Copolymer of CaSR positive allosteric modulator and aliphatic cyclic lactone monomer and application thereof

Abstract

The invention relates to a copolymer formed by a CaSR forward allosteric modulator and an aliphatic cyclic lactone monomer, the copolymer can be used as a tissue adhesion prevention and tissue fibrosis inhibitor, and an electrostatic spinning membrane of the copolymer can also be used as a tissue adhesion prevention material to effectively inhibit cell fibrosis.

Description

Technical Field

[0001] This invention relates to copolymers formed from CaSR positive allosteric modifiers and aliphatic cyclic lactone monomers and their applications, belonging to the field of medical materials. Background Technology

[0002] Ca 2+ The sensitive receptor (CaSR) belongs to the G protein-coupled receptor family and was first discovered in 1993. The discovery of CaSR established the Ca... 2+ A new paradigm for signal transmission. 2+ It can act as a first messenger, regulating various cellular processes through CaSR and 14 other G protein-coupled receptors. CaSR regulates extracellular Ca... 2+ Homeostasis plays a central role in many physiological and pathophysiological processes across multiple organs, and this regulation is largely mediated through its response to extracellular calcium. 2+ The coordination is achieved through the synergistic ability to handle minute changes in concentration and pH. A notable characteristic of CaSR is its ability to bind to a variety of natural ligands, including polyvalent cations such as Ca. 2+ Anions such as phosphates, L-amino acids, peptides, and polyamines; under different physiological conditions, changes in the relative concentrations of these ligands can promote or inhibit receptor activation. Therefore, CaSR appears to be a fine-tuned signaling platform that integrates various chemical inputs to trigger its physiological effects. The biological function of CaSR can be regulated by positive and negative allosteric modulators, enhancing its activation or inactivation, respectively. For example, cinacalcet, a drug used to treat secondary hyperparathyroidism and parathyroid cancer, and aromatic L-amino acids have both been shown to be positive allosteric modulators, enhancing their activation or inactivation of extracellular CaSR. 2+ The sensitivity to concentration promotes its activation.

[0003] CaSR participates in the regulation of numerous physiological processes, such as the regulation of fibroblast proliferation and apoptosis. Studies have shown that CaSR, under the regulation of the positive allosteric regulator L-phenylalanine, affects extracellular Ca2+ in fibroblasts. 2+ Increased sensitivity to concentration leads to its presence in normal extracellular Ca2+. 2+ Under the influence of concentration, it is overactivated, triggering intracellular endoplasmic reticulum Ca2+. 2+ The release of stored cells subsequently triggers apoptosis via the endoplasmic reticulum pathway in fibroblasts and arrests cell proliferation in the G1 phase.

[0004] Tissue adhesions and fibrosis are long-term pathological processes that require sustained intervention to inhibit. Currently, there are no commercially available products that are particularly effective in preventing tissue adhesions and fibrosis. There is an urgent need to develop more efficient biodegradable polymer molecules and processable materials.

[0005] Furthermore, current known biodegradable polymer technologies for preventing tissue adhesions and inhibiting fibrosis typically require solvent dissolution before molding, depending on the desired material. However, these technologies all rely on toxic fluorinated solvents (such as hexafluoroisopropanol), which are environmentally unfriendly and relatively expensive. Additionally, the materials processed from these existing biodegradable polymers suffer from insufficient mechanical strength, significantly limiting their applications. Summary of the Invention

[0006] This invention provides a series of copolymers formed from CaSR positive allosteric modulators and aliphatic cyclic lactone monomers. These copolymers, when co-cultured with fibroblasts, effectively inhibit fibroblast proliferation. Specifically, the CaSR positive allosteric modulators are integrated into a biodegradable polymer molecular chain. After application to the target site, the polymer continuously releases the modulators to the target site, thereby achieving the goal of sustained inhibition of fibroblast proliferation. Furthermore, the polymeric form imparts processability to the CaSR positive allosteric modulators, allowing the copolymers to be processed into nanoparticles, membranes, and gels to better act on the target site, thus providing physical effects in addition to their biological functions. The electrospun membranes of the copolymers of this invention can be used as materials or drugs for preventing tissue adhesions, effectively preventing tissue adhesions and fibrosis, and are particularly suitable for relieving postoperative adhesions after abdominal surgery.

[0007] On one hand, the present invention provides a copolymer formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer.

[0008] On the other hand, the present invention provides the application of a copolymer formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer in the inhibition of tissue adhesion or tissue fibrosis.

[0009] On the other hand, the present invention provides the application of a copolymer formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer in the field of drugs for inhibiting tissue adhesion or tissue fibrosis.

[0010] On the other hand, the present invention provides the application of a copolymer formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer in a material for preventing postoperative adhesions.

[0011] The present invention also provides an electrospun film of a copolymer formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer.

[0012] This invention provides the application of an electrospun membrane formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer in a tissue adhesion prevention material.

[0013] Specifically, the present invention provides a copolymer formed by a CaSR positive allosteric modifier and an aliphatic cyclic lactone monomer. Preferably, the CaSR positive allosteric modifier is selected from one or a combination of two or more of L-phenylalanine, L-tyrosine, L-tryptophan, and cinacalcet. More preferably, the aliphatic cyclic lactone monomer is selected from one or a combination of two or more of D,L-lactide (LA), glycolide (GA), ε-caprolactone (CL), and p-oxocyclohexanone (PDO).

[0014] In a preferred embodiment of the present invention, the present invention provides the following compounds:

[0015] Poly-D,L-lactide-co-glycolide-L-phenylalanine (PLGF)

[0016]

[0017] Poly(D,L-lactide-co-glycolic acid-co-L-tyrosine) - D,L-lactide-co-glycolide-L-tyrosine, PLGY)

[0018]

[0019] Poly(D,L-lactide-co-ε-caprolactone-co-L-phenylalanine) - D,L-lactide-co-ε-caprolactone-L-phenylalanine, PLCF)

[0020]

[0021] Poly-D,L-lactide-co-ε-caprolactone-L-tyrosine (PLCY)

[0022]

[0023] Poly-p-dioxanone-co-glycolide-L-tyrosine (PDPY)

[0024]

[0025] Poly-p-dioxanone-co-glycolide-L-tryptophan (PDPW)

[0026]

[0027] Cinacalcet-poly-p-dioxanone (Cin-PPDO)

[0028]

[0029] In a preferred embodiment of the present invention, the synthetic route of the copolymer is as follows:

[0030] Copolymers PLGF and PLGY were prepared by ring-opening polymerization using L-phenylalanine-N-carboxylic anhydride (L-Phe NCA), L-tyrosine-N-carboxylic anhydride (L-Tyr NCA), and aliphatic cyclic lactones LA and GA as raw materials, respectively, with octanoic acid imide as a catalyst.

[0031]

[0032] Alternatively, copolymers PLCF and PLCY can be prepared by ring-opening polymerization using L-Phe NCA, L-Tyr NCA and aliphatic cyclic lactones LA and CL as raw materials and octanoic acid imide as catalyst.

[0033]

[0034] Alternatively, copolymers PDPY and PDPW can be prepared by ring-opening polymerization using L-Tyr NCA, L-Trp NCA and aliphatic cyclic lactone PDO as raw materials and octanoic acid imide as catalyst.

[0035]

[0036] Alternatively, using octanoic acid imide as a catalyst and cinacalcet as an initiator, the aliphatic cyclic lactone PDO was used to initiate ring-opening polymerization to prepare the copolymer Cin-PPDO at a reaction temperature of 95℃ and a reaction time of 48h.

[0037]

[0038] In a preferred embodiment of the present invention, the DSC thermodynamic characterization data and GPC-determined molecular weight of the obtained copolymer are shown in Table 1 below. By introducing the CaSR allosteric modifier component, the molecular weight and thermodynamic properties of the obtained copolymer were adjusted. The molar content of the allosteric modifier component was 0.1%-15%, preferably 0.18%-10.17%. The weight-average molecular weight (Mw) of the copolymer was 7-50 kDa, preferably 8-40 kDa, and more preferably 10-40 kDa.

[0039] Table 1. DSC thermodynamic characterization data and GPC molecular weight determination of the copolymers of the present invention.

[0040]

[0041] In the series of CaSR positive allosteric modifiers and aliphatic cyclic lactone monomers copolymers provided by this invention, the inventors unexpectedly discovered that some of the polymer molecules have ideal strength and toughness, and also solved the problems of insufficient mechanical strength and limited application scenarios of existing materials.

[0042] In a preferred embodiment of the present invention, the copolymers PLGF, PLGY, PLCF, and PLCY formed by CaSR positive allosteric modifier and aliphatic cyclic lactone monomer are a new type of non-crystalline polymer molecules with good solubility, high molecular weight, and no need for toxic solvents, making them safe and environmentally friendly.

[0043] Specifically, this invention preferentially selects LA, GA, and CL as copolymer monomers based on the following considerations: LA, GA and amino acid copolymers PLGF and PLGY, and LA, CL and amino acid copolymers PLCF and PLCY, as shown in Table 1, are all amorphous polymers (viscous polymers), specifically exhibiting no crystallization peaks or crystallization melting peaks in the DSC heating and cooling curves. Compared to crystalline polymers with PDO as a monomer, amorphous polymers have better solubility in organic solvents; common solvents such as dimethyl carbonate and N,N-dimethylformamide can dissolve them. Therefore, these polymers will have advantages such as low solvent toxicity and low processing costs in processes requiring solution molding, such as casting and electrospinning.

[0044] Typically, the mechanical strength of polymer materials is influenced by both molecular weight and aggregation state (crystallinity). To improve solubility (reduce processing difficulty), the industry often adopts a strategy of reducing molecular weight, but this inevitably leads to a decrease in material strength. While increasing molecular weight can enhance strength, even high molecular weight amorphous polymers generally have lower strength than crystalline polymers due to the lack of reinforcing effect from crystal structure. This invention unexpectedly discovers that this series of amorphous biodegradable copolymers with specific molecular structures, formed from CaSR positive allosteric modifiers and aliphatic cyclic lactone monomers, avoids the use of fluorinated toxic solvents (such as those used in processing) during manufacturing and improves the mechanical strength of the processed material.

[0045] In a preferred embodiment of the present invention, the strength of the prepared PLGF, PLGY, PLCF, and PLCY electrospun films was tested and compared with that of PDPA. The results are shown in Table 2.

[0046] Table 2. Mechanical data of PLGF, PLGY, PLCF, PLCY electrospun films and PDPA electrospun films.

[0047]

[0048] As shown in the table above, the electrospun films of PLGF, PLGY, PLCF, and PLCY exhibit superior strength, modulus, and tensile strain compared to PDPA. This indicates that PLGF, PLGY, PLCF, and PLCY possess better strength and toughness than PDPA, thus solving the problem of insufficient mechanical strength limiting application scenarios. Therefore, materials based on the copolymers of this invention are more suitable for various processing methods and for use in more fields requiring higher mechanical properties.

[0049] As shown in Tables 1 and 2, polymers using LA, GA, and CL as copolymer monomers are amorphous polymers with high molecular weights, resulting in high mechanical strength after processing and molding. These polymers are suitable for applications requiring materials with certain mechanical strength, such as composite fixation devices for maxillofacial fractures. To ensure material mechanical strength, the weight-average molecular weight (Mw) of PLGF, PLGY, PLCF, and PLCY polymers is 10-50 kDa, more preferably 10-40 kDa. The molar content of the allosteric modifier component is preferably 2%-15%, more preferably 2%-7.5%.

[0050] In addition, LA, GA, and CL monomer polymers are mainly used in the field of materials or as biodegradable drug carriers. However, there have been no reports of using them as part of macromolecular prodrugs and directly random copolymerizing them with drug-active components in the form of chemical bonds. Therefore, these polymers of the present invention are not obvious to those skilled in the art.

[0051] In another preferred embodiment of the invention, since the polymerization of LA, GA, and CL monomers requires high temperatures, PDO is selected as the copolymer monomer for temperature-sensitive drugs such as cinacalcet or L-tryptophan. The copolymers PDPW, PDPY, and Cin-PPDO formed by the resulting CaSR allosteric modifier and aliphatic cyclic lactone monomers exhibit high inhibitory activity against fibroblast formation.

[0052] Specifically, PDO with a low polymerization temperature was selected for copolymerization to obtain PDPW, PDPY, and Cin-PPDO copolymers. These polymers exhibit good bioactivity, primarily reflected in their apoptosis rate. Figure 3 As shown, PDPA, PDPY, PDPW, and Cin-PPDO copolymers all exhibited significantly higher apoptosis-inducing efficiencies in fibroblasts compared to the control group poly(p-oxocyclohexanone-co-L-phenylalanine) (PDPA). Furthermore, compared to the crystalline copolymer PDPA, PDPY, PDPW, and Cin-PPDO copolymers all demonstrated significantly higher apoptosis-inducing efficiencies in fibroblasts.

[0053]

[0054] In the above preferred embodiments, cinacalcet, in particular, has a structure completely different from amino acids and is marketed as a drug for treating secondary hyperparathyroidism and parathyroid carcinoma, but its application in fibroblast apoptosis has never been observed. A Cin-PPDO copolymer prepared by copolymerizing cinacalcet and PDO, wherein the molar content of cinacalcet is 0.1%-1%, preferably 0.18%, exhibits superior molecular inhibitory fibroblast-inducing efficiency compared to PDPA in inducing apoptosis in fibroblasts. This invention is the first disclosure of a novel use of the cinacalcet polymer Cin-PPDO copolymer in the inhibition of tissue adhesion or tissue fibrosis.

[0055] Technical effect

[0056] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0057] Figure 1 Electron micrographs of PDPY, PDPW, and Cin-PPDO electrospun membranes are shown.

[0058] Figure 2 The study showed that PDPY, PDPW, and Cin-PPDO electrospun membranes inhibited the proliferation of L929 fibroblasts.

[0059] Figure 3This study demonstrates the apoptosis-inducing effects of PDPA, PDPY, PDPW, and Cin-PPDO electrospun membranes on the proliferation of L929 fibroblasts. Detailed Implementation

[0060] The present invention is further illustrated below by way of embodiments. The scope of the present invention is not limited to the following embodiments, but is defined by the specification and claims of the present invention.

[0061] Example 1

[0062] Synthesis of PLGF and PLGY:

[0063] 2.88 g (20 mmol) of LA, 0.128 g (1.1 mmol) of GA, 0.212 g (1.11 mmol) of L-Phe NCA or 0.230 g (1.11 mmol) of L-Tyr NCA, and 22 mg of Sn(Oct) were added to a 100 mL round-bottom flask. The flask was then sealed under vacuum for 2 h and stirred at 130 °C for 48 h. Afterward, the flask was restored to normal pressure, and 20 mL of hexafluoroisopropanol was added to dissolve the crude product. The filtrate was collected, and 40 mL of methanol was added dropwise. The polymer precipitated, and the precipitate was collected by filtration. This dissolution-precipitation process was repeated three times to obtain pure polymers PLGF or PLGY.

[0064] Example 2

[0065] Synthesis of PLCF and PLCY:

[0066] 2.37 g (16.48 mmol) of LA, 0.626 g (5.49 mmol) of CL, 0.212 g (1.11 mmol) of L-Phe NCA or 0.230 g (1.11 mmol) of L-Tyr NCA, and 22 mg of Sn(Oct) were added to a 100 mL round-bottom flask. The flask was then sealed under vacuum for 2 h and stirred at 140 °C for 48 h. Afterward, the flask was restored to normal pressure, and 20 mL of hexafluoroisopropanol was added to dissolve the crude product. The filtrate was collected by filtration, and 40 mL of methanol was added dropwise to the filtrate. The polymer precipitated, and the precipitate was collected by filtration. This dissolution-precipitation process was repeated three times to obtain pure PLCF or PLCY polymers.

[0067] Example 3

[0068] Synthesis of PDPY, PDPW, and Cin-PPDO:

[0069] 3.0 g (29.4 mmol) of PDO, 0.32 g (1.18 mmol) of L-Tyr NCA, or 0.356 g (1.18 mmol) of L-Trp NCA, or 5.5 mg (0.0154 mmol) of cinacalcet, and 22 mg of Sn(Oct) were added to a 100 mL round-bottom flask. The flask was then sealed under vacuum for 2 h and stirred at 140 °C for 48 h. Afterward, the flask was restored to normal pressure, and 20 mL of dimethyl carbonate was added to dissolve the crude product. The filtrate was collected by filtration, and 40 mL of methanol was added dropwise to the filtrate. The polymer precipitated, and the precipitate was collected by filtration. This dissolution-precipitation process was repeated three times to obtain pure PDPY, PDPW, or Cin-PPDO polymers.

[0070] Example 4

[0071] Preparation of PDPY, PDPW, and Cin-PPDO electrospun membranes and their inhibitory effects on fibroblast proliferation and adhesion prevention.

[0072] (1) Preparation of PDPY, PDPW, and Cin-PPDO electrospun films

[0073] Electrospun membranes were prepared by electrospinning 0.8 g of PDPY, PDPW, or Cin-PPDO, and 0.2 g of poly(D,L-lactide-cco-glycolic acid) (PLGA) (30 kDa) in 10 mL of hexafluoroisopropanol. The preparation conditions were: positive electrode voltage 12 kV, negative electrode -2.5 kV, positive and negative electrode distance 10 cm, and receiver rotation speed 100 rpm. Scanning electron microscopy was used to analyze the prepared electrospun membranes. Figure 1 As shown.

[0074] Depend on Figure 1 It is known that copolymers formed by CaSR positive allosteric modifiers and aliphatic cyclic lactone monomers can be processed into fibrous membranes and other forms using conventional polymer molding methods such as electrospinning. Therefore, integrating CaSR positive allosteric modifiers into polymer molecular chains allows for the one-step processing and molding of functional polymers into various materials that can be used in different scenarios to inhibit excessive fibroblast proliferation.

[0075] (2) The inhibitory effect of PDPY, PDPW, and Cin-PPDO electrospun membranes on fibroblast proliferation and the prevention of adhesion.

[0076] Electrospun membranes of PDPY, PDPW, or Cin-PPDO were co-cultured with mouse embryonic fibroblast L929 cells (L929 cells were purchased from Pronosei (Wuhan)) under the following conditions: DMEM + 10% FBS, at 37℃ and 5% CO2. After 24 and 72 h of culture, CCK-8 was added, and the cells were incubated at 37℃ and 5% CO2 for 1 h. The supernatant in the culture plate was then aspirated, and the absorbance was measured at 450 nm. The inhibitory effect on the proliferation of L929 fibroblasts was characterized by the formula: Cell Viability% = [OD(PPDY / PPDW / Cin-PPDO) - OD(PPDO) / OD(PPDO)] * 100%. Poly(p-oxycyclohexanone) (PPDO) is an aliphatic polyester without CaSR allosteric modulator and can be used as a control. After 72 hours of cell culture, the cells were stained with Calcein-AM / PI and then flow cytometry was used to detect apoptosis to characterize the apoptosis induction effect.

[0077] The inhibitory effects of PDPY, PDPW, or Cin-PPDO electrospun membranes on the proliferation and apoptosis-inducing effects of L929 fibroblasts, such as... Figure 2 As shown in &3. (By...) Figure 2 As shown in section 3, electrospun membranes of PDPY, PDPW, or Cin-PPDO effectively inhibited the excessive proliferation of L929 cells and induced apoptosis, demonstrating that the introduction of the CaSR allosteric regulator affected the biological behavior of fibroblasts. Specifically, in Figure 2 In cell proliferation experiments, L929 cells co-cultured with PDPY, PDPW, and Cin-PPDO electrospun membranes showed relatively viability less than 100% compared to cells co-cultured with aliphatic polyester PPDO membranes without CaSR allosteric modulators. The relative cell viability of the PDPW and Cin-PPDO groups was significantly lower than that of PDPY, indicating that the former two have superior fibroblast proliferation inhibitory functions. Furthermore, the relative cell viability of the PDPW and PDPY groups did not significantly increase with prolonged culture time, suggesting that they can sustainably inhibit fibroblast proliferation. This indicates that these CaSR positive allosteric modulators can intervene in excessive fibroblast proliferation over a long period. Figure 3The apoptosis experiment results showed that after co-culturing with PDPY, PDPW, and Cin-PPDO for 72 hours, the proportion of apoptotic fibroblasts (vertical axis) was significantly increased compared to cells co-cultured with PPDO membrane (Control) and PDPA membrane, indicating that the three agents had a better effect on inducing apoptosis in fibroblasts than PPDO and PDPA. This indicates that the copolymer material formed by the CaSR positive allosteric regulator and aliphatic cyclic lactone monomer can induce apoptosis in fibroblasts and is superior to PDPA. Therefore, PDPY, PDPW, and Cin-PPDO electrospun membranes have significant inhibitory effects on the proliferation of L929 fibroblasts and induce apoptosis.

[0078] A rat model of abdominal wall-cecum adhesion was established (mucosa was scraped at the corresponding location). Post-surgery, PDPY, PDPW, or Cin-PPDO electrospun membranes were placed between the intestinal wall and abdominal wall tissues, respectively, where adhesions were likely to occur. The muscle and skin layers were sutured in layers. Rats were housed in a clean environment with free access to food. After 10 days, treatment was terminated, and the adhesion between the intestinal and abdominal wall tissues was observed. The study found that PDPY, PDPW, or Cin-PPDO electrospun membranes could effectively prevent tissue adhesions, demonstrating that the introduction of the CaSR allosteric modifier endowed the polymer material with a biological function of continuously inhibiting fibrosis.

[0079] Example 5

[0080] Preparation and mechanical property testing of electrospun films of PLGF, PLGY, PLCF, and PLCY

[0081] (1) Preparation of electrospun films of PLGF, PLGY, PLCF, and PLCY

[0082] Electrospun membranes were prepared by electrospinning 0.8 g of PLGF, PLGY, PLCF, or PLCY with 0.2 g of PLGA (30 kDa) in 10 mL of dimethyl carbonate / dichloromethane (9 / 1, v / v). The preparation conditions were: positive electrode voltage 12 kV, negative electrode -2.5 kV, positive and negative electrode distance 10 cm, and receiver rotation speed 100 rpm.

[0083] (2) Determination of mechanical properties of electrospun films containing PLGF, PLGY, PLCF, and PLCY

[0084] Standard strips of 1cm*5cm were obtained by cutting PLGF, PLGY, PLCF, and PLCY electrospun films and then subjected to strength testing. After accurately measuring the film thickness, the strips were fixed on the fixture of an electronic universal testing machine and stretched at a rate of 5mm / min until the strips broke. The peak force, peak stress (strength), breaking force / stress, breaking strain, modulus, and other data were recorded. The results are shown in Table 3.

[0085] Table 3. Mechanical data of PLGF, PLGY, PLCF, PLCY electrospun films and PDPA electrospun films.

[0086]

[0087] As shown in the table above, the strength, modulus, and fracture strain of PLGF, PLGY, PLCF, and PLCY electrospun films are all superior to PDPA, indicating that PLGF, PLGY, PLCF, and PLCY have better strength and toughness than PDPA, making them more suitable for various processing and applications requiring higher mechanical properties.

[0088] Example 6

[0089] Inhibitory effects of PLGF, PLGY, PLCF, and PLCY electrospun membranes on fibroblast proliferation and prevention of adhesion.

[0090] Electrospun membranes of PLGF, PLGY, PLCF, and PLCY were co-cultured with mouse embryonic fibroblast L929 cells (L929 cells purchased from Pronosei (Wuhan)) under the following conditions: DMEM + 10% FBS, at 37℃ and 5% CO2. After 24 and 72 h of culture, CCK-8 was added, and the cells were incubated at 37℃ and 5% CO2 for 1 h. The supernatant in the culture plate was then aspirated, and the absorbance was measured at 450 nm. The inhibitory effect on the proliferation of L929 fibroblasts was characterized by the formula: Cell Viability% = [OD(PPDY / PPDW / Cin-PPDO) - OD(PLGA) / OD(PLGA)] * 100%. After 72 h of cell culture, the cells were stained with Calcein-AM / PI and apoptosis was detected by flow cytometry to characterize the apoptosis-inducing effect.

[0091] After co-culturing with PLGF, PLGY, PLCF, and PLCY electrospun membranes for 24 hours, the relative cell viability was 72%, 67%, 75%, and 69%, respectively. After 72 hours of culture, the relative cell viability was 66%, 62%, 70%, and 65%, respectively, and the apoptosis rates were 6.5%, 10.7%, 6.3%, and 10.2%, respectively. This indicates that PLGF, PLGY, PLCF, and PLCY electrospun membranes have a significant inhibitory effect on the proliferation of L929 fibroblasts and induce apoptosis.

[0092] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A copolymer formed from a CaSR allosteric modifier and an aliphatic cyclic lactone monomer, wherein, The CaSR positive allosteric modifier is selected from L-phenylalanine, L-tyrosine, L-tryptophan, and cinnacalcet; the aliphatic cyclic lactone monomer is selected from one or a combination of two or more of D,L-lactide, glycolide, ε-caprolactone, and p-oxocyclohexanone.

2. The copolymer of claim 1, selected from the following structures:

3. The copolymer of claim 1, wherein, The molar content of the CaSR positive allosteric modifier component is 0.1%-15%, preferably 0.18%-10.17%.

4. The use of the copolymer as described in claim 1 in materials for inhibiting tissue adhesion or tissue fibrosis.

5. The use of the copolymer as described in claim 1 in the preparation of drugs that inhibit tissue adhesion or tissue fibrosis.

6. The use of the copolymer as described in claim 1 in postoperative adhesion prevention materials.

7. The electrospun film of the copolymer as described in claim 1.

8. The application of the electrospun membrane as described in claim 7 in tissue adhesion prevention materials.

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