to about 0.19 mm, from about 0.12 mm to about 0.18 mm, from about 0.13 mm to about 0.17 mm, from about 0.14 mm to about 0.16 mm, or about 0.15 mm.

[0237] In various embodiments, each protrusion is digitally modelled / designed to have a height / depth (e.g., distance between the base and the tip) of from about 1 .0 mm to about 10.0 mm, from about 1 .5 mm to about 9.5 mm, from about 2.0 mm to about 9.0 mm, from about 2.5 mm to about 8.5 mm, from about 3.0 mm to about 8.0 mm, from about 3.5 mm to about 7.5 mm, from about 4.0 mm to about 7.0 mm, from about 4.5 mm to about 6.5 mm, from about 5.0 mm to about 6.0 mm, or about 5.5 mm. In various embodiments, the plurality of protrusions is digitally modelled / designed to be arranged in one or more arrays. In various embodiments, the plurality of protrusions is digitally modelled / designed to be arranged in one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty-one or more, twenty-two or more, twenty-three or more, twenty-four or more, or twenty-five or more arrays. For example, the plurality of protrusions may be digitally modelled / designed to be arranged in 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 arrays.

[0238] In various embodiments, the plurality of protrusions is digitally modelled / designed to be arranged in an orderly manner / arrangement, for e.g., in a linear arrangement / row / line / pattern. In various embodiments, each protrusion is digitally modelled / designed to be uniformly / evenly / regularly spaced apart from another protrusion.

[0239] In various embodiments, each array is digitally modelled / designed to comprise from about 1 to about 50 protrusions. In various embodiments, each array is digitally modelled / designed to comprise at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, or at least 15 protrusions. In various embodiments, each row / line of the array is digitally modelled / designed to comprises about 1 to about 50 protrusions. Each row / line of the array may be digitally modelled / designed to comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 protrusions.

[0240] In various embodiments, the distance between the protrusions is digitally modelled / designed to be from about 1.0 mm to about 10.0 mm, from about 1.5 mm to about 9.5 mm, from about 2.0 mm to about 9.0 mm, from about 2.5 mm to about 8.5 mm, from about 3.0 mm to about 8.0 mm, from about 3.5 mm to about 7.5 mm, from about 4.0 mm to about 7.0 mm, from about 4.5 mm to about 6.5 mm, from about 5.0 mm to about 6.0 mm, or about 5.5 mm.

[0241] In various embodiments, the plurality of protrusions is digitally modelled / designed to be extended from substantially centre / middle of the surface. In various embodiments, the material is digitally modelled / designed to comprise a zone / area surrounding the plurality of protrusions. In various embodiments, the zone / area is substantially devoid of protrusions and / or has substantially lesser protrusions than the area of the material it surrounds.

[0242] In various embodiments, the material is digitally modelled / designed to have a thickness / height / depth of from about 0.05 mm to about 0.50 mm, from about 0.06 mm to about 0.49 mm, from about 0.07 mm to about 0.48 mm, from about 0.08 mm to about 0.47 mm, from about 0.09 mm to about 0.46 mm, from about 0.10 mm to about 0.45 mm, from about 0.11 mm to about 0.44 mm, from about 0.12 mm to about 0.43 mm, from about 0.13 mm to about 0.42 mm, from about 0.14 mm to about 0.41 mm, from about 0.15 mm to about 0.40 mm, from about 0.16 mm to about 0.39 mm, from about 0.17 mm to about 0.38 mm, from about 0.18 mm to about 0.37 mm, from about 0.19 mm to about 0.36 mm, from about 0.20 mm to about 0.35 mm, from about 0.21 mm to about 0.34 mm, from about 0.22 mm to about 0.33 mm, from about 0.23 mm to about 0.32 mm, from about 0.24 mm to about 0.31 mm, from about 0.25 mm to about 0.30 mm, from about 0.26 mm to about 0.29 mm, or from about 0.27 mm to about 0.28 mm.

[0243] In various embodiments, the material is part of a structure digitally modelled / designed to have a length of from about 10.0 mm to about 200.0 mm, from about 15.0 mm to about 195.0 mm, from about 20.0 mm to about 190.0 mm, from about 25.0 mm to about 185.0 mm, from about 30.0 mm to about 180.0 mm, from about 35.0 mm to about 175.0 mm, from about 40.0 mm to about 170.0 mm, from about 45.0 mm to about 165.0 mm, from about 50.0 mm to about 160.0 mm, from about 55.0 mm to about 155.0 mm, from about 60.0 mm to about 150.0 mm, from about 65.0 mm to about 145.0 mm, from about 70.0 mm to about 140.0 mm, from about 75.0 mm to about 135.0 mm, from about 80.0 mm to about 130.0 mm, from about 85.0 mm to about 125.0 mm, from about 90.0 mm to about 120.0 mm, from about 95.0 mm to about 115.0 mm, from about 100.0 mm to about 110.0 mm, or about 105.0 mm.

[0244] In various embodiments, the material is part of a structure digitally modelled / designed to have a width of from about 5.0 mm to about 150.0 mm, from about 10.0 mm to about 145.0 mm, from about 15.0 mm to about 140.0 mm, from about 20.0 mm to about 135.0 mm, from about 25.0 mm to about 130.0 mm, from about 30.0 mm to about 125.0 mm, from about 35.0 mm to about 120.0 mm, from about 40.0 mm to about 115.0 mm, from about 45.0 mm to about 1 10.0 mm, from about 50.0 mm to about 105.0 mm, from about 55.0 mm to about 100.0 mm, from about 60.0 mm to about 95.0 mm, from about 65.0 mm to about 90.0 mm, from about 70.0 mm to about 85.0 mm, or from about 75.0 mm to about 80.0 mm.

[0245] In various embodiments, the method comprises configuring / designing / customizing / optimizing one or more of the following parameters: print temperature; fan cooling speed; retraction speed; and retraction distance, to reduce material oozing. In various embodiments, the method comprises designing / customizing / optimizing one or more of the following parameters: printing speeds and post-processing scripts, to prevent over-extrusion. In various embodiments, the method comprises configuring / designing / customizing / optimizing one or more of the following parameters: layer height and line width, to ensure precise printing.

[0246] In various embodiments, the step of printing is designed to stop / halt / pause after printing a pre-determined number of layers (e.g., after from about 10 layers to about 100 layers). The pre-determined number of layers may be from about 10 layers to about 100 layers, from about 15 layers to about 95 layers, from about 20 layers to about 90 layers, from about 25 layers to about 85 layers, from about 30 layers to about 80 layers, from about 35 layers to about 75 layers, from about 40 layers to about 70 layers, from about 45 layers to about 65 layers, from about 50 layers to about 60 layers, or about 55 layers. Advantageously, by stopping / halting / pausing printing after a pre-determined number of layers, good print quality and / or puncturing ability of the material is achieved and issues with the protrusions / needles (e.g., stringing issues between protrusions and / or excessive leaning) are minimized / avoided. In various embodiments, the stopping / halting / pausing is carried out for at least once or a plurality of times before printing is continued again to fully complete printing of the protrusions (e.g. to complete printing of an entire height of a protrusion).

[0247] In various embodiments, the step of printing is performed in the presence of a base plate / build plate / print bed having a temperature ranging from about 15.0°C to about 60.0°C, from about 16.0°C to about 59.0°C, from about 17.0°C to about 58.0°C, from about 18.0°C to about 57.0°C, from about 19.0°C to about 56.0°C, from about 20.0°C to about 55.0°C, from about 21 ,0°C to about 54.0°C, from about 22.0°C to about 53.0°C, from about 23.0°C to about 52.0°C, from about 24.0°C to about 51.0°C, from about 25.0°C to about 50.0°C, from about 26.0°C to about 49.0°C, from about 27.0°C to about 48.0°C, from about 28.0°C to about 47.0°C, from about 29.0°C to about 46.0°C, from about 30.0°C to about 45.0°C, from about 31 ,0°C to about 44.0°C, from about 32.0°C to about 43.0°C, from about 33.0°C to about 42.0°C, from about 34.0°C to about 41 ,0°C, from about 35.0°C to about 40.0°C, from about 36.0°C to about 39.0°C, from about 37.0°C to about 38.0°C, or about 37.5°C.

[0248] In various embodiments, the step of printing is performed at a temperature ranging from about 100°C to about 160°C, from about 105°C to about 155°C, from about 110°C to about 150°C, from about 115°C to about 145°C, from about 120°C to about 140°C, from about 125°C to about 135°C, or about 130°C.

[0249] In various embodiments, the step of printing comprises printing at least two different temperatures (i.e. first temperature and second temperature), wherein the first temperature is higher than the second temperature. In various embodiments, the step of printing is performed at the first temperature during the process of printing the first layer, first 2 layers, first 3 layers, first 4 layers, or first 5 layers.

[0250] In various embodiments, the step of printing is performed at the second temperature during the process of printing after the first layer, after the first 2 layers, after the first 3 layers, after the first 4 layers, or after the first 5 layers.

[0251] In various embodiments, the bioactive PLGA material is printed with a printing nozzle having a diameter of from about 0.05 mm to about 0.50 mm, from about 0.06 mm to about 0.49 mm, from about 0.07 mm to about 0.48 mm, from about 0.08 mm to about 0.47 mm, from about 0.09 mm to about 0.46 mm, from about 0.10 mm to about 0.45 mm, from about 0.11 mm to about 0.44 mm, from about 0.12 mm to about 0.43 mm, from about 0.13 mm to about 0.42 mm, from about 0.14 mm to about 0.41 mm, from about 0.15 mm to about 0.40 mm, from about 0.16 mm to about 0.39 mm, from about 0.17 mm to about 0.38 mm, from about 0.18 mm to about 0.37 mm, from about 0.19 mm to about 0.36 mm, from about 0.20 mm to about 0.35 mm, from about 0.21 mm to about 0.34 mm, from about 0.22 mm to about 0.33 mm, from about 0.23 mm to about 0.32 mm, from about 0.24 mm to about 0.31 mm, from about 0.25 mm to about 0.30 mm, from about 0.26 mm to about 0.29 mm, or from about 0.27 mm to about 0.28 mm.

[0252] In various embodiments, the bioactive PLGA material is printed with an infill density of from about 70.0% to about 100.0%, from about 71.0% to about 99.9%, from about 72.0% to about 99.8%, from about 73.0% to about 99.7%, from about 74.0% to about 99.6%, from about 75.0% to about 99.5%, from about 76.0% to about 99.0%, from about 77.0% to about 98.0%, from about 78.0% to about 97.0%, from about 79.0% to about 96.0%, from about 80.0% to about 95.0%, from about 81.0% to about 94.0%, from about 82.0% to about 93.0%, from about 83.0% to about 92.0%, from about 84.0% to about 91 .0%, from about 85.0% to about 90.0%, from about 86.0% to about 89.0%, or from about 87.0% to about 88.0%. In various embodiments, the step of printing is performed at a printing speed of from about 0.5 mm / s to about 50.0 mm / s, from about 1 .0 mm / s to about 45.0 mm / s, from about 1.5 mm / s to about 40.0 mm / s, from about 2.0 mm / s to about 35.0 mm / s, from about 2.5 mm / s to about 30.0 mm / s, from about 3.0 mm / s to about 25.0 mm / s, from about 3.5 mm / s to about 20.0 mm / s, from about 4.0 mm / s to about 15.0 mm / s from about 4.5 mm / s to about 10.0 mm / s, from about 5.0 mm / s to about 9.5 mm / s, from about 5.5 mm / s to about 9.0 mm / s, from about 6.0 mm / s to about 8.5 mm / s from about 6.5 mm / s to about 8.0 mm / s, or from about 7.0 mm / s to about 7.5 mm / s.

[0253] In various embodiments, the step of printing is performed at a travel speed of from about 0.5 mm / s to about 50.0 mm / s, from about 1 .0 mm / s to about 45.0 mm / s, from about 1.5 mm / s to about 40.0 mm / s, from about 2.0 mm / s to about 35.0 mm / s, from about 2.5 mm / s to about 30.0 mm / s, from about 3.0 mm / s to about 25.0 mm / s, from about 3.5 mm / s to about 20.0 mm / s, from about 4.0 mm / s to about 15.0 mm / s from about 4.5 mm / s to about 10.0 mm / s, from about 5.0 mm / s to about 9.5 mm / s, from about 5.5 mm / s to about 9.0 mm / s, from about 6.0 mm / s to about 8.5 mm / s from about 6.5 mm / s to about 8.0 mm / s, or from about 7.0 mm / s to about 7.5 mm / s.

[0254] In various embodiments, the bioactive PLGA material is printed with a layer height of from about 0.005 mm to about 0.50 mm, from about 0.01 mm to about 0.45 mm, from about 0.015 mm to about 0.40 mm, from about 0.02 mm to about 0.35 mm, from about 0.025 mm to about 0.30 mm, from about 0.03 mm to about 0.25 mm, from about 0.035 mm to about 0.20 mm, from about 0.04 mm to about 0.15 mm, from about 0.045 mm to about 0.10 mm, from about 0.05 mm to about 0.09 mm, from about 0.055 mm to about 0.085 mm, from about 0.06 mm to about 0.08 mm, from about 0.065 mm to about 0.075 mm, or about 0.07 mm.

[0255] In various embodiments, the bioactive PLGA material is printed with a line width falling in the range of from about 0.010 mm to about 1.00 mm, from about 0.015 mm to about 0.95 mm, from about 0.020 mm to about 0.90 mm, from about 0.025 mm to about 0.85 mm, from about 0.030 mm to about 0.80 mm, from about 0.035 mm to about 0.75 mm, from about 0.040 mm to about 0.70 mm, from about 0.045 mm to about 0.65 mm, from about 0.050 mm to about 0.60 mm, from about 0.055 mm to about 0.55 mm, from about 0.060 mm to about 0.50 mm, from about 0.065 mm to about 0.45 mm, from about 0.070 mm to about 0.40 mm, from about 0.075 mm to about 0.35 mm, from about 0.080 mm to about 0.30 mm, from about 0.085 mm to about 0.25 mm, from about 0.090 mm to about 0.20 mm, from about 0.095 mm to about 0.15 mm, or about 0.10 mm.

[0256] In various embodiments, the bioactive PLGA material is printed with an infill overlap falling in the range of from about 0.005 mm to about 0.50 mm, from about 0.006 mm to about 0.49 mm, from about 0.007 mm to about 0.48 mm, from about 0.008 mm to about 0.47 mm, from about 0.009 mm to about 0.46 mm, from about 0.010 mm to about 0.45 mm, from about 0.015 mm to about 0.44 mm, from about 0.020 mm to about 0.43 mm, from about 0.025 mm to about 0.42 mm, from about 0.030 mm to about 0.41 mm, from about 0.035 mm to about 0.40 mm, from about 0.040 mm to about 0.39 mm, from about 0.045 mm to about 0.38 mm, from about 0.050 mm to about 0.37 mm, from about 0.055 mm to about 0.36 mm, from about 0.060 mm to about 0.35 mm, from about 0.065 mm to about 0.34 mm, from about 0.070 mm to about 0.33 mm, from about 0.075 mm to about 0.32 mm, from about 0.080 mm to about 0.31 mm, from about 0.085 mm to about 0.30 mm, from about 0.090 mm to about 0.29 mm, from about 0.095 mm to about 0.28 mm, from about 0.10 mm to about 0.27 mm, from about 0.11 mm to about 0.26 mm, from about 0.12 mm to about 0.25 mm, from about 0.13 mm to about 0.24 mm, from about 0.14 mm to about 0.23 mm, from about 0.15 mm to about 0.22 mm, from about 0.16 mm to about 0.21 mm, from about 0.17 mm to about 0.20 mm, or about 0.18 mm to about 0.19 mm.

[0257] In various embodiments, the step of printing is performed at a retraction distance falling in the range of from about 1 .0 mm to about 50.0 mm, from about 2.0 mm to about 45.0 mm, from about 3.0 mm to about 40.0 mm, from about 4.0 mm to about 35.0 mm, from about 5.0 mm to about 30.0 mm, from about 6.0 mm to about 25.0 mm, from about 7.0 mm to about 20.0 mm, from about 8.0 mm to about 15.0 mm, or from about 9.0 mm to about 10.0 mm.

[0258] In various embodiments, the step of printing is performed at a retraction speed falling in the range of from about 10.0 mm / s to about 100.0 mm / s, from about 15.0 mm / s to about 95.0 mm / s, from about 20.0 mm / s to about 90.0 mm / s, from about 25.0 mm / s to about 85.0 mm / s, from about 30.0 mm / s to about 80.0 mm / s, from about 35.0 mm / s to about 75.0 mm / s, from about 40.0 mm / s to about 70.0 mm / s, from about 45.0 mm / s to about 65.0 mm / s, from about 50.0 mm / s to about 60.0 mm / s, or about 55.0 mm / s.

[0259] In various embodiments, the printing apparatus (e.g., FFF-based or FDM- based three-dimensional printing apparatus) is configured for filament feedstock having filament diameters falling in the range of from about 1 .0 mm to about 6.0 mm. The filament diameter may fall in the range of from about 1 .00 mm to about

[0260] 6.00 mm, from about 1.10 mm to about 5.90 mm, from about 1 .20 mm to about

[0261] 5.80 mm, from about 1.30 mm to about 5.70 mm, from about 1 .40 mm to about

[0262] 5.60 mm, from about 1.50 mm to about 5.50 mm, from about 1 .60 mm to about

[0263] 5.40 mm, from about 1.70 mm to about 5.30 mm, from about 1 .80 mm to about

[0264] 5.20 mm, from about 1.90 mm to about 5.10 mm, from about 2.00 mm to about 5.00 mm, from about 2.10 mm to about 4.90 mm, from about 2.20 mm to about

[0265] 4.80 mm, from about 2.30 mm to about 4.70 mm, from about 2.40 mm to about

[0266] 4.60 mm, from about 2.50 mm to about 4.50 mm, from about 2.60 mm to about

[0267] 4.40 mm, from about 2.70 mm to about 4.30 mm, from about 2.80 mm to about

[0268] 4.20 mm, from about 2.90 mm to about 4.10 mm, from about 3.00 mm to about 4.00 mm, from about 3.10 mm to about 3.90 mm, from about 3.20 mm to about

[0269] 3.80 mm, from about 3.30 mm to about 3.70 mm, from about 3.40 mm to about

[0270] 3.60 mm, or about 3.50 mm.

[0271] In various embodiments, the step of applying heat is at a temperature that is based on a predetermined melt / softening temperature and a predetermined onset degradation temperature of the bioactive PLGA. For example, the printing may be performed at a temperature (e.g. the temperature of the print head) that is no more than the temperature at which the bioactive moiety part of the filament degrades / decomposes / disintegrates / depolymerises / breaks down. In various embodiments, the printing is performed at a temperature that is between the melt / softening temperature of bioactive PLGA filament and the onset degradation temperature of the bioactive PLGA. In various embodiments, the printing temperature is dependent on the bioactive PLGA filament used for 3D printing.

[0272] In various embodiments, the step of printing is performed at a temperature that is from about 15°C to about 40°C above the melting / softening point of the bioactive PLGA filament and up to 5°C below the degradation point of the bioactive PLGA. In some embodiments, the printing is performed at a temperature that falling in the range of from about 15°C to about 40°C, from about 16°C to about 39°C, from about 17°C to about 38°C, from about 18°C to about 37°C, from about 19°C to about 36°C, from about 20°C to about 35°C, from about 21 °C to about 34°C, from about 22°C to about 33°C, from about 23°C to about 32°C, from about 24°C to about 31 °C, from about 25°C to about 30°C, from about 26°C to about 29°C, or from about 27°C to about 28°C above the melting / softening point / temperature of the bioactive polymer filament. In some embodiments, the printing is performed at a temperature that is no more than about 5°C, no more than about 4.5°C, no more than about 4°C, no more than about 3.5°C, no more than about 3°C, no more than about 2.5°C, no more than about 2°C, no more than about 1.5°C, no more than about 1 °C, no more than about 0.5°C, no more than about 0.4°C, no more than about 0.3°C, no more than about 0.2°C, or no more than about 0.1 °C below the degradation point / temperature of the bioactive PLGA.

[0273] In various embodiments, the step of printing is performed in the presence of a base plate / build plate / print bed that has a temperature that is no less than the temperature at which the thermoplastic solidifies or converts into solid state. In various embodiments, the base plate temperature is dependent on the bioactive polymer filament used for 3D printing. The temperature of the base plate may range from 15°C (e.g., no heating) and up to about 15°C above the melting / softening temperature of the bioactive PLGA filament. In some embodiments, the printing is performed in the presence of a base plate having a temperature that is no more than about 15°C, no more than about 14°C, no more than about 13°C, no more than about 12°C, no more than about 11 °C, no more than about 10°C, no more than about 9°C, no more than about 8°C, no more than about 7°C, no more than about 6°C, no more than about 5°C, no more than about 4°C, no more than about 3°C, no more than about 2°C, or no more than about 1 °C above the melting / softening point / temperature of the bioactive PLGA filament.

[0274] In various embodiments, the bioactive PLGA copolymer is present in powdered form. Accordingly, it will be appreciated that no additional / further step may be required / necessary to convert the bioactive PLGA copolymer into powdered form.

[0275] Advantageously, in various embodiments, the printing method and bioactive polymer filament feedstock is capable of being used by commercially available FFF or FDM based three-dimensional printers or extruders.

[0276] In various embodiments, the step (i-c) of extruding a bioactive PLGA filament from the formulation / mixture / blend is performed at an extrusion temperature profile that is based on a predetermined melt / softening temperature and a predetermined onset degradation temperature of the bioactive PLGA. In various embodiments, the extrusion temperature profile is based on a predetermined melt / softening temperature of the base polymer or the bioactive polymer, whichever is higher. For example, if the melt temperature of the base polymer is higher than the melt temperature of the bioactive polymer, then the extrusion temperature profile is based on the predetermined melt / softening temperature of the base polymer, and vice versa. In various embodiments, the bioactive polymer filament is suitable for use as a feedstock for fused filament fabrication (FFF) or fused deposition modelling (FDM) based 3D printing. FFF is an extrusion-based 3D printing technology which generally utilizes polymer filament feedstock. It deposits the molten polymer in 2- dimensional plane according to the deposition path set by the machine over several layers until the part is fully printed in 3-dimensional space. FFF technology typically uses filaments made of thermoplastic polymers where heat transfer characteristics and rheology are important properties required for good quality printed parts. FFF is preferred over other 3D printing technology as it enables good control over printing parameters which can influence the mechanical properties. However, due to high temperature utilized in FFF technology, living cells or other temperature-sensitive biological molecules may not be incorporated in its filament as it would denature the proteins, degrade polysaccharides or oligopeptides and kill the cells. Advantageously, various embodiments of the bioactive polymer filament disclosed herein provide desirable mechanical as well as biological characteristics that makes its suitable for use in printing medical-related structures using FFF 3D printing technologies.

[0277] In various embodiments, the bioactive polymer filament and / or bioactive copolymer is acellular or is substantially devoid of cells. Advantageously, in various embodiments, the bioactive polymer filament and / or bioactive copolymer do not rely on highly temperature sensitive biological moieties like stem cells or growth factors to impart bioactivity since these biological moieties are highly susceptible to cell death during the extrusion process to form the filament feedstock. Even more advantageously, embodiments of the bioactive polymer filament and / or bioactive copolymer are still able to stimulate host cells to proliferate which promotes tissue growth.

[0278] In various embodiments, the bioactive copolymer comprises biological molecules or biomolecules that are bonded / linked (e.g., chemically bonded / linked) to / on the bioactive copolymer. It will be appreciated that in various embodiments, the bioactive polymer filament and / or bioactive copolymer is substantially devoid of free (or unbound / unbonded / unlinked) biomolecules such as free (or unbound / unbonded / unlinked) oligopeptides or oligosaccharides.

[0279] In various embodiments, the method further comprises, prior to the step (ii) of printing, performing a post-extrusion thermal analysis on the extruded bioactive PLGA filament to assess onset degradation of the bioactive PLGA in the filament.

[0280] In various embodiments, the method further comprises performing one or more of post-printing analysis of the printed three-dimensional part or structure, the post-printing analysis selected from the group consisting of: i. a mechanical analysis of the printed three-dimensional part or structure e.g. to assess its mechanical properties; ii. a biocompatibility analysis of the printed three-dimensional part or structure e.g. to assess its biocompatibility with living cells; iii. a thermal analysis on the printed three-dimensional part or structure e.g. to assess onset degradation of the bioactive polymer in the printed three- dimensional part or structure; and iv. a spectrometric analysis of the printed three-dimensional part or structure to assess the presence of bioactive copolymer in the printed three- dimensional part or structure. For example, nuclear magnetic resonance (NMR) spectroscopy may be performed on the filament and / or the printed three-dimensional part or structure.

[0281] The mechanical analysis may be performed under ASTM standards or other equivalent standards to determine the properties of the printed structure and whether it is suitable for its specific use. It will be appreciated that any other test methods that are equivalent to the ASTM standards may be used as well. Furthermore, the biocompatibility tests may be carried out with various human cell lines which the materials are designed to interact with. The thermal analysis may comprise one or more of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). In various embodiments, the thermal analysis comprises simultaneous thermal analysis (STA) through the simultaneous application of TGA and DSC.

[0282] In various embodiments, the base PLGA powder is obtained from physical processes to reduce the size of base polymer pellets. Such physical processes may comprise grinding, pulverizing, milling, cryogenic milling / cryomilling or combinations thereof to obtain the powdered base polymer. Accordingly, in various embodiments, the method may further comprise performing one or more of grinding, pulverizing, milling, cryogenic milling / cryomilling of base polymer pellets to obtain base polymer powder. In one example, the base polymer powder is obtained from cryogenic milling / cryomilling of the base polymer pellets. The cryomilling / cryogenic milling may be performed in the presence of a cryogenic liquid selected from the group consisting of argon, helium, hydrogen, nitrogen and oxygen. Advantageously, using cryomilling / cryogenic milling / grinding in embodiments of the method disclosed herein aids in embrittlement process and / or prevents degradation of the polymer. It will be appreciated that the cryogen / cryogenic liquid used (e.g., liquid nitrogen) can lower the temperature significantly (< -196°C) which in turn may induce embrittlement on the polymer / material, and subsequently easing the milling process. It will also be appreciated that the cryogen / cryogenic liquid used can prevent any thermal degradation of the polymer / material from occurring during the high-energy milling process.

[0283] In various embodiments, the base PLGA powder has an average particle size of no more than about 1 mm; falling in the range from about 0.50 mm to about 1 mm, from about 0.55 mm to about 0.95 mm, from about 0.50 mm to about 0.90 mm, from about 0.50 mm to about 0.85 mm, from about 0.50 mm to about 0.80 mm, from about 0.60 mm to about 1 mm, from about 0.65 mm to about 1 mm, or from about 0.70 mm to about 0.95 mm. In various embodiments, the base PLGA powder has an average particle size falling in the range of from about 0.10 mm to about 1 .00 mm, from about 0.11 mm to about 0.99 mm, from about 0.12 mm to about 0.98 mm, from about 0.13 mm to about 0.97 mm, from about 0.14 mm to about 0.96 mm, from about 0.15 mm to about 0.95 mm, from about 0.20 mm to about 0.90 mm, from about 0.25 mm to about 0.85 mm, from about 0.30 mm to about 0.80 mm, from about 0.35 mm to about 0.75 mm, from about 0.40 mm to about 0.70 mm, from about 0.45 mm to about 0.65 mm, from about 0.50 mm to about 0.60 mm, from about 0.51 mm to about 0.59 mm, from about 0.52 mm to about 0.58 mm, from about 0.53 mm to about 0.57 mm, from about 0.54 mm to about 0.56 mm, or about 0.55 mm.

[0284] In various embodiments, the base PLGA and / or bioactive PLGA copolymer have been dried (e.g. vacuum dried) prior to mixing. Accordingly, in various embodiments, the method further comprises drying (e.g. vacuum drying) the base PLGA and / or bioactive PLGA copolymer prior to mixing them. For example, after cryomilling / cryogenic milling is carried out on base polymer pellets to obtain base polymer powder, the base polymer powder is dried (e.g. vacuum dried) prior to mixing with the bioactive copolymer. Advantageously, vacuum drying provides an inert environment whereby moisture may be reduced significantly allowing for more effective drying. Additionally, since airflow is absent in vacuum drying, materials in powder form are not blown around which would otherwise result in material loss. The drying step may be performed at an ambient or room temperature or at temperature falling in the range of from about 35°C to about 100°C, from about 40°C to about 95°C, from about 45°C to about 90°C, from about 40°C to about 85°C or from about 45°C to about 80°C. The drying step may be performed over a time period of about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, from about 4 hours to about 12 hours, about 24 hours, about 36 hours, or about 48 hours. In various embodiments, the drying step comprises vacuum drying at a drying pressure of from about -50 mmHg to about -10 mmHg, from about -40 mmHg to about -20 mmHg, or about -40 mmHg.

[0285] In various embodiments, the method further comprises performing a preextrusion thermal analysis on the bioactive copolymer and / or base polymer to determine the melt temperature and the onset degradation temperature of the bioactive polymer / copolymer and / or base polymer.

[0286] The method may further comprise performing thermal analysis on base polymer pellets prior to reducing their sizes (e.g. cryogenic milling / cryomilling) to obtain powdered forms and optionally performing thermal analysis on base polymer pellets after the powdered forms are obtained (e.g. cryogenic milling / cryomilling). Advantageously, the thermal analysis may be useful to determine the thermal properties of the base polymer prior to size reduction (e.g. cryogenic milling / cryomilling) and / or after size reduction and / or prior to filament extrusion so that a benchmark may be obtained and an assessment may be made on whether there is a detraction in the physical and / or thermal properties of the subsequently obtained filament feedstock or printed structure from that expected (e.g. based on the original mechanical properties of the base polymer). The thermal analysis may also provide useful information on the melting temperature (if any) and / or degradation temperature of the base polymer (e.g. pellet form or powdered form) so that the extrusion temperature profile may be customised for the particular base polymer e.g. based on the melt temperature and the onset degradation temperature of the base polymer that were determined. For instance, the extrusion temperature profile may be customised such that the extrusion temperature is between the melting / softening temperature and degradation temperature of the base polymer. It will also be appreciated that in some embodiments, the determination of the melting / softening temperature and degradation temperature of the base polymer may have already been completed previously or such information are already readily available for known / established polymers. Thus, in such embodiments, it may be optional for the presently disclosed method to have such active determination steps.

[0287] Similarly, the method may further comprise performing thermal analysis on bioactive copolymer prior to mixing with the base polymer and / or prior to filament extrusion. Advantageously, the thermal analysis may be useful to determine the thermal properties of the bioactive copolymer prior to mixing with the base polymer and / or prior to filament extrusion so that a benchmark may be obtained and an assessment may be made on whether there is a detraction in the physical and / or thermal properties of the subsequently obtained filament feedstock or printed structure that expected (e.g. based on the properties of the bioactive copolymer prior to extrusion). The thermal analysis may also provide useful information on the melting temperature and / or degradation temperature of the bioactive polymer / copolymer so that the extrusion temperature profile may be customised for the particular bioactive copolymer e.g. based on the melt temperature and the onset degradation temperature of the base polymer that were determined. For instance, the extrusion temperature profile may be customised such that the extrusion temperature is between the melting / softening temperature and degradation temperature of the bioactive polymer / copolymer. In various embodiments, such active determination steps are present in the method disclosed herein. Advantageously, adopting / employing such active determination steps in the method disclosed herein prevents degradation of the bioactive polymer / copolymer during filament extrusion and preserves bioactivity of the bioactive copolymer / bioadditive in the filament. As biomolecules linked / bonded to / on the polymer may be lost / melted / degraded during heat treatment, it may therefore be important to determine the temperature(s) at which such situation(s) may occur. It will also be appreciated that in some embodiments, the determination of the melting / softening temperature and degradation temperature of the bioactive polymer / copolymer may have already been completed previously or such information are already readily available for such polymers. Thus, in such embodiments, it may be optional for the presently disclosed method to have such active determination steps.

[0288] In various embodiments, the extrusion temperature profile is based on predetermined melt / softening temperatures and predetermined onset degradation temperatures of both the base polymer and the bioactive polymer. Accordingly, the extrusion temperature profile may be customised such that the extrusion temperature is between the melting / softening temperature and onset degradation temperature of the bioactive copolymer and also between the melting / softening temperature and onset degradation temperature of the base polymer (e.g. base polymer powder).

[0289] In various embodiments, the thermal analysis disclosed herein comprises one or more of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). In various embodiments, the thermal analysis comprises application of TGA and DSC. The application of TGA and DSC may be nonsimultaneous or simultaneous. For example, the thermal analysis comprising TGA and DSC may be performed either non-simultaneously (e.g., TGA-DSC) or simultaneously (e.g., STA). In various embodiments, the thermal analysis comprises simultaneous thermal analysis (STA) through the simultaneous application of TGA and DSC. For example, the post-extrusion thermal analysis may comprise STA.

[0290] In various embodiments, the extruded bioactive polymer filament has a filament diameter falling in the range of from about 1 .0 mm to about 6.0 mm, from about 1.10 mm to about 5.90 mm, from about 1.20 mm to about 5.80 mm, from about 1.30 mm to about 5.70 mm, from about 1.40 mm to about 5.60 mm, from about 1.50 mm to about 5.50 mm, from about 1.60 mm to about 5.40 mm, from about 1.70 mm to about 5.30 mm, from about 1.80 mm to about 5.20 mm, from about 1.90 mm to about 5.10 mm, from about 2.00 mm to about 5.00 mm, from about 2.10 mm to about 4.90 mm, from about 2.20 mm to about 4.80 mm, from about 2.30 mm to about 4.70 mm, from about 2.40 mm to about 4.60 mm, from about 2.50 mm to about 4.50 mm, from about 2.60 mm to about 4.40 mm, from about 2.70 mm to about 4.30 mm, from about 2.80 mm to about 4.20 mm, from about 2.90 mm to about 4.10 mm, from about 3.00 mm to about 4.00 mm, from about 3.10 mm to about 3.90 mm, from about 3.20 mm to about 3.80 mm, from about 3.30 mm to about 3.70 mm, from about 3.40 mm to about 3.60 mm, or about 3.50 mm.

[0291] In various embodiments, the material is a non-animal derived material. In various embodiments, the material / printed structure is acellular or is substantially devoid of cells. Advantageously, in various embodiments, the material / printed structure do not rely on highly temperature sensitive biological moieties like stem cells or growth factors to impart bioactivity. Even more advantageously, embodiments of the material / printed structure are still able to stimulate host cells to proliferate which promotes skin and / or tissue growth.

[0292] In various embodiments, the material / printed structure is biocompatible, i.e. the material is compatible with biological systems or parts of the biological systems without substantially or significantly eliciting an adverse physiological response such as a toxic reaction / response, an immune reaction / response, an injury or the like when used on the human or animal body. In various embodiments, the material is substantially devoid of substances that elicit an adverse physiological response.

[0293] There is also provided a bioactive PLGA material, blend, filament, or printed structure as disclosed herein for use in medicine. The material may also be a material that is suitable for use in preventing / reducing or lowering risk of scarring / scar formation of a wound. The material may also be a material that is suitable for use in treating and / or reducing inflammation of a wound. The material may also be a material that is suitable for use in stimulating / promoting skin regeneration, tissue regeneration, wound healing, wound regeneration, wound regrowth, wound repair, wound closure and / or wound treatment.

[0294] There is provided use of a bioactive PLGA material, blend, filament, or printed structure as disclosed herein in the manufacture of a medicament for preventing / reducing or lowering risk of scarring / scar formation of an incisional wound such as surgical wound, caesarean wound or the like. There is also provided use of a bioactive PLGA material, blend, filament, or printed structure as disclosed herein in the manufacture of a medicament for the prophylaxis or treatment of an incisional wound such as surgical wound, caesarean wound or the like. There is also provided use of a bioactive PLGA material, blend, filament, or printed structure as disclosed herein in the manufacture of a medicament for treating and / or reducing inflammation of a wound. There is also provided use of a bioactive PLGA material, blend, filament, or printed structure as disclosed herein in the manufacture of a medicament for stimulating / promoting skin regeneration, tissue regeneration, wound healing, wound regeneration, wound regrowth, wound repair, wound closure and / or wound treatment.

[0295] There is provided a method of preventing / reducing or lowering risk of scarring / scar formation of a wound, the method comprising applying the bioactive PLGA material, blend, filament, or printed structure as disclosed herein to a body of a subject in need thereof. There is also provided a method of treating and / or reducing inflammation of a wound, the method comprising applying the bioactive PLGA material, blend, filament, or printed structure as disclosed herein to a body of a subject in need thereof. There is also provided a method of stimulating / promoting skin regeneration, tissue regeneration, wound healing, wound regeneration, wound regrowth, wound repair, wound closure and / or wound treatment, the method comprising applying the bioactive PLGA material, blend, filament, or printed structure as disclosed herein to a body of a subject in need thereof. In various embodiments, the method further comprises evaluating one or more wound characteristic; determining a treatment needed; three- dimensionally printing a bioactive PLGA material that is / are responsive to the treatment needed; and / or administering / applying said material to the wound.

[0296] In various embodiments, the wound comprises an incisional wound incisions, excisions, surgical wound, caesarean wound, laceration wound, sutured wound, the like, and combinations thereof.

[0297] In various embodiments, the present technology is different from those of the art in that the present technology is related / directed to / focused on the 3D printing of skin patch with needles using PLGA-based materials for scar prevention in surgical wounds. Advantageously, embodiments of the present technology demonstrate promising porcine wound healing and scar prevention results of incisional wounds, which was designed using relevant test protocols for this application, that are not available / shown and cannot be expected from the art. Advantageously, embodiments of the present technology are suitable for use in scar prevention. In various embodiments, design of the patch of the present technology and its specific method of production is not disclosed or suggested in the art.

[0298] In various embodiments, the present technology is different from those of the art that use 3D printed porous sheets of bioactive PLGA for burn wound healing. It will be appreciated that such sheets (that are used for bum wound healing) are not suitable for surgical wounds as there is no contact with dermis in a sutured wound. In various embodiments, the present technology is different from those of the art in that the present technology is related / directed to / focused on the design and 3D printing of skin patch with needles using bioactive PLGA- based materials for scar prevention in surgical wounds. Epidermal penetration of needles designed on the patch allow for bioactive materials to reach dermal layer for incisional wound healing. Accordingly, the present technology is different from those of the art at least in the 3DP process used and the unique parameters for this design (of a skin patch). In various embodiments, the present technology is completely / totally different from those of the art at least in the application and the product design.

[0299] In various embodiments, the present technology is different from those of the art at least in the fabrication method and composition of the material used. For example, the present technology is different from those of the art that fabricate PLGA microneedle by molding and freeze-drying methods and with no incorporation of bioactive molecules. Furthermore, in various embodiments, the present technology is different from those of the art that specifically puncture the skin to cause bleeding and stimulate collagen production. In contrast, the present technology intentionally / deliberately avoid such a method to avoid skin injury on top of the original incision caused by surgery. It will be appreciated that extra breakage of skin can cause more scarring to occur. Advantageously, embodiments of the product of the present technology is designed to penetrate skin without creating extra breakages in skin. In various embodiments, the product design of the present technology is unique and the material used in the present technology is also unique.

[0300] In various embodiments, the present technology is different from those of the art at least in the composition of the material and mode of action of scar prevention. For example, the present technology is different from those of the art that use drug-free polymer microneedle for keloid scar reduction by physical contact between the microneedle and the keloid fibroblast which inhibits cell proliferation.

[0301] In various embodiments, the present technology is different from those of the art at least in the composition of material and mode of action. For example, the present technology is different from those of the art that use silk fibroin microneedle patch to reduce scarring via a mechanotherapeutic strategy (e.g., a microneedle patch is applied on day 30 to treat the hypertrophic scars after scarring has occurred). In contrast, the patch of the present technology is directly applied on the sutured wound to promote wound healing and scar prevention.

[0302] In various embodiments, the present technology is different from those of the art at least in that the present technology relates to 3D printing skin patch or microneedles using PLGA and bioactive PLGA materials. It is respectfully submitted that information and details available on 3D printing of skin patch or microneedles in the prior art will not provide any hint or motivation for one skilled in the art to arrive at the present technology. Specifically, the optimization of printing parameters for the present application involved very minute and tiny parts in comparison to those of the prior art. Thus, embodiments of the present technology require the use of smaller nozzle where print parameters are much narrower for the present technology to be successful. Advantageously, in various embodiments, it was found by the inventors that a balance between sufficient material extrusion and minimal material ooze during printing process allows the advantageous technical effects to be achieved, which is not shown and cannot be expected from the art.

[0303] Furthermore, in various embodiments, the present technology is different from those of the art that require mechanically breaching the epidermal layer to stimulate skin growth in order to reduce scarring. It will be appreciated that such a mechanical breaching of the epidermal layer comprises an entirely different mode of action from that of the present technology, which requires breaking the skin to potentially reduce an already-formed scar. In contrast, embodiments of the present technology is substantially devoid or is devoid of breaching the epidermis to avoid / prevent causing further skin injury and tissue inflammation. Advantageously, in various embodiments, the present technology aims to prevent a scar from forming right from the beginning of skin injury, that is, the incision due to surgery itself.

[0304] In various embodiments, the mechanism and concept involves in the present technology is completely / totally different from those of the art. In various embodiments, the needles in the present technology are designed to reach the dermis in a sutured wound and hence longer so that the dermis is accessible for skin repair. In various embodiments, the length of the needles is longer than a microneedle of the art that aim or is intended to cause bleeding in the skin to allow skin repair. In contrast, the needles of the present technology are meant to allow the bioactive ingredient to come into contact with the dermis where the active skin cells and integrins are.

[0305] Advantageously, in various embodiments, the design of present technology successfully achieves an intricate balance between printing temperature, printing speed and print cooling, thereby allowing small features using PLGA-based material such as needles of skin patch to be printed. In various embodiments, the present technology comprises further enhancements using post-processing scripts such as PauseAtHeight and ChangeatZ to alleviate issues which may occur / arise when the aforementioned 3 printing parameters are highly optimized.

[0306] In various embodiments, a post-processing script, namely PauseatHeight script is incorporated into embodiments of the method disclosed herein, which works by forcing the printing process to pause or stop at the set layer number or print height. This set value is dependent on the height of the needles. The exact value is set when the layer view of the slicing software (Ultimaker Cura) shows single dot material deposition only for that layer. Single dot deposition is the minimal amount of material deposition FFF nozzle could achieve, hence, it is indicative that subsequent layers would also comprise single dot depositions, which affect and does not improve the print quality (or may cause the print quality to worsen). By incorporating this script in embodiments of the present technology, issues such as poor print quality, excess printing time and material wastage are prevented. In conjunction with post-processing script, namely ChangeAtZ script, the printing temperature is reduced when it starts printing layer #3 (needle base) which comprises a smaller surface area as compared to the patch layers. Hence, the reduction substantially prevents any over-extrusion of molten material over the small surface areas, stringing between needles and needle-leaning phenomenon which may ultimately result in inferior print quality. These scripts allows for ensuring that the smaller printing areas have sufficient material volume deposited which translates to lesser material volume needed to be cooled down before a new layer starts to print.

[0307] In various embodiments, FFF printing quality is dependent on printing temperature, printing speed, cooling and material volume. It will be appreciated that, in various embodiments, increasing printing temperature increases the thermal energy of the material where the polymer undergoes chain scission resulting in a change of the polymer form and properties. However, extremely high print temperature could result in significantly low melt viscosity that causes over-extrusion, material ooze at the nozzle and stringing during the printing process (high melt flow). In contrast, extremely low print temperature could cause melt viscosity to be extremely high which hinders the material to flow sufficiently for FFF printing process (low melt flow) and this may cause under-extrusion to occur. Hence, identifying the lower and upper limit of print temperature allows for achieving the best material flow for FFF process. In various embodiments, cooling parameters assist in lowering the temperature of the deposited molten material whereby it does not get too hot or cold which would otherwise result in nozzle shearing and layer delamination respectively. Advantageously, the present technology incorporates cooling which ensures that the printed layer achieves sufficient temperature for the new layer to be printed on and adhered to without causing any defects arising from the molten state of the deposited material. It will also be appreciated that, in various embodiments, printing speed affects the printing time if the printing temperature and cooling are optimized effectively. However, it is dependent on the melt strength of the molten material which is directly affected by the above-mentioned parameters. Melt strength refers to how much a material can “stretch” in molten state during the printing process without thinning out resulting in differing line width as set value and / or breaking, resulting in incomplete deposition or under-extrusion, and ultimately affecting the quality and finishing of the printed part and / or even print failure.

[0308] BRIEF DESCRIPTION OF FIGURES

[0309] FIG. 1 shows a bioactive poly(lactic-co-glycolic acid) (PLGA) material 100 designed in accordance with various embodiments disclosed herein. The bioactive PLGA material 100 comprises a plurality of protrusions 102 extending substantially vertically from a surface of the material / substrate base 112. The bioactive PLGA material 100 also comprises a base PLGA and a bioactive PLGA copolymer. The bioactive PLGA copolymer comprises a polymer backbone 104 (e.g., poly(norbornene dicarboximide) backbone), pendant arms of PLGA 106a, 106b and 106c, and pendant arms of biomolecules / bioactive molecules 108a, 108b and 108c tethered on hydrophilic linker (e.g., PEG chains 110a, 110b and 110c). As shown in the schematic diagram, the pendant arms are attached to the poly(norbornene dicarboximide) backbone 104. 108a, 108b and 108c may be the same or different types of biomolecules or bioactive moieties. In various embodiments, biomolecules or bioactive moieties may, for example, be either RGD peptide or hyaluronic acid (HA) of 8 - 13 saccharide units.

[0310] FIG. 2 shows an image of the 3D printed skin patch designed in accordance with various embodiments disclosed herein. The scale bar represents 2 mm,

[0311] FIG. 3 shows images / photographs obtained from porcine incisional wound healing studies of 5% PLGA-RGD, 5% PLGA-HA, negative control, and positive control in accordance with an embodiment disclosed herein. Images were captured on Day 0, Day 7, Day 14 and Day 21 . Negative control is sutured wound. Positive control is Dermabond Prineo. As shown, the 3DP bioactive PLGA material designed in accordance with various embodiments disclosed herein is able to facilitate wound healing and prevent scar formation as compared to sutured wounds.

[0312] FIG. 4 shows images / photographs obtained from porcine incisional wound healing studies of 5% PLGA-RGD, 5% PLGA-HA, negative control, and positive control in accordance with an embodiment disclosed herein. Images were captured on Week 6 (i.e. Wk 6), Week 9 (i.e. Wk 9) and Week 13 (i.e. Wk 13). Negative control is sutured wound. Positive control is Dermabond Prineo. As shown, the 3DP bioactive PLGA material designed in accordance with various embodiments disclosed herein is able to facilitate wound healing and prevent scar formation as compared to sutured wounds.

[0313] FIG. 5 shows a 3D model of a skin patch designed in accordance with various embodiments disclosed herein. The base layer is dimensioned to 60 x 25 x 0.16 mm and the needles are created with a base of o1 mm, tip of 0.1 mm and height of 5.5 mm. Needle array is arranged in a single row consisting of 7 needles. The scale bar represents 5 mm. EXAMPLES

[0314] Example embodiments of the disclosure will be better understood and readily apparent to one of ordinary skill in the art from the following examples, tables and if applicable, in conjunction with the figures. It should be appreciated that other modifications related to structural, biological and / or chemical changes may be made without deviating from the scope of the invention. Example embodiments are not necessarily mutually exclusive as some may be combined with one or more embodiments to form new example embodiments. The example embodiments should not be construed as limiting the scope of the disclosure.

[0315] The following examples describe the development of 3D printed bioactive PLGA skin patches comprising needles. Advantageously, embodiments of the bioactive PLGA skin patch designed in accordance with various embodiments disclosed herein possess enhanced skin regeneration and / or inflammation reduction properties for use in surgical wound healing and scar prevention (or to expedite wound healing and prevent scar formation). The 3D printed PLGA skin patches with needles contain additives made of bioactive PLGA (e.g., PLGA- RGD or PLGA-HA brush copolymers where HA represents hyaluronic acid of 8- 13 saccharide units), that may be used for incisional or surgical wound treatment to expedite wound healing and prevent scar formation. Bioactive PLGA was blended at specific ratios in PLGA to create a formulation for 3D printing into skin patches with needles for incisional or surgical wound healing and scar prevention. The bioactive PLGA material contains integrin binding peptides that can promote wound healing through tissue regeneration and inflammation reduction, both of which are important to reduce scarring. Epidermal penetration of needles designed on the patch allow for tissue regenerative peptides to reach dermal layer for integrin binding to facilitate cell adhesion, migration and proliferation, thereby promoting wound healing.

[0316] In the following examples, the efficacy of the bioactive PLGA skin patch was demonstrated on incisional wounds in animal models. Porcine incisional wound model showed excellent healing and scarring outcomes relative to positive and negative controls. Advantageously, embodiments of the skin patch designed in accordance with various embodiments disclosed herein encourage wound closure with minimal scarring.

[0317] Example 1 : Design of Skin Patch and 3D Printing Parameters

[0318] Bioactive PLGA containing RGD peptides (i.e. PLGA-RGD) and bioactive PLGA containing short chain hyaluronic acid (HA, 8-13 saccharide units) (i.e. PLGA-HA) were used as bioadditives in PLGA base polymers. Both PLGA-RGD and PLGA-HA are able to encourage wound healing with minimal inflammation. The bioadditives were first blended with commercial PLGA base polymer in ratio of 5 wt% for PLGA-RGD and PLGA-HA brush copolymer using a mixer.

[0319] Once the additives are evenly blended into PLGA, the mixture is extruded into filaments using a twin-screw extruder to obtain 3DP quality filaments.

[0320] Skin patches were designed with the base layer dimensioned to 60 x 25 x 0.16 mm while the needles were created with a base of o1 mm, tip of 0.1 mm and height of 5.5 mm. Needle array was arranged in a single row consisting of 7 needles (FIG. 1 and FIG. 2).

[0321] Table 1 shows the 3D printing parameters used for skin patch fabrication. Parameters in Table 1 were finely optimized for the design on 3D models of the skin patches. It was found that stringing between needles and needle leaning were prominent which affected print quality and needle tip finishing which directly impacted the puncturing ability of the skin patches. Post-processing scripts such as “PauseAtHeight” and “ChangeAtZ” were introduced into the printing files to address these issues which resulted in acceptable print quality of skin patches. As “PauseAtHeight” script was utilized, it paused the print at the designated layer which then allowed user to intervene to stop the printing completely. By doing so at layer #70, needle height achieved was acceptable while producing good print quality without any stringing or excessive leaning while still maintaining its puncturing ability. The samples are then tested on porcine wound healing models for efficacy.

[0322] Table 1. 3D printing parameters Example 2: Porcine Wound Healing Models

[0323] Briefly, twelve 4 cm incisional wounds were created on the dorsum of a male juvenile Yorkshire pig (approx. 31 kg), for each of 2 pigs, using a size 11 scalpel blade. Wounds were sutured with monocryl 4 / 0 before samples were applied. The samples, negative control (sutured wound only) and positive control (Dermabond Prineo) were randomly distributed on each of the 12 wounds on each pig, with equal representation of each sample on all 3 sections of the pig’s dorsum. All groups had at least 3 wounds. Mepilex post-op, cotton gamgee and Elastoplast were used as secondary dressings overlay for exudate absorption and mechanical protection.

[0324] The secondary dressings were changed, and wounds inspected on Days 7, 14, 21. All skin patch samples and positive controls were removed on Day 7. From visual assessment by a trained plastic surgeon, all incisional wounds healed well by Day 21. The scars were then evaluated on weeks 6, 9 and 13 (FIG. 3 and FIG. 4). On week 6, the negative control group showed scars with mild erythema. The positive control group showed slightly depressed scar with patchy appearance. PLGA-RGD and PLGA-HA both showed good scarring outcomes. On week 9, negative control group showed mild hypertrophic scar while positive control group showed slightly depressed scar. Both PLGA-RGD and PLGA-HA showed almost imperceptible scars. On week 13, slightly depressed scars were observed in both negative and positive control groups. PLGA-HA showed slight hyperpigmentation while PLGA-RGD scar was almost imperceptible. From this preliminary incisional wound study, it has been shown that 3DP bioactive PLGA skin patch designed in accordance with various embodiments disclosed herein can indeed encourage healing and reduce scarring compared to sutured wounds. Technically, the technology would work with any oligopeptide of 3 - 20 amino acids in length or oligosaccharides up to 20 saccharide units. The skin patch can potentially be used in scar prevention products targeting incisional wounds such as surgical or caesarean wounds. Example 3: Experimental

[0325] Bioactive PLGA material synthesis is described in PCT / SG2020 / 050621 and PCT / SG2023 / 050288, the contents of which are fully incorporated herein. 3D printing (3DP) process is described in PCT / SG2022 / 050620, the contents of which are fully incorporated herein.

[0326] Skin patches for porcine animal study were designed with the base layer dimensioned to 60 x 25 x 0.16 mm while the needles were created with a base of 01 mm, tip of 0.1 mm and height of 5.5mm (FIG. 5). Needle array was arranged in a single row consisting of 7 needles.

[0327] Bioactive PLGA filaments were prepared by filament extrusion process using ThermoScientific Process 11 twin screw extruder connected to a melt pump, conveyor belt and spooling unit. The melt pump nozzle of o3mm was used to achieve filament diameter of 2.85 mm. Compressed dry air was utilized as the cooling medium for the extrudate. Prior to extrusion process, neat PLGA resins were pulverized into powder using cryogenic milling with liquid nitrogen. Bioactive PLGA mixtures were prepared by mixing neat PLGA and PLGA bioadditive powder using SPEX 8000D Dual Mixer / Mill for a minimum of 6 minutes. Ultimaker S5 dual nozzle printer with print nozzle of 00.25mm was used for the 3D printing process of the skin patches. Print parameters are as shown in Table 1 .

[0328] Porcine incisional wound healing study was carried out under IACUC study 2022 / SHS / 1758. Animals are handled by a trained vet and a plastic surgeon, Dr James Mok. Two male Yorkshire pigs of average weight of 31 kg were used in this study. The studies were carried out in National Large Animal Research Facility (NLARF), Singapore. 3.1. Experimental design: Porcine incisional wound model

[0329] Number of wounds to be created on each animal: 12 wounds of 4 cm each

[0330] Treatment of pig before wounding - Animal to be on anaesthetic and given preprocedural antibiotics with monitoring of vitals. Locations on the pig where wounds are to be created are outlined with an alcohol-based marker and shaved off hair with a razor before decontaminating with chlorhexidine solution. Each of these outlined wound locations are photographed. The skin incision wounds were created on the pig dorsum, upper half. The wounds are not expected to reach muscular depth, nor will it impede muscular movement; they will be skin deep only.

[0331] Method of incisional wound creation - Size 11 scalpel is used to create 4 cm horizontal craniocaudal skin incisions over the pig dorsum / flank. Each wound is separated from other wound areas by at least 6 cm to prevent site-to- site influence.

[0332] Preparation of the wound bed - Wound will be thoroughly cleansed with chlorhexidine and saline. Wounds will undergo closure with Monocryl 4 / 0 suture.

[0333] Application of the burns dressing - Randomized allocation to treatment groups will determine type of primary dressing applied to sequential wound locations along the pig dorsum. Sterile dressing is applied to the wounds. Mepilex post-op overlay will be placed over all wounds for mechanical protection and to absorb excess exudate. Cotton gamgee pads are used as a cushion before bandage is applied and taped down with Elastoplast. A pig jacket is then put over the animal.

[0334] Wound healing and biopsy - Under anaesthesia, the outer covering of Mepilex / Gamgee / bandage was removed, and the wounds inspected on Day 7, 14, 21 and Week 6, 9, 13 and photographed to monitor wound healing progress and scar progression. Skin biopsy (0.5 x 0.5 cm) was taken at Day 7 and Day 21 for histopathological analysis. The biopsy wound was sutured with silk 2 / 0 and dressed. At 13 weeks post-treatment, the study was terminated and the animals euthanized.

[0335] It will be appreciated by a person skilled in the art that other variations and / or modifications may be made to the embodiments disclosed herein without departing from the spirit or scope of the disclosure as broadly described. For example, in the description herein, features of different exemplary embodiments may be mixed, combined, interchanged, incorporated, adopted, modified, included etc. or the like across different exemplary embodiments. The present embodiments are, therefore, to be considered in all respects to be illustrative and not restrictive.

Claims

CLAIMS1 . A material for preventing or reducing scar formation during wound healing, the material comprising:(i) a base poly(lactic-co-glycolic acid) (PLGA); and(ii) a bioactive poly(lactic-co-glycolic acid) (PLGA) copolymer, wherein at least part of the material is in the form of a plurality of protrusions extending from a surface.

2. The material of claim 1 , wherein each protrusion comprises a structure having a base tapering to a tip.

3. The material of any one of the preceding claims, wherein each base has a diameter falling in the range of from 0.5 mm to 2.5 mm.

4. The material of any one of the preceding claims, wherein each tip has a diameter falling in the range of from 0.05 mm to 0.25 mm.

5. The material of any one of the preceding claims, wherein the distance between the base and the tip falls in the range of from 1 mm to 10 mm.

6. The material of any one of the preceding claims, wherein the plurality of protrusions is arranged in one or more arrays, each array comprising at least 5 protrusions.

7. The material of any one of the preceding claims, wherein the distance between the protrusions falls in the range of from 1 mm to 10 mm.

8. The material of any one of the preceding claims, wherein the ratio of the (i) base PLGA to (ii) bioactive PLGA copolymer present in the material is 60.0 - 99.9 : 0.1 - 40.0.

9. The material of any one of the preceding claims, wherein the material comprises from 60 wt% to 99.9 wt% of the base PLGA.

10. The material of any one of the preceding claims, wherein the material comprises from 0.1 wt% to 40 wt% of the bioactive PLGA copolymer.

11. The material of any one of the preceding claims, wherein the material is part of a three-dimensional (3D) printed structure.

12. The material of any one of the preceding claims, wherein the bioactive PLGA copolymer comprises a bioactive PLGA copolymer with a poly(norbornene-dicarboximide) backbone having one or more repeating units represented by general formula (I) and one or more repeating units represented by general formula (II):whereinR1is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl or optionally substituted alkylcarbonylalkyl;R2is optionally substituted alkyl;R3is selected from H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;L is heteroalkylene;X comprises a bioactive moiety selected from the group consisting of proteins, peptides, oligopeptides, carbohydrates, oligosaccharides, sugar, collagen, hyaluronic acid, therapeutic / drug molecules and derivatives thereof;Z1and Z2are each independently selected from CRaRb, O, NRC, SiRaRb, PRaor S, wherein Ra, Rband Rcare each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; p > 1 ; and q > 1.

13. The material of any one of the preceding claims, wherein X is selected from the group consisting of RGD, SRGDS, RGDS, A5G81 (AGQWHRVSVRWGC), SVVYGLR, (IRIK)2, (IKKI)3, heparin oligosaccharide DP8, DP10, DP12, DP14, DP16, DGEA, (PHypG)n type sequence, (PGHyp)ntype sequence, (HypGP)n type sequence, (HypPG)n type sequence, (GHypP)n type sequence, (GPHyp)n type sequence, hyaluronic acid and combinations thereof.

14. A method of preparing a material of any one of claims 1 to 13, the method comprising:(i) providing a bioactive PLGA filament comprising a base poly(lactic- co-glycolic acid) (PLGA) and a bioactive poly(lactic-co-glycolic acid) (PLGA) copolymer ; and(ii) printing a bioactive PLGA material from the bioactive PLGA filament according to a design model to obtain a printed structure or part with a plurality of protrusions printed thereon.

15. The method according to claim 14, wherein the step (i) of providing a bioactive PLGA filament comprises:(i-a) providing a base PLGA powder and a bioactive PLGA copolymer;(i-b) mixing the base PLGA powder with the bioactive PLGA copolymer to obtain a bioactive PLGA formulation; and(i-c) extruding a bioactive PLGA filament from the formulation.

16. The method according to any one of claims 14 to 15, wherein the step (ii) of printing a bioactive PLGA material from the bioactive PLGA filament comprises:(ii-a) feeding the bioactive PLGA filament into a printing apparatus;(ii-b) applying heat to the bioactive PLGA filament to obtain a molten form of the bioactive PLGA; and(ii-c) depositing the molten bioactive PLGA on a print bed to form a printed part or structure.

17. The material of any one of claims 1 to 13 for use in medicine.

18. The material of any one of claims 1 to 13 for use in treatment of wounds.

19. The material of any one of claims 1 to 13 for use in preventing and / or reducing scar formation.

20. Use of a material of any one of claims 1 to 13 in the manufacture of a medicament for treatment of wounds.

21. Use of a material of any one of claims 1 to 13 in the manufacture of a medicament for preventing and / or reducing scar formation.

22. A method of treating a wound, the method comprising applying the material of any one of claims 1 to 13 to a wound of a subject in need thereof.

23. A method of preventing and / or reducing scar formation in a subject in need thereof, the method comprising applying the material of any one of claims 1 to 13 to a body part of the subject in need thereof.

24. The material of claim 18, the use of claim 20 or the method of claim 22, wherein the wound is selected from the group consisting of incisions, excisions, surgical wound, caesarean wound, laceration wound, sutured wound, and combinations thereof.

25. A medical device comprising the material of any one of claims 1 to 14.

26. The medical device according to claim 25, wherein the medical device is selected from the group consisting of skin patch, dermal template, skin scaffold, wound care product, wound dressing, personal care product, beauty product and combinations thereof.

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