Polyester staple fiber-microsphere composite medical filling material as well as preparation method and application thereof

Abstract

The invention provides a composite composition containing polyester staple fibers and polyester microspheres and application of the composite composition as a medical beauty filling material. The invention also provides a method for preparing the polyester staple fiber. The invention provides a brand-new medical beauty filling material solution by utilizing good biocompatibility, biodegradability and unique linear structure after the polyester staple fibers and the microspheres are compounded.

Description

Technical Field

[0001] This disclosure pertains to the field of biomedical materials, specifically relating to a composition comprising polyester short fibers and polyester microspheres, its preparation method, and its application as a main functional material in the preparation of medical aesthetic filler materials. Background Technology

[0002] With the rapid development of modern medical aesthetics technology, soft tissue filling has become an important non-surgical cosmetic procedure. Currently, materials used for soft tissue filling mainly include hyaluronic acid, collagen, and polyester materials. Hyaluronic acid, due to its good biocompatibility and biodegradability, currently dominates the field of medical aesthetic filling. However, hyaluronic acid is easily degraded in the human body by hyaluronidase, and its effects typically last only 3-12 months, classifying it as a temporary filler. This characteristic necessitates frequent repeated injections, increasing the financial burden on patients and causing the inconvenience of repeated medical procedures. Collagen, another commonly used filler, provides a relatively natural filling effect, but it carries the risk of inducing allergic reactions, and some patients may experience adverse reactions such as granuloma formation, limiting the safety of its clinical application.

[0003] Polyester materials, such as polylactic acid (PLA), polycaprolactone (PCL), and polylactic-glycolic acid copolymer (PLGA), are widely used in the medical field due to their excellent biocompatibility and controllable biodegradability. In the field of cosmetic fillers, polyester materials are usually applied in microsphere form. Their mechanism of action mainly involves stimulating macrophages and fibroblasts in local tissues to promote the synthesis and secretion of endogenous collagen, thereby improving skin texture and achieving relatively long-lasting cosmetic effects. However, the effectiveness of existing polyester microspheres in stimulating collagen production still needs further improvement due to the limitations of their spherical geometry. The contact area between spherical microspheres and cells is relatively limited, and their surface morphology lacks sufficient cell adhesion sites, making it difficult to fully activate the proliferation of fibroblasts and collagen secretion. Other polyester filler materials, such as fibrous, sheet-like, or irregularly shaped ones, can clog needles during injection, causing difficulties in injection and pain for patients.

[0004] Therefore, there is an urgent need to develop a new type of medical aesthetic filler material that can maintain the inherent biocompatibility and controllable degradation characteristics of polyester materials, and significantly enhance the stimulation effect on collagen production through innovative morphological design. Invention Overview

[0005] In view of the shortcomings of the existing technology and the existing needs, the inventors have innovatively designed the morphology of the material and prepared polyester short fibers with uniform diameter and suitable length using a specific preparation process. These fibers are then compounded with polyester microspheres in a suitable dispersion system to obtain an injectable formulation of polyester fiber and polyester microsphere composite. This formulation provides a novel solution for medical aesthetic filler materials. Utilizing the excellent biocompatibility, biodegradability, and unique morphological combination of the polyester short fibers and microspheres, it can be uniformly distributed in the dispersion medium, has good injectability, and exhibits better biodegradability in vivo, which is more conducive to fibroblast adhesion and thus better promotes collagen formation. Therefore, the composite provided in this disclosure is expected to overcome the bottleneck of existing medical aesthetic filler materials in terms of collagen stimulation efficiency, providing a more effective technical solution for the field of medical aesthetic fillers.

[0006] Therefore, in a first aspect, this disclosure provides a method for preparing polyester staple fibers, comprising the following steps:

[0007] S1. Prepare continuous polyester fiber materials from polyester raw materials through melt spinning or solution spinning processes;

[0008] S2. The continuous fiber material obtained in step S1 is frozen and fixed in the presence of an embedding agent;

[0009] S3. Freeze and slice the material fixed in step S2 to obtain short fiber slices of a certain size; and optionally...

[0010] S4. Post-process the short fiber slices obtained in step S3.

[0011] Secondly, this disclosure provides a biomedical composite composition comprising polyester short fibers (preferably polyester short fibers prepared by the method of this disclosure) and polyester microspheres; specifically, wherein the polyester short fibers have a fiber diameter ranging from about 2 to 20 μm and a length ranging from about 5 to 300 μm.

[0012] Thirdly, this disclosure provides a method for preparing a biomedical composite composition, comprising mixing polyester short fibers (preferably prepared according to the first aspect of this disclosure) with polyester microspheres and optionally one or more pharmaceutical excipients.

[0013] Fourthly, this disclosure provides the use of the polyester staple fibers of this disclosure or the biomedical composite compositions of this disclosure in promoting collagen formation, or in the preparation of biomedical materials for promoting collagen formation.

[0014] Fifthly, this disclosure provides the use of the polyester staple fibers of this disclosure or the biomedical composite compositions of this disclosure in medical aesthetics, specifically for skin rejuvenation or anti-skin aging, such as improving wrinkles and fine lines, enhancing skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, or as a collagen stimulant used in combination with other medical aesthetic procedures.

[0015] Sixthly, this disclosure also provides the use of the polyester staple fibers of this disclosure or the biomedical composite compositions of this disclosure in the preparation of biomedical materials for medical aesthetics, specifically for skin rejuvenation or anti-skin aging, such as improving wrinkles and fine lines, enhancing skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, or as a collagen stimulant used in combination with other medical aesthetic procedures.

[0016] In a seventh aspect, this disclosure provides a method for promoting collagen formation, comprising administering the biomedical composite composition of this disclosure to an individual in need.

[0017] Eighthly, this disclosure provides a medical aesthetic method, specifically for skin rejuvenation or anti-skin aging, such as improving wrinkles and fine lines, enhancing skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, including applying the biomedical composite composition of this disclosure to an individual in need. Attached Figure Description

[0018] Figure 1 The image shown is a scanning electron microscope (SEM) image of the PLA continuous fibers obtained in step S1 of the embodiment.

[0019] Figure 2 The image shows a scanning electron microscope (SEM) image of the PLA short fibers prepared for the example.

[0020] Figure 3 The image shows a scanning electron microscope (SEM) image of the PLA microspheres used in the application example.

[0021] Figure 4 An optical microscope image of the injection solution obtained in the application example.

[0022] Figure 5 The injection force curves and average injection force data of the injection solutions obtained in Application Examples 1, 2 and 3 are shown.

[0023] Figure 6 The cytotoxicity of the injection solution obtained in the application example at different concentrations is shown.

[0024] Figure 7The H&E, Masson's red, and Sirius red staining results of the tissue in the injection area 28 days after the injection solution obtained in Examples 2-7 was injected subcutaneously into rats. Invention Details

[0025] definition

[0026] The terms “a”, “an”, “the”, and similar terms used herein, and especially in the context of the claims, shall be construed as covering both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context.

[0027] The term “approximately” as used herein will vary by ±10% for numerical values ​​used with it, or more specifically, by ±5%. With respect to proportions, the term “approximately” is used to specify each number in a given proportion. For example, a proportion of approximately 1:1 means a proportion of 0.9 to 1.1 : 0.9 to 1.1.

[0028] The term "individual" as used herein refers to primates and is not limited to a specific age or sex. In specific implementations, the individual being referred to is a human being, including children, adolescents, or adults.

[0029] The term "promoting collagen formation" as used in this article refers to materials that, through one or more means, create favorable conditions for the synthesis, deposition, or stabilization of collagen, thereby resulting in an increase in the net collagen content.

[0030] The term "cosmetic medicine" as used in this article refers to a branch of medicine that uses drugs, surgery, medical devices, and other invasive or traumatic medical techniques to repair and reshape the shape of various parts of the human body in order to maintain, repair, and reshape the body's contours.

[0031] The term "cosmetic filler" as used in this article refers to a minimally invasive medical aesthetic method that involves injecting or implanting materials to immediately increase the volume of soft tissue in order to fill depressions, smooth wrinkles, sculpt or repair contours, and achieve normalization, rejuvenation or beautification of facial or body contours.

[0032] As used herein, the term "polyester" or "polyester-based materials" refers to aliphatic polyesters suitable for use in the pharmaceutical field, primarily made from hydroxy acids or their derivatives such as lactones through condensation or ring-opening polymerization, and which are biocompatible and biodegradable in vivo. Representative examples of such polyesters include, but are not limited to, polylactic acid (PLA), poly-L-lactide (PLLA), poly(ε-caprolactone) (PCL), polyvalerol (PVL), polyglycolic acid (PGA), polylactic-glycolic acid (PLGA) copolymers, and polyhydroxyalkanoates (PHAs) such as polyhydroxybutyrate (PHB).

[0033] The term "polyester staple fiber" as used in this article refers to fibrous materials made of polyester polymers that are relatively short in length (typically a few micrometers to tens of millimeters).

[0034] The term "melt spinning" used in this article refers to a chemical fiber spinning method in which polymer raw materials are heated to a molten state, extruded through a spinneret, and rapidly cooled and solidified in air or water to form fibers.

[0035] The term "solution spinning" as used in this article refers to a spinning method in which polymer raw materials are dissolved in a solvent to prepare a spinning solution with a suitable concentration, and then the spinning solution is extruded from a micro-hole into a coagulation bath (wet method) or a hot gas (dry method) to precipitate the polymer into solid fibers.

[0036] As used herein, the term "microsphere" refers to spherical particles composed of natural or synthetic polymeric materials, with a size between approximately 1 and 1000 μm, more typically between approximately 1 and 250 μm. In the pharmaceutical field, microspheres are commonly used as drug delivery systems or fillers. The term "polyester microsphere" as used herein refers to microspheres made of biodegradable aliphatic polyester materials, such as microspheres made of "polyester" as defined herein, such as PLA microspheres, PLGA microspheres, PCL microspheres, etc.

[0037] As used herein, the term "medical excipient" refers to substances that can be used in the preparation or use of medical compositions, such as suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, suspending agents, thickeners, fillers, and combinations thereof, as known to those skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 22). nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0038] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0039] All methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context. The use of any and all embodiments or exemplary language (e.g., “as”) provided herein is intended only to better illustrate this disclosure and does not constitute a limitation on the scope of this disclosure as otherwise claimed. Technical solution

[0040] This disclosure provides a method for preparing and compounding polyester short fibers and polyester microspheres, as well as their application as a medical aesthetic filler material, to further improve the collagen-stimulating effect of existing medical aesthetic fillers. The method precisely controls the diameter and length of the fibers, ensuring high uniformity and excellent physical properties while combining the morphological characteristics of both microspheres and fibers. This ensures that the short fibers can be smoothly injected through 27G or higher injection needles, while simultaneously achieving a synergistic promoting effect of both short fibers and microspheres on collagen formation.

[0041] on the one hand This disclosure provides a method for preparing polyester staple fibers, comprising the following steps:

[0042] S1. Polyester raw materials are prepared into continuous polyester fiber materials through melt spinning or solution spinning processes;

[0043] S2. The continuous fiber material obtained in step S1 is frozen and fixed in the presence of an embedding agent;

[0044] S3. Freeze and slice the material fixed in step S2 to obtain short fiber slices of a certain size; and optionally...

[0045] S4. Post-process the short fiber slices obtained in step S3.

[0046] In some embodiments, the polyester raw material used in step S1, as defined herein, is preferably selected from one or more of polylactic acid (PLA), poly-L-lactide (PLLA), poly(ε-caprolactone) (PCL), polyvalerol (PVL), polyglycolic acid (PGA), polylactic acid-glycolic acid (PLGA) copolymer, and polyhydroxy fatty acid esters (PHA) such as polyhydroxybutyrate (PHB), more preferably polylactic acid (PLA).

[0047] In some implementations, step S1 is carried out using a melt spinning process, which may specifically include the following steps: adding polyester raw materials into the barrel of an extruder such as a screw extruder, melting and plasticizing them at a certain temperature, then conveying the melt to a spinneret via a metering pump, and cooling the nascent fibers obtained by spinning in an air or inert gas environment before winding and stretching to obtain continuous fibers.

[0048] In some implementations, step S1 can be performed using a solution spinning process, which specifically includes the following steps: dissolving polyester raw materials in a suitable solvent to prepare a spinning solution; after filtration and degassing, the spinning solution is delivered to a spinneret via a metering pump; the nascent fibers obtained by spinning are solidified in a coagulation bath; then, residual solvent is removed by washing with water; wet stretching (wet method) is performed, or the solvent is evaporated and solidified in hot air (dry method); and then dried and wound to obtain continuous fibers.

[0049] In some embodiments, in step S1, the heating temperature for melt plasticization in the melt spinning process varies depending on the polymer material, and is generally about 100~300°C, for example about 100~250°C, 150~250°C, 180~250°C, 200~240°C, 220~240°C; preferably about 200~250°C.

[0050] In some embodiments, in step S1, the orifice diameter of the spinneret in the melt spinning process is about 100~500μm, for example about 200~500μm, about 200~400μm, about 100~250μm, for example about 300μm.

[0051] In some embodiments, in step S1, the aspect ratio (length to diameter ratio L / D) of the spinneret in the melt spinning process is about (2~10):1, for example about 2:1 to 10:1, about 2:1 to 8:1, about 2:1 to 6:1, about 2:1 to 5:1, about 2:1 to 4:1, about 2:1 to 3:1, for example about 2:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1; preferably about 8:1.

[0052] In some embodiments, in step S1, the cooling temperature of the resulting nascent fibers is about 10 to 30°C, for example about 15 to 25°C, 18 to 22°C, or about 20 to 25°C, for example about 25°C.

[0053] In some embodiments, in step S1, the resulting nascent fibers are cooled in an inert gas environment selected from nitrogen, argon or carbon dioxide, preferably in nitrogen.

[0054] In some embodiments, in step S1, the diameter of the resulting polyester continuous fiber material is about 1 to 50 μm, for example about 1 to 40 μm, 1 to 30 μm, 2 to 20 μm, for example about 2 to 15 μm, 5 to 15 μm, 2 to 10 μm.

[0055] In some embodiments, in step S1, the crystallinity of the polyester continuous fiber material is about 1 to 60%, for example, about 5 to 60%, about 5 to 50%, about 5 to 40%, about 5 to 30%, about 5 to 20%, about 10 to 60%, about 10 to 50%, about 10 to 40%, about 10 to 30%, about 10 to 20%, about 20 to 60%, about 20 to 50%, about 20 to 40%, about 20 to 30%, about 30 to 60%, about 30 to 50%, about 30 to 40%, about 40 to 60%, about 40 to 50%. This crystallinity can be determined using differential scanning calorimetry, X-ray diffraction, or density gradient methods well known to those skilled in the art.

[0056] In some embodiments, in step S1, the elastic modulus of the polyester fiber material is about 2 to 8 GPa, for example, about 2 to 6 GPa, about 3 to 6 GPa, or about 4 to 8 GPa. This elastic modulus can be determined using methods well known to those skilled in the art, such as tensile testing, bending testing, etc.

[0057] In some embodiments, in step S2, the freezing temperature is about -80 to -5°C, for example, it can be about -80 to -10°C, -70 to -10°C, -60 to -10°C, -50 to -10°C, -40 to -10°C, -30 to -10°C, -20 to -10°C, -80 to -20°C, -70 to -20°C, -60 to -20°C, -50 to -20°C, -40 to -20°C, -30 to -20°C, -80 to -30°C, -70 to -30°C, -60 to -30°C, -50 to -30°C, or -40 to -30°C; preferably about -30 to -20°C.

[0058] In some implementations, the freezing time in step S2 is about 0.5 to 5 hours, for example, about 0.5 to 4.5 hours, 0.5 to 4 hours, 0.5 to 3.5 hours, 0.5 to 3 hours, 0.5 to 2.5 hours, 0.5 to 2 hours, 0.5 to 1.5 hours, 0.5 to 1 hour, 1 to 5 hours, 1 to 4.5 hours, 1 to 4 hours, 1 to 3.5 hours, 1 to 3 hours, 1 to 2.5 hours, 1 to 2 hours, 1 to 1.5 hours, 2 to 5 hours, 2 to 4.5 hours, 2 to 4 hours, 2 to 3.5 hours, 2 to 3 hours, 2 to 2.5 hours, 3 to 5 hours, 3 to 4.5 hours, 3 to 4 hours; preferably about 0.5 to 1.5 hours, for example, about 1 hour.

[0059] In some embodiments, in step S2, the embedding agent is a reagent commonly used in immunohistochemistry experiments to support tissue, increase tissue continuity, and reduce wrinkles and fragmentation during frozen sections. Typically, it is an OCT embedding agent, i.e., an aqueous solution of a PEG-PVA blend, which is commercially available, such as SAKURA, or can be replaced by Tissue-Tek® CryomoldCompound, Cryo-Gel™, Neg-50™, gelatin solution, or sodium carboxymethyl cellulose solution.

[0060] In some embodiments, in step S3, the thickness of the short fiber slice is about 5 to 300 μm, for example, about 10 to 300 μm, 20 to 300 μm, 30 to 300 μm, 40 to 300 μm, 50 to 300 μm, 60 to 300 μm, 70 to 300 μm, 80 to 300 μm, 100 to 300 μm, 5 to 250 μm, 50 to 250 μm, 80 to 250 μm, 100 to 250 μm, 150 to 250 μm; preferably about 80 to 250 μm.

[0061] In some implementations, in step S3, the short fiber slicing can be performed using methods well known to those skilled in the art, such as commercially available cryostats, like the ZD-LQ3300 or Leica Biosystems series of slicers.

[0062] In some embodiments, the method for preparing polyester staple fibers disclosed herein further includes step S4, wherein the staple fibers obtained in step S3 are post-treated, specifically including washing, centrifugation, and drying.

[0063] In some implementations, in step S4, the cleaning step is performed using a suitable solvent to remove impurities, such as water, methanol, ethanol, ethylene glycol, isopropanol, preferably water.

[0064] In some implementations, in step S4, the centrifugation speed of the centrifugation separation step is about 2000 to 20000 rpm, for example, about 5000 to 20000 rpm, 5000 to 15000 rpm, or 8000 to 12000 rpm; preferably about 10000 rpm.

[0065] In some implementations, in step S4, the centrifugation separation step is performed for about 1 to 20 minutes, for example, about 1 to 15 minutes, 1 to 10 minutes, 1 to 8 minutes, 2 to 20 minutes, 2 to 15 minutes, 2 to 10 minutes, or 2 to 8 minutes; preferably about 5 minutes.

[0066] In some implementations, in step S4, the drying time is about 5 h to 48 h, for example about 5 to 40 h, 5 to 35 h, 5 to 30 h, 5 to 25 h, 10 to 48 h, 10 to 40 h, 10 to 30 h, 15 to 48 h, 15 to 40 h, 15 to 30 h, 20 to 48 h, 20 to 40 h, 20 to 30 h; preferably about 20 to 30 h, for example about 20 to 25 h, for example about 24 h.

[0067] In some implementations, the drying temperature in step S4 is 30~60°C.

[0068] It should be noted that the method for preparing polyester staple fibers disclosed herein includes any combination of specific or preferred features of any of the above steps and specific or preferred features of one or more other steps to obtain the method technical solution.

[0069] In a specific implementation, this disclosure provides a method for preparing polyester staple fibers, comprising the following steps:

[0070] S1' prepares polyester continuous fiber materials from polyester raw materials through melt spinning. The polyester raw materials are selected from one or more of polylactic acid (PLA), poly-L-lactide (PLLA), poly(ε-caprolactone) (PCL), polyvalerol (PVL), polyglycolic acid (PGA), polylactic acid-glycolic acid (PLGA) copolymer, and polyhydroxybutyrate (PHB). The fibers are spun at a temperature of about 200-250°C using a spinneret with an aperture of about 200-400 μm and cooled at about 20-25°C. The diameter of the resulting polyester continuous fiber material is about 2-20 μm.

[0071] S2' The continuous fiber material obtained in step S1 is frozen and fixed at approximately -30 to -20°C for approximately 0.5 to 1.5 hours in the presence of OCT embedding agent;

[0072] S3' Freeze-slices the material fixed in step S2 to obtain short fiber slices with a length of approximately 80 ~ 250 μm; and

[0073] S4' Wash the short fiber slices obtained in step S3 with an aqueous solvent, centrifuge at approximately 5000 ~ 15000 rpm for about 2 ~ 10 minutes, and dry for about 20 ~ 30 hours.

[0074] It should be noted that the features of each step in this specific method implementation scheme can also be independently taken as more specific or better values ​​as defined above for each step feature.

[0075] Second aspect This disclosure provides a biomedical composite composition comprising polyester staple fibers and polyester microspheres. In one specific embodiment, the polyester staple fibers in the biomedical composite composition are polyester staple fibers prepared according to the method of the first aspect of this disclosure, as generally or specifically defined in this disclosure.

[0076] In some embodiments, the polyester short fibers in the biomedical composite composition of this disclosure have a fiber diameter range of about 1 to 50 μm and a length of about 5 to 300 μm; specifically, they may be the corresponding general or specific ranges defined by the method technical solution of the first aspect of this disclosure, for example, the fiber diameter range may be about 2 to 20 μm, 2 to 15 μm, 2 to 10 μm, or 5 to 10 μm, and the length may be about 50 to 250 μm or 80 to 250 μm.

[0077] In the biomedical composite composition disclosed herein, the polyester microspheres included are microspheres made of biodegradable aliphatic polyester materials, such as one or more of PLA microspheres, PCL microspheres, PLGA microspheres, and PGA microspheres; in one specific embodiment, the polyester microspheres included are PLA microspheres.

[0078] In the biomedical composite composition disclosed herein, the polyester microspheres contained are commercially available or can be obtained by those skilled in the art using microsphere preparation methods well known in the art.

[0079] In the biomedical composite composition disclosed herein, the diameter of the included polyester microspheres is between about 1 and 200 μm, more typically between about 1 and 150 μm, and preferably between about 20 and 60 μm.

[0080] In some embodiments, the mass ratio of polyester microspheres to polyester short fibers in the biomedical composite composition disclosed herein is about 50:1 to 1:50, for example about 40:1 to 1:40, 30:1 to 1:30, 20:1 to 1:20, 10:1 to 1:10, 5:1 to 1:5, or even about 5:1 to 2:1, or about 5:1 to 3:1, or about 5:1, 4:1, 3:1, or 2:1. At this ratio, the composition in injectable form can be readily injected through a 27G needle.

[0081] In some embodiments, the mass percentage of polyester short fibers and polyester microspheres in the biomedical composite composition disclosed herein is about 2 to 30%, for example about 2 to 30%, 2 to 20%, 2 to 10%, 2 to 8%, 3 to 20%, 3 to 10%, 3 to 8%, preferably about 2 to 10%, 2 to 8%, 2 to 5%, for example about 3%.

[0082] In some embodiments, the biomedical composite composition of this disclosure is an injectable preparation, such as a lyophilized injectable preparation, wherein, in addition to the said polyester staple fibers and polyester microspheres, it optionally contains one or more pharmaceutically acceptable excipients, such as, but not limited to, thickeners or suspending agents, filler carriers, buffers and / or injection media.

[0083] In some embodiments, the injectable biomedical composite composition of this disclosure includes a thickener or suspending agent to, for example, prevent the sedimentation of microspheres or short fibers. Suitable thickeners or suspending agents include, but are not limited to, sodium carboxymethyl cellulose, hydroxyethyl cellulose, and sodium alginate, with sodium carboxymethyl cellulose being preferred.

[0084] In some embodiments, the injectable biomedical composite composition disclosed herein contains about 1 to 40% by weight of a thickener or suspending agent, such as about 1 to 40%, 1 to 30%, 1 to 20%, 1 to 10%, 2 to 10%, 2 to 8%, 2 to 6%, preferably about 2 to 10%, 2 to 6%, or 3 to 5%.

[0085] In some embodiments, the injectable biomedical composite composition of this disclosure includes a filler carrier to, for example, provide a suitable hydration environment immediately and prevent microsphere aggregation. Suitable filler carriers include, but are not limited to, hyaluronic acid, chondroitin sulfate, polyglutamic acid, and collagen solutions, preferably hyaluronic acid with a molecular weight of 200,000 to 1,000,000 Da, and more preferably hyaluronic acid with a molecular weight of about 300,000 Da.

[0086] In some embodiments, the injectable biomedical composite composition of this disclosure contains about 0.5 to 40% by weight of a filler carrier, such as about 0.5 to 40%, 0.5 to 20%, 0.5 to 10%, 0.5 to 5%, 0.5 to 3%, 1 to 20%, 1 to 10%, 1 to 5%, 1 to 3%, preferably about 0.5 to 5%, 0.5 to 3%, 1 to 2%.

[0087] In some embodiments, the injectable biomedical composite composition of this disclosure includes a buffer to, for example, adjust the osmotic pressure of the injection and / or provide lyophilization protection. Suitable buffers include, but are not limited to, mannitol, sucrose, trehalose, glycine, sorbitol, etc., with mannitol being preferred.

[0088] In some embodiments, the injectable biomedical composite composition of this disclosure contains about 1 to 30% by weight of a buffer, such as about 1 to 25%, 1 to 20%, 1 to 15%, 5 to 30%, 5 to 20%, 5 to 15%, 10 to 30%, 10 to 25%, 10 to 20%, 10 to 15%, preferably about 10 to 20%, 10 to 15%, or 10 to 13%.

[0089] In some embodiments, the injectable biomedical composite composition of this disclosure includes an injection medium, such as sterile water for injection.

[0090] In some embodiments, the injectable biomedical composite composition disclosed herein contains about 60 to 90% by weight of an injection medium, such as about 70 to 90% or 75 to 85%.

[0091] In some embodiments, the injectable biomedical composite composition of this disclosure, in addition to the polyester staple fibers and polyester microspheres of the types and amounts generally or specifically defined in this disclosure, also includes a thickener of the types and amounts generally or specifically defined in this disclosure, a filler carrier of the types and amounts generally or specifically defined in this disclosure, a buffer of the types and amounts generally or specifically defined in this disclosure, and an injection medium of the types and amounts generally or specifically defined in this disclosure; in more specific embodiments,

[0092] The diameter of the polyester staple fiber ranges from about 1 to 50 μm, for example, about 2 to 15 μm, 2 to 10 μm or 5 to 10 μm, and the length is about 50 to 250 μm or 80 to 250 μm;

[0093] The mass ratio between polyester microspheres and polyester staple fibers is approximately 50:1 to 1:50, for example, approximately 5:1 to 2:1, for example, approximately 5:1 to 3:1;

[0094] The mass percentage of polyester staple fibers and polyester microspheres is approximately 2 to 10%, for example, approximately 2 to 5%;

[0095] The thickener is approximately 2 to 10% by mass, for example, approximately 2 to 6%;

[0096] The mass percentage of the filler carrier is approximately 0.5% to 5%, for example, approximately 0.5% to 3%.

[0097] The buffer has a mass percentage of approximately 10-20%, for example, approximately 10-15%.

[0098] The mass percentage of the injection medium is approximately 60-90%, for example, approximately 75-85%.

[0099] In some specific embodiments, the injectable biomedical composite composition of this disclosure comprises PLA short fibers, PLA microspheres, sodium carboxymethyl cellulose, hyaluronic acid, mannitol, and water for injection as generally or specifically defined in this disclosure; in more specific embodiments,

[0100] PLA short fibers have a diameter range of approximately 1–50 μm, such as approximately 2–15 μm, 2–10 μm, or 5–10 μm, and a length of approximately 50–250 μm or 80–250 μm.

[0101] The mass ratio between PLA microspheres and PLA short fibers is approximately 50:1 to 1:50, for example, approximately 5:1 to 2:1, for example, approximately 5:1 to 3:1;

[0102] The mass percentage of PLA short fibers and PLA microspheres is approximately 2 to 10%, for example, approximately 2 to 5%.

[0103] The mass percentage of sodium carboxymethyl cellulose is approximately 2 to 10%, for example, approximately 2 to 6%;

[0104] The mass percentage of hyaluronic acid is approximately 0.5% to 5%, for example, approximately 0.5% to 3%.

[0105] The mass percentage of mannitol is approximately 10-20%, for example, approximately 10-15%;

[0106] The mass percentage of water for injection is approximately 60-90%, for example, approximately 75-85%.

[0107] The disclosed biomedical composite composition for injection can be successfully injected through a 27G needle.

[0108] Third aspect This disclosure provides a method for preparing a biomedical composite composition, comprising mixing polyester staple fibers with polyester microspheres and optionally one or more pharmaceutical excipients. In a specific embodiment, the polyester staple fibers are prepared according to the method of the first aspect of this disclosure.

[0109] In some embodiments, the biomedical composite composition of this disclosure is an injectable formulation, which can be prepared by methods well known to those skilled in the art, such as by uniformly mixing polyester staple fibers (preferably polyester staple fibers prepared by methods generally or specifically defined in the first aspect of this disclosure), polyester microspheres, a thickener, a filler carrier, a buffer, and an injection medium to obtain a suspension, which is then filled, capped, and packaged to obtain an injectable formulation. The polyester microspheres, thickener, filler carrier, buffer, and injection medium are reagents conventionally used in such formulations in the art, preferably reagents as defined herein.

[0110] Fourth aspect This disclosure provides the use of the polyester short fibers of this disclosure, alone or in combination with other materials, for promoting collagen formation, or alone or in combination with other materials, for promoting collagen formation, or alone or in combination with other materials, in the preparation of biomedical materials for promoting collagen formation.

[0111] This disclosure also provides biomedical composite compositions for promoting collagen formation, or for use in promoting collagen formation, or for use in the preparation of biomedical materials for promoting collagen formation.

[0112] It should be noted that the biomedical composite composition disclosed herein can be used alone or in combination with other medical repair or cosmetic procedures.

[0113] Fifth aspect This disclosure provides the polyester staple fibers of this disclosure for use, alone or in combination with other materials, in medical aesthetics, or for use in medical aesthetics; this disclosure also provides the biomedical composite compositions of this disclosure for use, or for use in medical aesthetics; wherein the medical aesthetics includes, but is not limited to:

[0114] It can be used for skin rejuvenation or anti-aging, such as improving wrinkles and fine lines, enhancing skin firmness, and improving skin texture and radiance; or for cosmetic fillers such as soft tissue filling and contouring.

[0115] Or it can be used for skin repair or regeneration.

[0116] It can also be used as a collagen stimulant in combination with other cosmetic procedures.

[0117] Sixth aspect This disclosure also provides the use of the polyester staple fibers of this disclosure or the biomedical composite compositions of this disclosure in the preparation of biomedical materials for medical aesthetics, specifically for skin rejuvenation or anti-skin aging, such as improving wrinkles and fine lines, enhancing skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, or as a collagen stimulant used in combination with other medical aesthetic procedures.

[0118] Seventh aspect This disclosure provides a method for promoting collagen formation, comprising administering to an individual in need a biomedical composite composition as generally or specifically defined in this disclosure.

[0119] Eighth aspect This disclosure provides a medical aesthetic method, specifically for skin rejuvenation or anti-skin aging, such as improving wrinkles and fine lines, enhancing skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, including the application of a biomedical composite composition as generally or specifically defined in this disclosure to an individual in need.

[0120] Beneficial effects

[0121] This disclosed method for preparing polyester staple fibers effectively improves fiber uniformity and preparation efficiency by combining spinning technology with cryo-cutting technology, ensuring precise control of fiber size and thus providing a novel form of medical aesthetic filler material. Furthermore, compared to traditional methods, the polyester staple fibers disclosed herein offer significant advantages as a medical aesthetic filler material. They exhibit better biodegradability in vivo and their morphology is more conducive to fibroblast adhesion, thereby promoting collagen secretion. Moreover, combining these staple fibers with microspheres effectively avoids the needle clogging problems that may occur when using pure staple fiber materials as fillers, allowing the resulting composite material to be successfully injected through a 27G needle. Simultaneously, together with the microspheres, it enhances the collagen-promoting effect, thus potentially significantly improving the efficacy of medical aesthetic treatments.

[0122] The preparation method disclosed herein has the advantages of controllable operation, mild conditions, and readily available raw materials, and can be conveniently applied to the field of medical aesthetic soft tissue filling, with good market application prospects. Detailed Implementation

[0124] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the invention and should not be construed as limiting the scope of protection of the invention. All technical solutions implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0125] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0126] Example: Preparation of polyester staple fibers

[0127] Step S1: Add high-purity PLA particles (NatureWork 2002D) to a laboratory-made melt spinning machine, set a suitable heating zone temperature, and feed it to a spinneret with a certain aperture to cool and solidify the resulting nascent fibers. Use high-speed rollers to draw and collect the fibers, and then wind them up to obtain continuous PLA fibers.

[0128] The PLA continuous fibers obtained in step S1 were analyzed using a Jeol JSM 7500F scanning electron microscope (accelerating voltage 5.0 kV). The results are shown in the figure. Figure 1 The fibers are uniform in diameter and have a smooth surface.

[0129] Step S2: Take an appropriate amount of OCT embedding agent to immerse the PLA fiber material and freeze-fix it in a low-temperature environment;

[0130] Step S3: Set a certain slice thickness and use a ZD-LQ3300 cryostat (Zhuode Instruments (Shanghai) Co., Ltd.) to cut the fixed embedded block into short fiber slices of the predetermined thickness;

[0131] Step S4: After washing the short fiber slices with water to remove impurities, centrifuge and collect the precipitate, then dry them to obtain polyester short fiber material.

[0132] Following the general method steps above, PLA short fibers of Examples 1-4 were prepared according to the conditions shown in the table below:

[0133]

[0134] The PLA short fibers obtained in Examples 1-4 were analyzed using a scanning electron microscope. The results are shown in the figure. Figure 2 The results show that the short fibers in Examples 1 and 2 have uniform diameter and length, while the short fibers in Examples 3 and 4 are too fine, resulting in uneven length after slicing. Therefore, Example 1 was selected for the preparation of the application example.

[0135] Application example: Preparation of injectable solutions

[0136] According to the dosage (mass percentage) in the table below, the PLA short fibers obtained in the example and the self-made PLA microspheres (particle size 54.7±7.2 μm, its scanning electron microscope image is shown below) were used. Figure 3 The sample (showing uniform particle size, indicating smoothness) was mixed evenly with sodium carboxymethyl cellulose, hyaluronic acid (molecular weight approximately 300,000), mannitol, and sterile water for injection to obtain a suspension. After filling, capping, and packaging, the injectable formulations of Application Examples 1-7 were obtained.

[0137]

[0138] Take appropriate amounts of the injection solutions from Application Examples 1, 2, and 3, and observe them using a Leica DMLP optical microscope. See the photographs below. Figure 4 It can be seen that the short fibers and microspheres are evenly mixed and well dispersed in the injection solution.

[0139] Example 1: Injection force test of the injection solution

[0140] For injection force testing, the INSTRON 3400 universal testing machine is used for quantitative detection. It is usually used to evaluate and analyze the injectability of medical aesthetic injection products and can determine the average injection force.

[0141] Specifically, the sample to be tested is removed from the storage environment and equilibrated in a test environment of 23±2°C for at least 2 hours; the product is drawn using a 1 mL sterile syringe equipped with a 27G needle, and the syringe is gently flicked vertically upwards to remove air bubbles; a small amount of product is ejected to confirm patency; the universal testing machine is turned on and preheated for 30 minutes to perform zero-point and range calibration of the force sensor; the test speed is set to 100 mm / min, the trigger force to 0.05 N, and the data acquisition frequency to 50-200 Hz; the syringe containing the sample is vertically fixed in the fixture with the needle pointing downwards, ensuring that the syringe axis is aligned with the probe's pushing direction; the probe is adjusted so that its center is aligned with the piston center, ensuring complete vertical contact without tilting; the test program is started, and the probe pushes the piston at the set speed, recording the force-displacement curve in real time; the injection stops automatically after reaching the set distance; the average injection force data is extracted from the curve; at least 5 parallel samples are tested repeatedly; finally, the data are statistically analyzed, the mean, standard deviation, and relative standard deviation are calculated, the results are determined to meet the acceptance criteria, and a test report is issued.

[0142] Test results are available Figure 5 As can be seen from the figure, the injection solution prepared from pure short fibers in Application Example 1 could not be successfully injected through a 27G needle, while the injection solutions in Application Examples 2 and 3 could be successfully injected, and the injection force met the requirements of injectable medical aesthetic products.

[0143] Example 2: Cytotoxicity test

[0144] L929 cells from Wuhan Pronosei Life Sciences Co., Ltd. were thawed and passaged at least 2-3 times before use in experiments. The cultured L929 cells were removed from the culture flask using enzymatic digestion enzymes (trypsin / EDTA), and the cell suspension was centrifuged at 200g for 3 min. The cell suspension was then resuspended in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin, and the density was adjusted to 1×10⁶ cells / mL. 5 Cells / mL. Using a multichannel pipette, 100 μL of culture medium was added to the outer wells of a 96-well microtiter plate for tissue culture. 100 μL of culture medium at a density of 1 x 10⁻⁶ cells / mL was added to the remaining wells. 5 Cell suspensions of 100 cells / mL were prepared. Cells were incubated for 24 h to form a semi-confluent monolayer. The culture medium was then aspirated, and culture medium containing different concentrations and application examples of the injection solution was added. For the control group, only an equal volume of culture medium was added. After 24 h of incubation, 50 μL of MTT solution was added to each well, and the mixture was incubated at 37°C. oIncubate for another 2 hours in a C20 incubator. Then discard the MTT solution and add 100 μL of isopropanol solution to each well. Shake the plate and measure the absorbance of each well at 570 nm using a Thermo Scientific Multiskan FC microplate reader. Calculate cell viability using the following formula:

[0145] Survival rate (%) =

[0146] In the formula:

[0147] OD 570e —The average optical density of 100% extract of the test sample;

[0148] OD 570b — Average blank optical density.

[0149] Test results are available Figure 6 As can be seen from the figure, none of the injection solutions of different concentrations in the various application examples exhibited cytotoxicity.

[0150] Example 3: Collagen formation staining test

[0151] The injection solution (100 μL / mouse) of the application examples disclosed herein was subcutaneously injected into the sacral region of the back of 6-week-old female Balb / c mice. In application example 1, the needle became blocked during injection, while applications 2-7 were successfully injected. Twenty-eight days after injection, tissue samples were taken from the injection area, and tissue sections were prepared. The collagen-stimulating activity of applications 2-7 was compared and investigated using H&E (hematoxylin and eosin), Masson's red, and Sirius red staining assays.

[0152] For H&E staining, fix the slide for 30 seconds to 1 minute, then rinse briefly with water for 1 to 2 seconds. Immerse the slide in a staining jar containing hematoxylin for about 3 to 5 minutes, then rinse with water for about 5 to 10 seconds to remove the hematoxylin. Next, immerse the slide in 1% hydrochloric acid ethanol for 2 seconds, then rinse with water for 1 to 2 seconds. Under the microscope, the cell nuclei appear purplish-blue, while the cytoplasm is colorless. Use a blue-promoting solution (water or 1% ammonia) to restore the blue color for 5 to 10 seconds, then rinse briefly with water for 1 to 2 seconds. Under the microscope, the cell nuclei appear blue. Finally, immerse the slide in a staining jar containing eosin for 30 to 60 seconds, then rinse the surface clean with water. Under the microscope, the cell nuclei appear blue, while the cytoplasm, muscle fibers, collagen fibers, and erythrocytes show varying shades of red.

[0153] Masson staining uses multiple dyes for compound staining and is typically used to observe and analyze collagen fibers in tissues, distinguishing collagen fibers, muscle fibers, and other cellular structures. Specifically, the tissue is fixed in Bouin's solution or Zenker's solution, rinsed with running water, and then routinely dehydrated and embedded. The sections are dewaxed and returned to the aqueous solution. They are stained with prepared Weigert iron hematoxylin staining solution for 5-10 minutes; differentiated using acidic ethanol differentiation solution, followed by rinsing with running water; treated with Masson's blue solution for blue reversion, then washed with distilled water for 1 minute; stained with Ponceau S and fuchsin staining solution for 5-10 minutes; washed with a weak acid working solution prepared with distilled water and a weak acid solution in a 2:1 ratio for 1 minute; washed with phosphomolybdic acid solution for 1-2 minutes; washed again with the prepared weak acid working solution for 1 minute; directly immersing the sections in aniline blue staining solution for 1-2 minutes; washing with the prepared weak acid working solution for 1 minute; finally, the sections are dehydrated, cleared, and mounted.

[0154] Sirius red staining is a more specific staining method that, in addition to showing the total amount of collagen, also distinguishes the main types of collagen. Specifically, paraffin sections are dewaxed to water: the sections are sequentially immersed in xylene I for 20 min, xylene II for 20 min, anhydrous ethanol I for 10 min, anhydrous ethanol II for 10 min, 95% ethanol for 5 min, 90% ethanol for 5 min, 80% ethanol for 5 min, 70% ethanol for 5 min, and then washed with distilled water; then the washed sections are immersed in Sirius red staining solution for 1 hour; the sections are directly immersed in pure ethanol for differentiation and dehydration; then placed in xylene I for 5 min, xylene II for 5 min for dehydration and clearing, and mounted with neutral resin.

[0155] Staining results are shown Figure 7 As can be seen from the figures, the injection solutions in Application Examples 3-7, which contain the short fibers and microspheres of this disclosure, are more effective at stimulating collagen formation than the injection solution in Application Example 2, which is prepared from pure microspheres. Among them, the injection solution obtained in Application Example 3 shows the best effect in stimulating collagen formation.

[0156] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing polyester staple fibers, comprising the following steps: S1. Polyester raw materials are prepared into continuous polyester fiber materials through melt spinning or solution spinning processes; S2. The continuous fiber material obtained in step S1 is frozen and fixed in the presence of an embedding agent; S3. Freeze and slice the material fixed in step S2 to obtain short fiber slices of a certain size; and optionally... S4. Post-process the short fiber slices obtained in step S3.

2. The method of claim 1, wherein step S1 is carried out by melt spinning, wherein the polyester raw material is selected from one or more of polylactic acid (PLA), poly-L-lactide (PLLA), poly(ε-caprolactone) (PCL), polyvalerol (PVL), polyglycolic acid (PGA), polylactic-glycolic acid (PLGA) copolymer, and polyhydroxybutyrate (PHB), and / or heated at a temperature of about 200 to 250°C, and / or spun using a spinneret with an aperture of about 200 to 400 μm, and / or cooled at about 20 to 25°C.

3. The method of claim 1 or 2, wherein the diameter of the polyester continuous fiber material obtained in step S1 is about 1 to 50 μm, for example about 2 to 20 μm.

4. The method of any one of claims 1-3, wherein the embedding agent in step S2 is an OCT embedding agent or an aqueous solution of a blend of PEG and PVA, and / or the freezing conditions are freeze-fixation at about -30 to -20°C for about 0.5 to 1.5 hours.

5. The method of any one of claims 1-4, wherein in step S3, the length of the short fiber slice is about 5 to 300 μm, for example about 80 to 250 μm.

6. The method of any one of claims 1-5, wherein in step S4, the short fiber slices are washed with an aqueous solvent, centrifuged at about 5000-15000 rpm for about 2-10 minutes, and dried for about 20-30 hours.

7. A biomedical composite composition comprising polyester staple fibers and polyester microspheres, and optionally one or more pharmaceutical excipients, wherein the polyester staple fibers have a fiber diameter ranging from about 1 to 50 μm, for example, about 2 to 20 μm, and a length ranging from about 5 to 300 μm; preferably, the polyester staple fibers have a fiber diameter ranging from about 2 to 15 μm, 2 to 10 μm, or 5 to 10 μm, and a length ranging from about 50 to 250 μm or 80 to 250 μm.

8. The biomedical composite composition of claim 7, wherein the polyester staple fiber is a polyester staple fiber prepared by the method according to any one of claims 1 to 6.

9. The biomedical composite composition of claim 7 or 8, wherein the polyester microspheres are selected from one or more of PLA microspheres, PCL microspheres, PLGA microspheres, and PGA microspheres, preferably PLA microspheres, and / or the polyester microspheres have a diameter of about 1 to 200 μm, for example about 20 to 60 μm.

10. The biomedical composite composition of any one of claims 7-9, wherein the mass ratio of the polyester microspheres to the polyester short fibers is about 50:1 to 1:50, for example about 5:1 to 2:1, for example about 5:1 to 3:

1.

11. The biomedical composite composition according to any one of claims 7-10, wherein the total content of the polyester short fibers and polyester microspheres is about 2-30%, preferably about 2-5%.

12. The biomedical composite composition of any one of claims 7-11, which is in the form of an injection solution, further comprising a thickener, a filler carrier, a buffer, and an injection medium; preferably further comprising sodium carboxymethyl cellulose, hyaluronic acid, mannitol, and water for injection.

13. The biomedical composite composition according to any one of claims 7-12, wherein... PLA short fibers have diameters ranging from approximately 2 to 15 μm, 2 to 10 μm, or 5 to 10 μm, and lengths ranging from approximately 50 to 250 μm or 80 to 250 μm. The mass ratio of PLA microspheres to PLA short fibers is approximately 5:1 to 2:1, preferably approximately 5:1 to 3:1; The mass percentage of PLA microspheres and PLA short fibers is about 2 to 10%, preferably about 2 to 5%; The sodium carboxymethyl cellulose is present in a mass percentage of about 2 to 10%, preferably about 2 to 6%; The mass percentage of hyaluronic acid is approximately 0.5% to 5%, preferably approximately 0.5% to 3%. The mass percentage of mannitol is about 10 to 20%, preferably about 10 to 15%; The mass percentage of water for injection is approximately 60-90%, preferably approximately 75-85%.

14. The polyester short fibers prepared according to any one of claims 1-6 may be used alone or in combination with other materials for medical aesthetic purposes, such as for promoting collagen formation, for example for skin rejuvenation or anti-skin aging, such as improving wrinkles and fine lines, improving skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, or as a collagen stimulant in combination with other medical aesthetic procedures.

15. The use of the biomedical composite composition of any one of claims 7-13 in medical aesthetics, for example, for promoting collagen formation, for example, for skin rejuvenation or anti-skin aging such as improving wrinkles and fine lines, improving skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, or as a collagen stimulant used in combination with other medical aesthetic procedures.

16. Use of the polyester staple fiber prepared according to any one of claims 1-6 or the biomedical composite composition according to any one of claims 7-13 in the preparation of biomedical materials for medical aesthetics, for example, for promoting collagen production, specifically for skin rejuvenation or anti-skin aging such as improving wrinkles and fine lines, improving skin firmness, improving skin texture and radiance, or for medical aesthetic filling such as soft tissue filling and contouring, or for skin repair or regeneration, or as a collagen stimulant used in combination with other medical aesthetic procedures.

17. A method for promoting collagen formation, comprising administering to an individual in need the biomedical composite composition of any one of claims 7-13.

18. A medical aesthetic method, specifically a skin rejuvenation or anti-skin aging method such as improving wrinkles and fine lines, enhancing skin firmness, improving skin texture and radiance, or a medical aesthetic filling method such as soft tissue filling and contouring, or a skin repair or regeneration method, comprising applying the biomedical composite composition of any one of claims 7-13 to an individual in need.

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