WO2018026204A1 - 과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법 및 이의 생의학적 용도 - Google Patents
과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법 및 이의 생의학적 용도 Download PDFInfo
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- WO2018026204A1 WO2018026204A1 PCT/KR2017/008386 KR2017008386W WO2018026204A1 WO 2018026204 A1 WO2018026204 A1 WO 2018026204A1 KR 2017008386 W KR2017008386 W KR 2017008386W WO 2018026204 A1 WO2018026204 A1 WO 2018026204A1
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- hydrogel
- calcium peroxide
- oxygen
- sustained release
- releasing
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/11—Peroxy compounds, peroxides, e.g. hydrogen peroxide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
- A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2371/02—Polyalkylene oxides
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- C08J2389/00—Characterised by the use of proteins; Derivatives thereof
- C08J2389/04—Products derived from waste materials, e.g. horn, hoof or hair
- C08J2389/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2201/00—Properties
- C08L2201/52—Aqueous emulsion or latex, e.g. containing polymers of a glass transition temperature (Tg) below 20°C
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2203/00—Applications
- C08L2203/02—Applications for biomedical use
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2312/00—Crosslinking
Definitions
- the present invention relates to a method for preparing a sustained-release oxygen-releasing in situ crosslinked hydrogel using calcium peroxide and its biomedical use. More specifically, the in situ crosslinked hydrogel uses a new hydrogel crosslinking method using calcium peroxide.
- the present invention relates to a new type of injection polymer hydrogel that can be prepared using and capable of releasing high concentration oxygen in a sustained release form in a formed hydrogel matrix.
- the present invention can be prepared by a simple method compared to the manufacturing method of the conventional injection-type hydrogel, there is an advantage that can easily control the physical / chemical / biological properties of the in situ cross-linked hydrogel according to the production conditions .
- the polymer hydrogel which consists of a three-dimensional network of hydrophilic polymers, is suitable for various biomedical applications due to its biocompatibility, high water content, excellent permeability of nutrients and metabolites, structural similarity to natural tissue, and multi-tunable properties. It has been widely used.
- in situ crosslinked hydrogels have been widely studied as drug / cell carriers, tissue fillers, or tissue engineering scaffolds based on minimally invasive techniques.
- Such in situ crosslinked hydrogels can be prepared using natural and synthetic polymers, and can form hydrogels through various chemical and physical crosslinks.
- Oxygen acts as a substrate and signal molecule for metabolism and plays an important role in maintaining homeostasis and wound healing in vivo.
- high levels of oxygen promote intracellular oxygen production and wound healing by increasing intracellular oxygen pressure and increasing free radicals to secrete growth factors that promote angiogenesis, or to allow stem cells to migrate from bone marrow.
- several techniques for transporting oxygen have recently been developed.
- HBOT hyperbaric oxygen therapy
- oxygen carriers such as hemoglobin-based oxygen carriers and perfluorocarbon (PFC) technology.
- High concentration oxygen treatment is technically simple and the oxygen can be continuously provided during the treatment, the oxygen carrier has the advantage that can release the oxygen in accordance with the surrounding oxygen partial pressure.
- the present invention is to meet the above conventional needs, a new type of in situ cross-linked polymer hydrogel that releases a high concentration of oxygen in a sustained release, which can easily control the physical / chemical / biological properties of such a hydrogel It is a technical problem to provide a method for preparing a sustained release oxygen-injectable hydrogel, and various biomedical uses thereof.
- the present invention induces the formation of disulfide bonds (-SS-) by decomposition of calcium peroxide in an aqueous solution of a natural / synthetic polymer having a thiol (-SH) reactor in
- the present invention provides a new type of in situ crosslinked polymer hydrogel which produces a situ crosslinked polymer hydrogel and simultaneously releases a high concentration of oxygen in a sustained release by decomposition of calcium peroxide in an aqueous solution.
- the natural / synthetic polymer containing a thiol group is prepared using Traut's reagent (TR), the thiol reactor introduced into the polymer main chain can be adjusted according to the amount of the initial TR used in the synthesis.
- TR Traut's reagent
- the present invention can easily control the physical / chemical / biological properties of in situ crosslinked hydrogels such as hydrogel formation time, mechanical strength, biodegradability, oxygen release behavior according to the control of the polymer, calcium peroxide, TR substitution degree, etc.
- a method for preparing a sustained release oxygen release in situ crosslinked hydrogel is provided.
- the present invention also provides an implant material for tissue regeneration and filling, comprising an in situ crosslinked sustained release oxygen release hydrogel.
- the present invention also provides a material for tissue adhesion and hemostasis comprising an in situ crosslinked sustained release oxygen-releasing hydrogel.
- the present invention also provides a carrier for the delivery of a bioactive substance or drug, including an in situ crosslinked sustained release oxygen-releasing hydrogel.
- the new form of in situ crosslinked hydrogel according to the present invention has the characteristics of controlling the formation of hydrogel by oxygen generated by decomposition of calcium peroxide and the sustained release behavior of oxygen generated in the hydrogel.
- the present invention can overcome the limitations of the existing oxygen-producing hydrogel, and based on excellent biocompatibility, various biomedical applications (eg, tissue regeneration, artificial tissue manufacturing, wound healing material, tissue adhesion material, drug) Carrier, etc.) is possible.
- various biomedical applications eg, tissue regeneration, artificial tissue manufacturing, wound healing material, tissue adhesion material, drug) Carrier, etc.
- FIG. 2 is a schematic diagram of the production of GtnSH hydrogel using calcium peroxide.
- 3 is a graph showing the thiol content in the gelatin derivatives according to the amount of TR introduced.
- Figure 4 is a graph showing the gelation time of the hydrogel according to the amount of TR introduction, the concentration of calcium peroxide and the polymer concentration.
- 5 is a graph showing the oxygen release behavior of hydrogel according to calcium peroxide concentration and polymer concentration.
- FIG. 6 is a graph showing the mechanical strength of a hydrogel.
- the inventors of the present invention have prepared a new form of in situ-forming hydrogel using calcium peroxide, and have confirmed that oxygen generated in the hydrogel is released for a long time (more than 14 days) in a sustained release form.
- the polymer hydrogel material which can release a high concentration of oxygen by a simple method was found to be able to easily control physical / chemical / biological properties.
- the present invention induces disulfide bonds by applying calcium peroxide to a natural / synthetic polymer having a thiol reactor, thereby producing a sustained-release oxygen-releasing in situ hydrogel.
- the polymer main chain having a thiol reactor is prepared using Traut's reagent (TR), the thiol reactor introduced into the polymer main chain can be adjusted according to the amount of the initial TR used in the synthesis.
- TR Traut's reagent
- the polymer main chain is gelatin, chitosan, heparin, cellulose, dextran, dextran sulfate, chondroitin sulfate, keratin, keratan sulfate, dermatan sulfate, alginate, collagen, albumin, fibronectin, laminin, elastin, vitronectin, hyaluronic acid It may be any one selected from the group consisting of fibrinogen and multi-polymer, but is not necessarily limited thereto.
- the multi-polymer is 3-arm-polyethylene glycol (3armPEG), 4-arm-polyethylene glycol (4armPEG), 6-arm (6-arm) polyethylene glycol (6armPEG) and 8 At least one multi-polyethylene glycol selected from 8-arm-polyethylene glycol (8armPEG); And Tetronic series (4arm-PPO-PEO); but may be any one or two or more polymers selected from the group consisting of, but is not limited thereto.
- the sustained-release oxygen-releasing hydrogel may be prepared by in situ crosslinking of a polymer main chain having a thiol reactor by inducing a disulfide bond through an oxidation reaction under a solution containing calcium peroxide.
- Oxygen-releasing type in situ crosslinked hydrogel production method of the present invention can flexibly control the physicochemical properties such as gelation time, mechanical strength, oxygen release behavior by controlling the introduction amount of the thiol reactor, the concentration of the polymer and the concentration of calcium peroxide There is an advantage.
- the present invention also provides an implant material for tissue regeneration, tissue engineering support and filling, comprising an oxygen release in situ crosslinked hydrogel.
- Such materials include cartilage regeneration, bone regeneration, alveolar regeneration, skin regeneration, cardiac tissue regeneration, artificial intraocular lens, spinal nerve Spinal cord regeneration, cranial regeneration, vocal regeneration and augmentation, adhesion barrier, urinary incontinence treatment, fillers for wrinkles removal, burns
- the material may be applied to any one selected from the group consisting of a wound dressing, tissue augmentation, and intervertebral disc treatment, but is not necessarily limited thereto.
- the present invention also provides a material for tissue adhesion and hemostasis, including the oxygen-releasing in situ crosslinked hydrogel.
- the hemostatic material includes cerebral neurosurgery including vascular surgery, orthopedic surgery including bone adhesion, hemostasis in laceration patients, femoral artery closure, cataract incision closure, cartilage healing, skin bonding, organ / secretory incision hemostasis, It may be applied to any one selected from the group consisting of gastrointestinal division and tendon / ligament healing, but is not necessarily limited thereto.
- the present invention also provides a carrier for a bioactive substance or drug delivery agent comprising the oxygen release in situ crosslinked hydrogel.
- the bioactive substance or drug may be any one or two or more selected from the group consisting of peptide or protein medicines, antibacterial agents, anticancer agents and anti-inflammatory agents, but is not necessarily limited thereto.
- the peptide or protein drug may include fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF), and bone morphogenetic factor.
- FGF fibroblast growth factor
- VEGF vascular endothelial growth factor
- TGF transforming growth factor
- protein (BMP) human growth hormone (hGH), porcine growth hormone (pGH), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO) , Macrophage colony-stimulating factor (M-CSF), tumor necrosis factor (TNF), epidermal growth factor (EGF), platelet-derived growth factor PDGF), interferon- ⁇ , ⁇ , ⁇ , interleukin-2 (IL-2), calcitonin, nerve growth factor (NGF), growth hormone release Factor, engiotensin, luteinizing hormone releasing hormone (luteiniz ing hormone-releasing hormone (LHRH), LHRH agonist, insulin
- the antimicrobial agent may be minocycline, tetracycline, oploxacin, phosphomycin, mergain, profloxacin, ampicillin, penicillin, doxycycline, thienamycin, cephalosporin, norcardycin, gentamicin, neomycin, kanamycin, With paromomycin, micronomycin, amikacin, tobramycin, dibecacin, cytotaxime, cefacller, erythromycin, ciprofloxacin, levofloxacin, endoxacin, vancomycin, imipenem, fusidic acid and mixtures thereof It may be any one selected from the group consisting of, but is not necessarily limited thereto.
- the anticancer agents include paclitaxel, taxotier, adriamycin, endostatin, angiostatin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, idarubicin, 5-fluorouracil, methotrexate, It may be any one selected from the group consisting of actinomycin-D and mixtures thereof, but is not necessarily limited thereto.
- the anti-inflammatory agents may be acetoaminephene, aspirin, ibuprofen, diclofenac, indomethacin, pyricampam, phenopropene, flubiprofen, ketoprofen, naproxen, supropene, roxofene, synoxy It may be any one selected from the group consisting of kam, tenoxycamp and mixtures thereof, but is not necessarily limited thereto.
- Gelatin type A from porcine skin,> 300 bloom
- 2-iminothiolane hydrochloride TR
- calcium peroxide CaO 2
- anhydrous Dimethyl sulfoxide anhydrous DMSO
- collagenase type II were purchased from Sigma Aldrich (St. Louis, MO, USA).
- DMEM medium Dulbecco's Modified Eagle's Medium
- P / S penicillin-streptomycin
- trypsin / EDTA trypsin / EDTA
- Dulbecco's phosphate buffered saline (DPBS) solutions are Gibco (Grand Island, NY, USA)
- Fetal Bovine Serum (FBS) was purchased from Research and Diagnostic Technology
- EGM-2 Single quots medium Endothelial Cell Growth Medium; EGM was purchased from Lonza.
- EGM Endothelial Cell Growth Medium
- Cell Proliferation reagent WST-1 was also purchased from Roche Diagnostics and Live / Dead Viability / Cytotoxicity Kit was purchased from Life Science.
- the reaction mixture was ultrafiltered from a dialysis tube with a molecular weight cut-off (MWCO) of 3.5 kD at 37 ° C., and the media was filtered for 5 days with 5 mM Hydrogen chloride (HCl). The solution and 1 mM HCl solution were replaced daily.
- MWCO molecular weight cut-off
- the thiol-bound gelatin derivative (thiolated gelatin; GtnSH) polymer was obtained by freeze drying.
- Hydrogel was prepared by mixing a solution of GtnSH polymer in DPBS at 37 ° C. and calcium peroxide (0 to 1 wt%).
- the amount of TR introduced was changed to 1 mg, 5 mg, 10 mg, and 20 mg under a constant composition of gelatin (100 mg) and anhydrous DMSO (10 ml).
- the mixture was absorbed at 405 nm using an absorbance detector and a cysteine standard curve was created to calculate the thiol content in GtnSH.
- the amount of TR introduced was controlled to control the thiol content in the gelatin derivative up to 5.224-25.145 ⁇ mol / g (polymer). As the amount of TR was increased, the content of the thiol in GtnSH increased.
- the TR introduction amount was changed to 1 mg, 5 mg, 10 mg, 20 mg.
- the gelation time of the hydrogel was controlled by 3 to 42 minutes by adjusting the concentration of TR, and the gel formation time decreased as the amount of TR was increased. This may be explained by the fact that the amount of thiol in GtnSH is increased due to the increase in the amount of TR introduced, thereby shortening the hydrogel formation time because the number of reactors capable of forming crosslinks is increased.
- the GtnSH concentration was changed to 3 wt%, 5 wt%, and 7 wt% under constant composition of TR introduction amount (10 mg), CaO 2 (1 wt%), DPBS (100 ⁇ l). More detailed hydrogel production conditions are shown in Table 1.
- the gelation time of the hydrogel was controlled to 2-6 minutes by controlling the polymer concentration, and the gel formation time decreased as the concentration of the polymer was increased. This can be explained by the fact that the hydrogel formation time is shortened because the reactor attached to the gelatin also increases due to the increase in the polymer concentration.
- the gelation time of the hydrogel was controlled by 5 ⁇ 329 minutes by adjusting the concentration of calcium peroxide, and the gel peroxide concentration was increased in the solution where the calcium peroxide concentration was less than 0.01% by weight.
- the gel formation time of the hydrogel was shortened. The reason is that as the concentration of calcium peroxide increases, the gel formation time is shortened because it promotes the production of hydrogen peroxide, which promotes the formation of disulfide bonds.
- Oxygen release behavior of the hydrogel according to calcium peroxide concentration was checked for 3 days using an oxygen sensor.
- the concentration of calcium peroxide was changed to 0.5 wt%, 0.75 wt%, and 1 wt% under a constant composition of TR introduction amount (10 mg) and GtnSH (5 wt%).
- a hydrogel 300 ⁇ l was prepared, and after 10 minutes, a medium (600 ⁇ l) was added thereto, and the dissolved oxygen content of the media was measured.
- the maximum dissolved oxygen content of the hydrogel-containing medium was controlled from 46.22% to 61.74% by controlling the concentration of calcium peroxide, and the maximum dissolved oxygen content of the medium containing the hydrogel was increased as the concentration of calcium peroxide increased. .
- the reason is that as the concentration of calcium peroxide increases, the amount of oxygen released from the hydrogel to the medium is increased by promoting the production of oxygen.
- Oxygen release behavior of the hydrogels according to the polymer concentration was checked using an oxygen sensor for 3 days.
- the polymer concentration was changed to 0 wt%, 3 wt%, 5 wt%, and 7 wt% under a constant composition of TR introduction amount (10 mg) and calcium peroxide (1 wt%).
- a hydrogel 300 ⁇ l was prepared, and after 10 minutes, a medium (600 ⁇ l) was added thereto, and the dissolved oxygen content of the media was measured.
- the maximum dissolved oxygen content of the medium containing the hydrogel was controlled to 51.49% ⁇ 86.12% by controlling the polymer concentration, and the maximum dissolved oxygen content of the medium containing the hydrogel decreased as the polymer concentration increased, It was maintained for a long time. This is because the crosslinking degree increases as the polymer concentration increases, and thus the permeability of the hydrogel is decreased, so that oxygen is not released rapidly but is released in a sustained release form.
- Oxygen release behavior of the hydrogel according to calcium peroxide concentration was measured for 14 days using an oxygen sensor.
- the concentration of calcium peroxide was changed to 0 wt%, 0.5 wt%, 0.75 wt%, and 1 wt% under a constant composition of TR introduction amount (10 mg) and GtnSH (5 wt%).
- a hydrogel 300 ⁇ l was prepared, and after 10 minutes, a medium (600 ⁇ l) was added thereto, and the dissolved oxygen content of the media was measured at specific time intervals.
- the concentration of calcium peroxide could be adjusted to 23.68% ⁇ 51.62% of the maximum dissolved oxygen in the medium containing hydrogel, and the maximum dissolved oxygen in the medium containing hydrogel increased as the concentration of calcium peroxide increased. .
- the reason for this is that as the concentration of calcium peroxide increases, the amount of oxygen released from the hydrogel to the medium is increased by promoting the production of oxygen.
- the mechanical strength of the GtnSH hydrogel was measured using a rheometer, and the change of mechanical strength was evaluated by adjusting the concentration of calcium peroxide.
- the concentration of calcium peroxide was changed to 0 wt%, 0.5 wt%, 0.75 wt%, and 1 wt% under a constant composition of TR introduction amount (10 mg) and GtnSH (5 wt%).
- the concentration of calcium peroxide it was confirmed that the mechanical strength of the hydrogel can be controlled, the range was 100 ⁇ 810 Pa.
- the calcium peroxide concentration of 0% by weight did not form a hydrogel. This is because calcium peroxide was absent and did not promote disulfide bond formation between thiol groups.
- the hydrogel was prepared in a micro tube by the same preparation method as the gelation time test.
- the hydrogel weight was weighed after removing the supernatant completely at specific time intervals and then 200 ⁇ l fresh medium was added.
- Biodegradability was calculated using the following equation (1).
- W d and W i represent the weight of the deteriorated hydrogel and the original hydrogel, respectively.
- the sample treated with DPBS did not decompose the hydrogel over time, whereas the hydrogel treated with the collagenase enzyme at 0.01 mg / ml concentration degraded the sample over time. It is confirmed that even if a thiol group is introduced into gelatin, it can still be degraded by collagenase.
- cytotoxicity evaluation was performed by culturing human dermal fibroblasts (hDFBs) after putting a GtnSH solution in a 96-well plate.
- the concentration of the cells used in the experiment was 2.0 X 10 3 cells / wells, and cell viability was measured using the WST-1 assay after incubation for 24 hours in 37 °C, 5% CO 2 atmosphere.
- a hydrogel carrying human umbilical vein endothelial cells (HUVEC) in three dimensions in a 96-well plate was formed and cultured to perform cytotoxicity evaluation.
- HUVEC human umbilical vein endothelial cells
- the concentration of the cells used in the experiment was 2 ⁇ 10 5 cells / wells, and cell viability was measured by using Live / Dead Viability / Cytotoxicity Kit after 7 days incubation in 37 °C, 5% CO 2 atmosphere.
- Hydrogel was prepared by mixing catalase 0-50,000 U / mL to decompose hydrogen peroxide generated during hydrogel formation.
- Live / Dead analysis is a method for evaluating cytotoxicity, in which cells killed by cytotoxicity are colored red and living cells are colored green.
- GtnSH showed more than 90% cell viability compared to the control group, and hydrogel showed 70-80% live cells depending on the concentration of calcium peroxide in the Live / Dead assay. That is, it was confirmed that the cell compatibility of the hydrogel is excellent.
- Porcine skin was 2.5 cm in diameter and all parts of the pig skin were attached onto a rectangular plastic substrate by ethyl cyanoacrylate glue.
- the skin surface was washed for decellularization using 70% isopropanol in deionized water, and after 15 minutes after the washing process, 100 ⁇ l adhesive was applied to the area of the pig skin, and then the two surfaces Were wrapped together.
- the adhesive was applied for 100 g of force to hold for 60 minutes at room temperature in a humid environment.
- the sample was then loaded with poor delivery at a crosshead speed of 10 mm / min.
- At least five samples were used for the measurement.
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Abstract
본 발명은 과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법에 관한 것으로, 이처럼 제조된 새로운 형태의 산소 방출형 in situ 가교 하이드로젤은 과산화칼슘의 분해로 발생되는 산소에 의해 티올 반응기를 갖는 고분자 주사슬에 이황화결합이 유도되어 하이드로젤이 형성됨은 물론, 하이드로젤 내에 발생한 산소가 서방형으로 방출되는 것을 특징으로 한다. 또한, 본 발명은 기존 산소 전달 시스템이 가지고 있는 제한점을 개선할 수 있고, 간단하면서도 신속한 방법으로 서방형 산소 방출형 in situ 가교 하이드로젤을 제조할 수 있으며, 나아가 제조 조건에 따라 하이드로젤의 물리/화학/생물학적 특성을 쉽게 제어할 수 있는 장점이 있다.
Description
본 발명은 과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법 및 이의 생의학적 용도에 관한 것으로, 보다 상세하게는 상기 in situ 가교 하이드로젤은 과산화칼슘을 이용한 새로운 하이드로젤 가교방법을 사용하여 제조 가능하며 형성된 하이드로젤 매트릭스에서 서방형으로 고농도 산소를 방출할 수 있는 새로운 형태의 주입형 고분자 하이드로젤에 관한 것이다.
또한, 본 발명은 기존 주입형 하이드로젤의 제조방법에 비해 간편한 방법으로 제조할 수 있을 뿐 아니라 제조 조건에 따라 상기 in situ 가교 하이드로젤의 물리/화학/생물학적 특성을 쉽게 제어할 수 있는 장점이 있다.
친수성 고분자의 3차원 네트워크로 이루어진 고분자 하이드로젤은 생체 적합성, 높은 수분함량, 영양분과 대사산물의 우수한 투과성, 천연 조직과의 구조적 유사성 및 다중 가변성(multi-tunable properties)으로 인해 다양한 생의학적 응용분야에 널리 상용되어 왔다.
특히, in situ 가교 하이드로젤은 최소침습성 기술(minimally invasive techniques)을 기반으로 약물/세포 전달체, 조직 충진제, 혹은 조직공학용 지지체로서 널리 연구되었다. 이러한 in situ 가교 하이드로젤은 천연 및 합성 고분자를 이용하여 제조가 가능하며, 다양한 화학적 및 물리적 가교를 통하여 하이드로젤 형성이 가능하다.
산소는 대사작용의 기질과 신호분자로서 작용하여 생체 내 항상성 유지와 상처 치료에 중요한 역할을 한다. 특히, 고농도 산소는 세포 내 산소 분압을 높이고 활성산소를 증가시켜 세포가 혈관생성을 촉진하는 성장인자를 분비하게 하거나 골수로부터 줄기세포가 이동하게 함으로써 상처에의 새로운 혈관 생성 내지 상처 치료를 촉진한다. 이러한 맥락으로 최근 산소를 운반할 수 있는 여러 기술들이 개발되고 있다.
예를 들어, 고농도 산소 치료(hyperbaric oxygen therapy; HBOT)를 이용하거나 헤모글로빈 기반의 산소운반체, 퍼플루오로카본(perfluorocarbon; PFC) 기술 등의 산소 운반체를 사용하는 것이 이에 속한다. 고농도 산소 치료는 기술적으로 간단하고 치료가 진행되는 동안에는 산소가 지속적으로 제공될 수 있으며, 산소 운반체는 주변을 둘러싼 산소 분압에 따라 산소를 방출할 수 있다는 장점이 있다.
하지만, 전자는 치료를 받기 위한 전문시설이 필요하며 산소가 호흡에 의해서만 제공될 수 있고, 후자는 산소의 초기 방출이 빠르게 일어난다는 제한점을 가지고 있다.
이를 해결하기 위해, 국부적인 산소 전달 및 서방형 산소 전달을 위해 in situ에서 산소를 생성하는 생체 재료에 관한 연구가 진행된 바 있다. 이러한 산소를 생성하는 물질로서는 과산화수소(hydrogen peroxide), 과탄산나트륨(sodium percarbonate) 및 과산화칼슘(calcium peroxide)이 대표적이다.
그러나, 이러한 물질들은 초기에 빠른 산소 방출 거동이 보이고 장기간 산소 방출이 한계라는 제한점이 있다.
이에, 고농도의 산소를 서방형으로 방출하면서도 생체안정성이 우수한 in situ 형성 하이드로젤을 개발할 필요성이 크게 부각되고 있다.
본 발명은 상기와 같은 종래의 요구를 충족시키기 위한 것으로, 고농도의 산소를 서방형으로 방출하는 새로운 형태의 in situ 가교 고분자 하이드로젤, 이러한 하이드로젤의 물리/화학/생물학적 특성을 쉽게 제어할 수 있는 서방형 산소 방출형 주입형 하이드로젤의 제조방법, 및 이의 다양한 생의학적 용도를 제공함을 기술적 과제로 한다.
상기한 기술적 과제를 달성하고자, 본 발명은 티올(thiol, -SH) 반응기를 갖는 천연/합성 고분자를 수용액 상태에서 과산화칼슘의 분해에 의한 이황화결합(disulfide bonds; -S-S-) 형성을 유도하여 in situ 가교형 고분자 하이드로젤을 제조하고, 동시에 수용액에서의 과산화칼슘 분해에 의해 서방형으로 고농도의 산소를 방출하는 새로운 형태의 in situ 가교 고분자 하이드로젤을 제공한다.
본 발명에서, 티올기를 포함하는 천연/합성 고분자는 Traut's reagent(TR)를 이용하여 제조하며, 고분자 주사슬에 도입되는 티올 반응기는 합성 시 사용되는 초기 TR의 사용량에 따라 조절할 수 있다.
또한, 본 발명은 고분자, 과산화칼슘, TR 치환도 등의 조절에 따라 하이드로젤 형성 시간, 기계적 강도, 생분해도, 산소 방출 거동 등과 같은 in situ 가교 하이드로젤의 물리/화학/생물학적 특성을 쉽게 조절할 수 있는 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법을 제공한다.
또한, 본 발명은 in situ 가교 서방형 산소 방출형 하이드로젤을 포함하는, 조직 재생 및 충진용 임플란트 소재를 제공한다.
또한, 본 발명은 in situ 가교 서방형 산소 방출형 하이드로젤을 포함하는, 조직 접착 및 지혈용 소재를 제공한다.
또한, 본 발명은 in situ 가교 서방형 산소 방출형 하이드로젤을 포함하는, 생리활성 물질 또는 약물의 전달체용 담체를 제공한다.
본 발명에 따른 새로운 형태의 in situ 가교 하이드로젤은 과산화칼슘의 분해로 생성된 산소에 의한 하이드로젤 형성과 하이드로젤 내부에서 생성된 산소의 서방형 방출 거동을 조절할 수 있는 특징을 가지고 있다.
즉, 본 발명을 통해 기존 산소 발생 하이드로젤이 가지고 있는 제한점을 극복할 수 있으며, 우수한 생체 적합성을 기반으로 다양한 생의학적 응용(예: 조직 재생, 인공조직체 제조, 상처 치유 소재, 조직 접착 소재, 약물 전달체 등)이 가능하다.
도 1은 GtnSH의 합성 모식도이다.
도 2는 과산화칼슘을 이용한 GtnSH 하이드로젤 제조의 모식도이다.
도 3은 TR 도입량 변화에 따른 젤라틴 유도체 내의 티올 함량을 나타낸 그래프이다.
도 4는 TR 도입량 변화, 과산화칼슘의 농도 및 고분자 농도에 따른 하이드로젤의 젤화 시간을 나타낸 그래프이다.
도 5는 과산화칼슘 농도와 고분자 농도에 따른 하이드로젤의 산소 방출 거동을 보여주는 그래프이다.
도 6은 하이드로젤의 기계적 강도를 보여주는 그래프이다.
도 7은 하이드로젤의 효소분해 정도를 보여주는 그래프이다.
도 8은 하이드로젤의 세포 적합성을 보여주는 도면이다.
도 9는 하이드로젤의 조직 접착성을 보여주는 그래프이다.
이하, 본 발명을 보다 상세하게 설명한다.
본 발명자들은 예의 연구를 거듭한 결과 과산화칼슘을 이용한 새로운 형태의 in situ 형성 하이드로젤을 제조함과 동시에, 이러한 하이드로젤 내에서 발생한 산소가 서방형으로 장기간(14일 이상) 방출되는 것을 확인하였다. 또한, 간단한 방법으로 고농도의 산소를 방출할 수 있는 고분자 하이드로젤 소재를 제조함과 동시에, 물리/화학/생물학적 특성을 쉽게 제어할 수 있음을 밝혀내었다.
본 발명은 티올 반응기를 갖는 천연/합성 고분자에 과산화칼슘을 적용하여 이황화결합을 유도하고, 이를 통해 서방형 산소 방출형 in situ 하이드로젤을 제조한다.
도 1을 참조하면, 티올 반응기를 갖는 고분자 주사슬은 Traut's reagent(TR) 를 이용하여 제조하며, 고분자 주사슬에 도입되는 티올 반응기는 합성 시 사용되는 초기 TR의 사용량에 따라 조절할 수 있다.
상기 고분자 주사슬은 젤라틴, 키토산, 헤파린, 셀룰로스, 덱스트란, 덱스트란 설페이트, 콘드로이틴 설페이트, 케라틴, 케라탄 설페이트, 더마탄 설페이트, 알지네이트, 콜라겐, 알부민, 피브로넥틴, 라미닌, 엘라스틴, 비트로넥틴, 히알루론산, 피브리노겐 및 다지-고분자로 이루어진 군에서 선택된 어느 하나일 수 있으나, 반드시 이에 한정되는 것은 아니다.
여기서, 상기 다지-고분자는 3지(3-arm)-폴리에틸렌글리콜(3armPEG), 4지(4-arm)-폴리에틸렌글리콜(4armPEG), 6지(6-arm)-폴리에틸렌글리콜(6armPEG) 및 8지(8-arm)-폴리에틸렌글리콜(8armPEG) 중에서 선택된 1종 이상의 다지-폴리에틸렌글리콜; 및 테트로닉 시리즈(4arm-PPO-PEO);로 이루어진 군에서 선택된 어느 하나 또는 둘 이상의 고분자일 수 있으나, 반드시 이에 한정되는 것은 아니다.
도 2를 참조하면, 상기 서방형 산소 방출형 하이드로젤은 티올 반응기를 갖는 고분자 주사슬을 과산화칼슘을 포함한 용액 하에서 산화반응을 통해 이황화결합을 유도하여 in situ 가교시켜 제조할 수 있다.
본 발명의 산소 방출형 in situ 가교 하이드로젤 제조방법은 티올 반응기의 도입량, 고분자의 농도 및 과산화칼슘의 농도를 조절하여 젤화 시간, 기계적 강도, 산소 방출 거동과 같은 물리화학적 성질을 유연하게 조절할 수 있는 장점이 있다.
또한, 본 발명은 산소 방출형 in situ 가교 하이드로젤을 포함하는, 조직 재생, 조직공학용 지지체 및 충진용 임플란트 소재를 제공한다.
이러한 소재로는 연골 재생(cartilage regeneration), 골 재생(bone regeneration), 치조골 재생(alveolar regeneration), 피부 재생(skin regeneration), 심근 재생(cardiac tissue regeneration), 인공 수정체(artificial intraocular lens), 척수 신경 재생(spinal cord regeneration), 뇌신경 재생(cranial regeneration), 성대 재생 및 충진제(vocal regeneration and augmentation), 유착 방지막(adhesion barrier), 요실금 치료제(urinary incontinence treatment), 주름 제거(wrinkles removal)용 충진제, 화상 치료제(wound dressing), 조직 충진제(tissue augmentation) 및 척추 추간판 치료제(intervertebral disc treatment)로 이루어진 군에서 선택된 어느 하나에 적용되는 소재를 들 수 있으나, 반드시 이에 한정되는 것은 아니다.
또한, 본 발명은 상기 산소 방출형 in situ 가교 하이드로젤을 포함하는, 조직 접착 및 지혈용 소재를 제공한다.
상기 지혈용 소재는 혈관 외과 영역을 포함한 뇌신경 외과수술, 뼈의 접착을 포함한 정형외과 수술, 열상 환자의 지혈, 대퇴동맥의 봉합, 백내장 절개 봉합, 연골 치유, 피부 접합, 장기/분비선 절개면 지혈, 위장관 분합 및 힘줄/인대 치유로 이루어진 군에서 선택된 어느 하나에 적용될 수 있으나, 반드시 이에 한정되는 것은 아니다.
또한, 본 발명은 상기 산소 방출형 in situ 가교 하이드로젤을 포함하는, 생리활성 물질 또는 약물 전달체용 담체를 제공한다.
상기 생리활성물질 또는 약물은 펩타이드 또는 단백질 의약품, 항균제, 항암제 및 항염증제로 이루어진 군에서 선택된 어느 하나 또는 둘 이상일 수 있으나, 반드시 이에 한정되는 것은 아니다.
상기 펩타이드 또는 단백질 의약품은 섬유아세포 성장인자(fibroblast growth factor; FGF), 혈관내피세포 성장인자(vascular endothelial growth factor; VEGF), 전환 성장인자(transforming growth factor; TGF), 골형성 성장인자(bone morphogenetic protein; BMP), 인간성장 호르몬(human growth hormone; hGH), 돼지성장 호르몬(porcine growth hormone; pGH), 백혈구 성장인자(granulocyte colony-stimulating factor; G-CSF), 적혈구 성장인자(erythropoietin; EPO), 대식세포 성장인자(macrophage colony-stimulating factor; M-CSF), 종양 괴사 인자(tumor necrosis factor; TNF), 상피세포 성장인자(epidermal growth factor; EGF), 혈소판유도 성장인자(platelet-derived growth factor; PDGF), 인터페론-α,β,γ(interferon-α,β,γ), 인터루킨-2(interleukin-2; IL-2), 칼시토닌, 신경 성장인자(nerve growth factor; NGF), 성장호르몬 방출인자, 엔지오텐신, 황체형성 호르몬 방출 호르몬(luteinizing hormone-releasing hormone; LHRH), 황체 형성 호르몬 방출 호르몬 작동약(LHRH agonist), 인슐린, 갑상선 자극 호르몬 방출 호르몬(thyrotropin-releasing hormone; TRH), 엔지오스타틴, 엔도스타틴, 소마토스타틴, 글루카곤, 엔도르핀, 바시트라신, 머게인, 콜리스틴, 바시트라신, 단일 항체, 백신류 및 이들의 혼합물로 이루어진 군에서 선택된 어느 하나일 수 있으나, 반드시 이에 한정되는 것은 아니다.
상기 항균제는 미노싸이클린, 테트라싸이클린, 오플록사신, 포스포마이신, 머게인, 프로플록사신, 암피실린, 페니실린, 독시싸이클린, 티에나마이신, 세팔로 스포린, 노르카디신, 겐타마이신, 네오마이신, 카나마이신, 파로모마이신, 미크로 노마이신, 아미카신, 토브라마이신, 디베카신, 세포탁심, 세파클러, 에리스로마이신, 싸이프로플록사신, 레보플록사신, 엔옥사신, 반코마이신, 이미페넴, 후시딕산 및 이들의 혼합물로 이루어진 군에서 선택된 어느 하나일 수 있으나, 반드시 이에 한정되는 것은 아니다.
상기 항암제는 파클리탁셀, 텍소티어, 아드리아마이신, 엔도스타틴, 앤지오 스타틴, 미토마이신, 블레오마이신, 시스플레틴, 카보플레틴, 독소루비신, 다우노 루비신, 이다루비신, 5-플로로우라실, 메토트렉세이트, 엑티노마이신-D 및 이들의 혼합물로 이루어진 군에서 선택된 어느 하나일 수 있으나, 반드시 이에 한정되는 것은 아니다.
상기 항염증제는 아세토아민펜, 아스피린, 이부프로펜, 디크로페낙, 인도메 타신, 피록시캄, 페노프로펜, 플루비프로펜, 케토프로펜, 나프록센, 수프로펜, 록소프로펜, 시녹시캄, 테녹시캄 및 이들의 혼합물로 이루어진 군에서 선택된 어느 하나일 수 있으나, 반드시 이에 한정되는 것은 아니다.
이하, 실시예 및 실험예를 통해 본 발명을 보다 구체적으로 설명한다. 그러나 이들 예는 본 발명의 이해를 돕기 위한 것일 뿐 어떠한 의미로든 본 발명의 범위가 이들 예로 한정되는 것은 아니다.
<실시예 1> 재료 준비
젤라틴(type A from porcine skin, >300 bloom), 2-이미노티올란 하이드로클로라이드(2-iminothiolane hydrochloride; TR), 과산화칼슘(calcium peroxide; CaO2), 무수 디메틸 설폭사이드(anhydrous Dimethyl sulfoxide; anhydrous DMSO) 및 콜라게나아제 타입 Ⅱ(collagenase type Ⅱ)는 Sigma Aldrich(St. Louis, MO, USA)로부터 구입하였다.
DMEM 배지(Dulbecco's Modified Eagle's Medium; DMEM), 페니실린-스트렙토마이신(penicillin-streptomycin; P/S), 트립신/EDTA(trypsin/EDTA) 및 DPBS(Dulbecco's phosphate buffered saline; DPBS) 용액은 Gibco(Grand Island, NY, USA)로부터 구입하였고, 소태아혈청(Fetal Bovine Serum; FBS)은 Research and Diagnostic Technology로부터 구입하였으며, EGM-2 Single quots 배지(Endothelial Cell Growth Medium; EGM)는 Lonza로부터 구입하였다. 또한, Cell Proliferation reagent WST-1은 Roche Diagnostics로부터 구입하였고, Live/Dead Viability/Cytotoxicity Kit는 Life science로부터 구입하였다.
다른 화학 물질 및 용매들은 추가적인 정제 없이 사용하였다.
<실시예 2> 티올(thiol)이 결합된 젤라틴 유도체 합성 및 구조 분석 (도 1)
젤라틴 100mg을 anhydrous DMSO 10ml에 용해시킨 후, 이 용액을 TR(1~20mg)을 DMSO 1ml에 용해시킨 용액과 혼합하였다. 이때, 반응 온도는 37℃였고, 질소 분위기에서 24시간 동안 반응을 진행하였다.
상기 반응된 혼합물을 37℃에서 3.5kD의 분획분자량(molecular weight cut-off; MWCO)을 갖는 투석막(dialysis tube)으로부터 한외여과하였고, 배지(media)를 2일 동안 5mM 염화수소(Hydrogen chloride; HCl)용액과 1mM HCl용액에 하루씩 교체하였다.
상기 티올이 결합된 젤라틴 유도체(thiolated gelatin; GtnSH) 고분자를 동결 건조하여 수득하였다.
<실시예 3> 하이드로젤 형성 (도 2)
GtnSH 고분자를 37℃의 DPBS에 녹인 용액과 과산화칼슘(0~1 중량%)을 혼합하여 하이드로젤을 제조하였다.
< 실험예 1> 2- iminothiolane hydrochloride(TR) 도입량에 따른 젤라틴 유도체 내의 티올(thiol) 함량 조절 (도 3)
엘만 분석(Ellman's assay)을 통해 GtnSH 내의 티올 함량을 측정하였다.
TR 도입량에 따른 티올 함량을 분석하기 위해, 합성 시 젤라틴(100mg), anhydrous DMSO(10ml)의 일정한 조성 하에 TR 도입량을 1mg, 5mg, 10mg, 20mg로 변화시켰다.
기준으로 쓰인 시스테인(L-cystein)과 1mg/ml GtnSH 용액 100μl를 엘만 시약 용액(Ellman's reagent solution) 100μl와 혼합한 후 20분 동안 상온에 두었다.
상기 혼합물을 흡광 검출기를 이용해 405nm에서 흡광도를 측정하고 시스테인 표준곡선을 만들어 GtnSH 내의 티올 함유량을 계산하였다.
측정 결과, TR의 도입량을 조절하여 젤라틴 유도체 내의 티올 함유량을 5.224~25.145 μmol/g(폴리머)까지 조절이 가능하였으며, TR의 도입량이 증가함에 따라 GtnSH 내의 티올 함유량이 증가하였다.
TR의 도입량을 10mg에서 20mg으로 증가시켰을 때는 젤라틴 유도체 내의 티올 함유량이 감소하였는데, 이는 젤라틴에 도입될 수 있는 티올 양이 포화되어 감소된 것이다.
<실험예 2> 티올(thiol) 도입량에 따른 젤화 시간 분석 (도 4)
티올 도입량에 따른 젤화 시간을 분석하기 위해 바이알 틸팅 방법(vial tilting method)을 이용하여 평가하였다.
GtnSH(5 중량%), CaO2(1 중량%), DPBS(100μl)의 일정한 조성 하에 TR도입량을 1 mg, 5 mg, 10 mg, 20 mg로 변화시켰다.
실험 결과, TR의 농도를 조절하여 하이드로젤의 젤화 시간을 3~42분까지 조절이 가능하였으며, TR의 도입량이 증가함에 따라 젤 형성 시간이 감소하였다. 이는 TR 도입량의 증가로 인해 GtnSH 내의 티올 양이 증가되어 가교를 형성할 수 있는 반응기가 증가하였기 때문에 하이드로젤 형성 시간이 짧아지게 된 것으로 설명할 수 있다.
<실험예 3> 고분자 농도에 따른 젤화 시간 분석 (도 4)
고분자 농도에 따른 젤화 시간을 분석하기 위해 vial tilting method를 이용하여 평가하였다.
TR 도입량(10mg), CaO2(1 중량%), DPBS(100μl)의 일정한 조성 하에 GtnSH 농도를 3 중량%, 5 중량%, 7 중량%로 변화시켰다. 보다 상세한 하이드로젤의 제조 조건은 표 1에 나타내었다.
[표 1]
실험 결과, 고분자 농도를 조절하여 하이드로젤의 젤화 시간을 2~6분까지 조절이 가능하였으며, 전체적으로 고분자의 농도가 증가함에 따라 젤 형성 시간이 감소하였다. 이는 고분자 농도의 증가로 인해 젤라틴에 붙어있는 반응기 또한 증가하였기 때문에 하이드로젤 형성 시간이 짧아지게 된 것으로 설명할 수 있다.
<실험예 4> 과산화칼슘 농도에 따른 젤화 시간 분석 (도 4)
과산화칼슘 농도에 따른 젤화 시간을 분석하기 위해 vial tilting method를 이용하여 평가하였다.
TR 도입량(10mg), GtnSH(5 중량%), DPBS(100μl)의 일정한 조성 하에 과산화칼슘의 농도를 0 중량%, 0.01 중량%, 0.05 중량%, 0.1 중량%, 0.5 중량%, 1 중량%로 변화시켰다. 보다 상세한 하이드로젤의 제조 조건은 표 2에 나타내었다.
[표 2]
실험 결과, 과산화칼슘의 농도를 조절하여 하이드로젤의 젤화 시간을 5~329분까지 조절이 가능하였으며, 과산화 칼슘의 농도가 0.01 중량% 미만인 용액에서는 젤이 형성되지 못하였으나 전체적으로 과산화칼슘의 농도가 증가함에 따라 하이드로젤의 젤 형성 시간이 짧아졌다. 그 이유는 과산화칼슘의 농도가 증가함에 따라 과산화수소의 생성을 촉진하여 티올기가 이황화결합(disulfide bond)을 형성하는 것을 촉진하기 때문에 젤 형성 시간이 짧아지게 된 것이다.
<실험예 5> 과산화칼슘 농도에 따른 산소 방출거동 분석 (도 5)
산소센서를 사용하여 과산화칼슘 농도에 따른 하이드로젤의 산소 방출 거동을 3일간 확인하였다.
TR 도입량(10mg), GtnSH(5 중량%)의 일정한 조성 하에 과산화칼슘의 농도를 0.5 중량%, 0.75 중량%, 1 중량%로 변화시켰다.
상기 하이드로젤이 담긴 배지(media)의 용존산소량을 측정하기 위해 하이드로젤(300μl)을 제조하고 10분 뒤 배지(600μl)를 넣어준 후 미디어의 용존산소량을 측정하였다.
실험 결과, 과산화칼슘의 농도를 조절하여 하이드로젤이 담긴 배지의 최대 용존산소량을 46.22%~61.74%까지 조절할 수 있었으며, 과산화칼슘의 농도가 증가함에 따라 하이드로젤이 담긴 배지의 최대 용존산소량이 더 높아졌다. 그 이유는 과산화칼슘의 농도가 증가함에 따라 산소의 생성을 촉진하여 하이드로젤로부터 배지로 방출되는 산소의 양이 많아지게 되기 때문이다.
<실험예 6> 고분자 농도에 따른 산소 방출거동 분석 (도 5)
산소센서를 사용하여 고분자 농도에 따른 하이드로젤의 산소 방출거동을 3일간 확인하였다.
TR 도입량(10mg), 과산화칼슘(1 중량%)의 일정한 조성 하에 고분자 농도를 0중량%, 3 중량%, 5 중량%, 7 중량%로 변화시켰다.
상기 하이드로젤이 담긴 배지(media)의 용존산소량을 측정하기 위해 하이드로젤(300μl)을 제조하고 10분 뒤 배지(600μl)를 넣어준 후 미디어의 용존산소량을 측정하였다.
실험 결과, 고분자 농도를 조절하여 하이드로젤이 담긴 배지의 최대 용존산소량을 51.49%~86.12%까지 조절할 수 있었으며, 고분자 농도가 증가함에 따라 하이드로젤이 담긴 배지의 최대 용존산소량은 감소하였지만, 높은 산소가 오랜 기간 유지되었다. 이는 고분자 농도가 증가함에 따라 가교도가 증가하여 하이드로젤의 투과성이 감소하였기 때문에 산소가 급격히 방출되지 않고 서방형으로 방출된 것이다.
<실험예 7> 과산화칼슘 농도에 따른 산소 방출거동 장기간 분석 (도 5)
산소센서를 사용하여 과산화칼슘 농도에 따른 하이드로젤의 산소 방출 거동을 14일 동안 측정하였다.
TR 도입량(10mg), GtnSH(5 중량%)의 일정한 조성 하에 과산화칼슘의 농도를 0 중량%, 0.5 중량%, 0.75 중량%, 1 중량%로 변화시켰다.
상기 하이드로젤이 담긴 배지(media)의 용존산소량을 측정하기 위해 하이드로젤(300μl)을 제조하고 10분 뒤 배지(600μl)를 넣어준 후 특정 시간 간격으로 미디어의 용존산소량을 측정하였다.
실험 결과, 과산화칼슘의 농도를 조절하여 하이드로젤이 담긴 배지의 최대 용존산소량을 23.68%~51.62%까지 조절할 수 있었으며, 과산화칼슘의 농도가 증가함에 따라 하이드로젤이 담긴 배지의 최대 용존산소량이 더 높아졌다. 그 이유는 과산화칼슘의 농도가 증가함에 따라 산소의 생성을 촉진하여 하이드로젤로부터 배지로 방출되는 산소의 양이 많아졌기 때문이다.
또한, 하이드로젤 내에서 발생한 산소가 14일 동안 방출되는 것을 확인하였다.
<실험예 8> 기계적 강도(Elastic modulus) 분석 (도 6)
레오미터(rheometer)를 이용하여 GtnSH 하이드로젤의 기계적 강도를 측정하였으며, 과산화칼슘의 농도를 조절하여 기계적 강도의 변화 평가를 수행하였다.
TR 도입량(10mg), GtnSH(5 중량%)의 일정한 조성 하에 과산화칼슘의 농도를 0 중량%, 0.5 중량%, 0.75 중량%, 1 중량%로 변화시켰다.
과산화칼슘의 농도를 조절하여 하이드로젤의 기계적 강도 조절이 가능함을 확인하였으며, 그 범위는 100~810 Pa이었다. 한편, 과산화칼슘의 농도를 0 중량%로 한 것은 하이드로젤을 형성하지 못하였다. 이는 과산화칼슘이 부재하여 티올기 간의 이황화결합 형성을 촉진하지 못했기 때문이다.
<실험예 9> 하이드로젤의 생분해성 평가 (도 7)
하이드로젤의 생분해성을 평가하기 위해, 젤화 시간 시험과 동일한 제조방법으로 마이크로 튜브 내에 하이드로젤을 제조하였다.
실온에서 상기 하이드로젤 샘플의 안정을 위해 30분 동안 방치한 후, 각 하이드로젤 샘플의 무게(Wi)를 기록하였으며, 이후 DPBS 혹은 콜라게나아제(0.01mg/ml) 효소를 처리하였다.
특정 시간 간격으로 완전히 상청액(supernatant)을 제거한 후에 상기 하이드로젤 무게를 계량하였고, 그 후 200μl 신선한 배지를 추가하였다.
생분해성 정도는 하기 수학식 1을 이용하여 계산하였다.
[수학식 1]
(여기서, 상기 Wd 및 Wi는 각각 열화된 하이드로젤 및 원래의 하이드로젤의 무게를 나타낸다.)
실험 결과, DPBS로 처리한 샘플은 시간이 지나도 하이드로젤이 분해되지 않은 반면, 0.01mg/ml 농도의 콜라게나아제 효소로 처리한 하이드로젤은 시간에 따라 샘플이 분해되었다. 젤라틴에 티올기가 도입되어도 여전히 콜라게나아제에 의해 분해될 수 있음을 확인한 것이다.
<실험예 10> 하이드로젤의 세포 독성 평가 (도 8)
GtnSH의 세포 적합성 평가를 위해, 96-웰 플레이트에 GtnSH 용액을 넣은 후 인간 피부 섬유아세포(human dermal fibroblast; hDFBs)를 배양하여 세포 독성 평가를 수행하였다.
실험에 사용된 세포의 농도는 2.0 X 103 cells/wells이며, 37℃, 5% CO2 분위기 하에서 24시간 배양 후 WST-1 assay를 이용하여 세포 생존능(cell viability)을 측정하였다.
하이드로젤의 세포 적합성 평가를 위해, 96-웰 플레이트에 3차원으로 인간 탯줄정맥 혈관 내피 세포(human umbilical vein endothelial cells; HUVEC)를 담지한 하이드로젤을 형성한 후 배양하여 세포 독성 평가를 수행하였다.
실험에 사용된 세포의 농도는 2 × 105 cells/wells이며, 37℃, 5% CO2 분위기 하에서 7일간 배양 후 Live/Dead Viability/Cytotoxicity Kit를 이용하여 세포 생존능을 측정하였다.
하이드로젤 형성 과정에서 생성되는 과산화수소의 분해를 위해 카탈레이즈(catalase) 0~50,000 U/mL를 혼합하여 하이드로젤을 제조하였다.
Live/Dead 분석은 세포 독성으로 사멸된 세포는 붉은 색으로, 살아있는 세포는 초록색으로 나타내어 세포 독성 유무를 평가하는 방법이다.
실험 결과, GtnSH는 대조군 대비 90% 이상의 세포 생존능을 보였고, 하이드로젤은 Live/Dead assay 결과 과산화칼슘의 농도에 따라 70~80%의 살아있는 세포가 관찰되었다. 즉, 상기 하이드로젤의 세포 적합성이 우수함을 확인하였다.
<실험예 11> 하이드로젤의 조직 접착성 평가 (도 9)
ASTM F2255-03("Test Method for Strength Properties of Tissue Adhesives in Lap-Shear by Tension Loading") 평가방법을 기준으로, 유압식 만능 재료 시험기(Universal testing machine; UTM)를 이용하여 돼지 피부에서 하이드로젤의 조직 접착 강도(tissue adhesive strength)를 측정하였다.
돼지 피부(porcine skin)의 치수는 직경 2.5cm이었으며, 에틸 시아노아크릴레이트 접착제(ethyl cyanoacrylate glue)에 의해 직사각형 플라스틱 기판 상에 돼지 피부의 모든 부분을 부착하였다.
실험 전에, 탈이온수에 아이소프로판올 70%를 사용하여 세포제거(decellularization)를 위해 피부 표면을 세척하였고, 상기 세척 과정이 끝난 다음 15분 후에 100μl 접착제를 돼지 피부의 영역에 도포한 후, 2개의 표면을 함께 랩핑하였다.
상기 접착부는 100g의 힘을 인가하여 습윤 환경의 실온에서 60분 동안 유지하였다.
이어서, 상기 시료를 10mm/min의 크로스헤드 속도(crosshead speed)로 전달 불량으로 로딩하였다.
변위(displacement)에 대한 최대 강도를 측정하였고, 각 샘플의 접착력을 특성화하기 위해 파단(최종 접착 강도)시 전단 응력(shear stress)을 사용하였다.
적어도 5개의 샘플을 측정에 이용하였다.
돼지 피부를 이용하여 조직 접착력을 평가한 결과, 사용한 과산화칼슘의 농도가 증가함에 따라 향상된 접착 강도를 나타내었다.
TR 도입량(10mg), GtnSH(5 중량%)의 일정한 조성 하에 과산화칼슘의 농도를0.5 중량%, 0.75 중량%, 1 중량%로 변화시켰을 때 9.9~28.8 kPa까지 조절할 수 있었으며, 특히 1 중량%일 때 가장 높은 접착 강도를 보였다.
이상과 같이, 본 발명은 비록 한정된 실시예와 도면에 의해 설명되었으나, 본 발명은 이것에 한정되지 않으며 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에 의해 본 발명의 기술사상과 아래에 기재될 청구범위의 균등 범위 내에서 다양한 수정 및 변형이 가능함은 물론이다.
Claims (18)
- a) 천연 또는 합성 고분자와 Traut's reagent(TR)를 용매 내에서 반응시켜, 주사슬에 티올기가 도입된 유도체 고분자를 합성하는 단계; 및b) 티올기가 도입된 유도체 고분자 용액과 과산화칼슘(CaO2)을 혼합 및 반응시켜, 하이드로젤을 형성하는 단계;를 포함하며,상기 b) 단계는 과산화칼슘(CaO2)의 분해에 의해 티올기가 도입된 고분자 주사슬 간에 이황화결합(disulfide bonds; -S-S-)이 유도되어 in situ 가교되는 것임을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,상기 과산화칼슘의 분해에 의해 발생된 산소가 하이드로젤로부터 서방형으로 방출되는 것임을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,상기 a) 단계의 천연 또는 합성 고분자는 젤라틴, 키토산, 헤파린, 셀룰로스, 덱스트란, 덱스트란 설페이트, 콘드로이틴 설페이트, 케라틴, 케라탄 설페이트, 더마탄 설페이트, 알지네이트, 콜라겐, 알부민, 피브로넥틴, 라미닌, 엘라스틴, 비트로넥틴, 히알루론산, 피브리노겐 및 다지-고분자로 이루어진 군에서 선택된 어느 하나인 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제3항에 있어서,상기 다지-고분자는 3지(3-arm)-폴리에틸렌글리콜(3armPEG), 4지(4-arm)-폴리에틸렌글리콜(4armPEG), 6지(6-arm)-폴리에틸렌글리콜(6armPEG) 및 8지(8-arm)-폴리에틸렌글리콜(8armPEG) 중에서 선택된 1종 이상의 다지-폴리에틸렌글리콜; 및 테트로닉 시리즈(4arm-PPO-PEO);로 이루어진 군에서 선택된 어느 하나 또는 둘 이상의 고분자인 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제3항에 있어서,상기 a) 단계의 천연 또는 합성 고분자는 젤라틴인 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,상기 a) 단계의 천연 또는 합성 고분자 : Traut's reagent(TR) = 100 : 1~20의 중량비율로 사용되는 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,상기 a) 단계의 용매는 무수 디메틸 설폭사이드(anhydrous DMSO)인 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법
- 제1항에 있어서,상기 b) 단계의 고분자 용액은 티올기가 도입된 유도체 고분자를 DPBS(Dulbecco's phosphate buffered saline; DPBS)에 녹인 것임을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,상기 b) 단계의 티올기가 도입된 유도체 고분자는 반응용액 중 3~7 중량%의 함량으로 사용되는 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,상기 b) 단계의 과산화칼슘은 반응용액 중 0.01~1 중량%의 함량으로 사용되는 것을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,티올기가 도입된 젤라틴 유도체(GtnSH) 5 중량%, Traut's reagent(TR) 10mg의 사용 조건 및 하이드로젤 2배 부피의 배지 조건에서,상기 제조된 하이드로젤은 사용된 과산화칼슘의 농도가 0.5~1 중량%로 변화함에 따라,배지의 최대 용존산소량을 46.22%~61.74%로 증가시키는 고농도 산소 방출거동을 보임을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,Traut's reagent(TR) 10mg, 과산화칼슘 1 중량%의 사용 조건 및 하이드로젤 2배 부피의 배지 조건에서,상기 제조된 하이드로젤은 사용된 티올기가 도입된 젤라틴 유도체(GtnSH)의 농도가 0~7 중량%로 변화함에 따라,배지의 최대 용존산소량을 86.12%~51.49%로 천천히 감소시키는 서방성 산소 방출거동을 보임을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항에 있어서,티올기가 도입된 젤라틴 유도체(GtnSH) 5 중량%, Traut's reagent(TR) 10mg의 사용 조건 및 하이드로젤 2배 부피의 배지 조건에서,상기 제조된 하이드로젤은 사용된 과산화칼슘의 농도가 0~1 중량%로 변화함에 따라,배지의 최대 용존산소량을 23.68%~51.62%로 증가시키고 14일 이상 산소를 방출시키는 지속성 산소 방출거동을 보임을 특징으로 하는,과산화칼슘을 이용한 서방형 산소 방출형 in situ 가교 하이드로젤의 제조방법.
- 제1항 내지 제13항 중 어느 한 항의 방법에 따라 제조된,서방형 산소 방출형 in situ 가교 하이드로젤.
- 제14항에 있어서,상기 하이드로젤은 주입형 하이드로젤인 것을 특징으로 하는,서방형 산소 방출형 in situ 가교 하이드로젤.
- 제14항에 따른 서방형 산소 방출형 in situ 가교 하이드로젤을 포함하는,조직 재생, 조직공학용 지지체 또는 충진용 임플란트 소재.
- 제14항에 따른 서방형 산소 방출형 in situ 가교 하이드로젤을 포함하는,조직 접착, 상처 치유 또는 지혈용 소재.
- 제14항에 따른 서방형 산소 방출형 in situ 가교 하이드로젤을 포함하는,생리활성 물질 또는 약물의 전달체용 담체.
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EP4230212A1 (en) | 2022-02-16 | 2023-08-23 | UNIVERSITÄTSmedizin der Johannes Gutenberg- Universität Mainz | Composition and kits for the prevention or treatment of gum diseases |
WO2023156508A1 (en) | 2022-02-16 | 2023-08-24 | Universitätsmedizin Der Johannes Gutenberg-Universität Mainz | Compositions and kits for use in wound healing, tissue regeneration and/or bone regeneration |
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