KR20160117050A - Microgel comprising biodegradable polymer and method for preparing the same - Google Patents
Microgel comprising biodegradable polymer and method for preparing the same Download PDFInfo
- Publication number
- KR20160117050A KR20160117050A KR1020150045636A KR20150045636A KR20160117050A KR 20160117050 A KR20160117050 A KR 20160117050A KR 1020150045636 A KR1020150045636 A KR 1020150045636A KR 20150045636 A KR20150045636 A KR 20150045636A KR 20160117050 A KR20160117050 A KR 20160117050A
- Authority
- KR
- South Korea
- Prior art keywords
- microgel
- drug
- pegsda
- polyethylene glycol
- polymer
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a biodegradable microgel (PEGSDA microgel) containing polyethylene glycol-sebacic acid-diacrylate (PEGSDA) polymer and a process for preparing the same.
The microgels have high mechanical strength by adding sebacic acid, which is a hydrophobic molecule, to the known degradable polyethylene glycol diacrylate, and the drug release rate can be controlled by introducing an ester group into the backbone of the polymer, Which is biodegradable and has a drug-impregnating property of 60% or higher, including polyethylene glycol-sebacic acid-diacrylate polymer exhibiting biodegradation characteristics in the body while being effectively biodegradable and effective in tissue engineering in vivo drug delivery system or artificial extracellular matrix Can be used.
Description
The present invention relates to a microgel comprising a biodegradable polymer and a method for producing the microgel.
Tissue engineering and regenerative medicine, which has been actively researched recently in advanced countries, is a fusion science of dentistry, biology and engineering, ultimately restoring damaged human tissues or organs and improving life quality and life by treating diseases The importance of this is increasing day by day, and studies for the production of artificial product materials composed of components similar to those of the human body are being actively carried out in order to recover human tissue or organ.
In particular, a product called "INFUSE", which was developed by Medtronic Corp. based on tissue engineering in the 2000s, uses a collagen sponge impregnated with bone-forming protein (rhBMP-2) (Greenward AS, Boden SD, Barrak RL, Bostrom MPG, Goldberg VM, Yaszemski MJ, et al.) And lumbar spine fusion have been used clinically. Have been widely used in clinical fields such as used autografts, allografts and synthetic grafts.
However, recent reports have reported some side effects and instability when using INFUSE for clinical use (Carragee EJ, Hurwitz EL, Weiner BK, Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, et al.), Although the cause of this has not yet been clearly elucidated, the use of large quantities of drug (1 to 3 mg / L) to demonstrate clinical efficacy and the disproportionate distribution of drugs in collagen sponge And so on.
In order to solve the above-mentioned problems, in the prior patent document (Patent Document 1), polyethylene glycol diacrylate (PEGDA) is added to a host animal for in vivo transplantation in vivo or in vitro Discloses a technique for preparing a gel-like polyethylene glycol-diacrylate (PEG diacrylate, PEGDA) and using it as a drug delivery vehicle.
However, the above-mentioned synthetic hydrogel, PEGDA, is not biodegradable, has poor mechanical properties, and has an excessively high swelling rate, which limits its use to a tissue-engineered support or a drug delivery system.
Therefore, there is a need for a study on a material capable of developing a new drug delivery system exhibiting biodegradability in the body while minimizing drug use by controlling the drug release rate by controlling the drug release rate in a uniform distribution.
The inventors of the present invention have been studying a material capable of developing a drug delivery system. In the past, by adding sebacic acid, which is a hydrophobic molecule to polyethylene glycol diacrylate, by increasing the mechanical strength and introducing an ester group into the polymer chain (backbone) It has been found that biodegradable polymers that can be biodegraded in the body can be prepared into microgels while the drugs can be uniformly carried and the drug release rate can be controlled to minimize drug use.
Accordingly, the present invention provides a technical content of a microgel and a manufacturing method thereof that can be efficiently used as a new drug delivery system.
In order to accomplish the above object, the present invention provides a microgel comprising a polyethylene glycol-sebacic acid-diacrylate polymer.
In one embodiment, the drug impregnation efficiency of the microgel may be greater than 60% and the average particle size may be between 60 and 120 탆.
In one embodiment, the molecular weight of the polyethylene glycol-sebacic acid-diacrylate polymer may be from 5,000 to 100,000 Da, and the polyethylene glycol contained in the polyethylene glycol-sebacic acid-diacrylate polymer may have a molecular weight of 1,000 to 10,000 Da .
(A) dissolving a polyethylene glycol-sebacic acid-diacrylate polymer in a buffer solution; (b) dissolving the radical initiator in the solution obtained in step (a); (c) dropping the solution obtained in step (b) on an oil phase; And (d) stirring the mixture obtained in step (c).
The present invention also provides a drug delivery system prepared by supporting a delivery drug on the microgel described above.
In one embodiment, the delivery drug may be at least one selected from the group consisting of compounds, proteins, nucleic acids, polysaccharides, and extracellular matrix materials.
The microgel according to the present invention exhibits a size of micrometer (쨉 m) unit level and a characteristic of being decomposed in vivo, exhibits high drug impregnation characteristics of 60% or more, and can solve the nonuniform distribution of drugs of a conventional drug delivery system And can be used effectively as a drug delivery system because it can control not only the mechanical strength but also the drug release rate.
1 is a graph showing the results of 1 H-NMR analysis of a PEGSDA polymer.
Figure 2 is a microscopic image of (a) PEGSDA microgel and (b) PLGA microparticles.
3 is a graph showing average particle size and particle size distribution of (a) PEGSDA microgel and (b) PLGA microparticles.
4 is a graph showing the drug impregnation efficiency of PEGSDA microgel, PLGA microparticle and PEGSDA hydrogel impregnated with (a) TRD and (b) rhBMP-2.
Figure 5 is a confocal laser microscope image of TRD impregnated PEGSDA microgel.
6 is a graph showing the drug release rate of PEGSDA microgel, PLGA microparticle and PEGSDA hydrogel impregnated with (a) TRD and (b) rhBMP-2.
As used herein, the term "microgel" refers to a polymer having a small particle size at a micrometer (mu m) unit level, a large surface area, and excellent workability and is formed by emulsion polymerization and intramolecular crosslinking. Quot; refers to swellable spherical gel particles having a net-like structure.
The microgel according to the present invention includes polyethylene glycol-sebacic acid-diacrylate (PEGSDA) polymer.
In the polyethylene glycol-sebacic acid-diacrylate polymer, polyethylene glycol has a high solubility in water and organic solvents, is non-toxic, has no rejection to the immune function, and has chemical bonding with biodegradable ester-based compounds that are hydrophobic To form a polymer and cross-link it to synthesize a microgel having a three-dimensional structure. When applied to a living body, it may play a role of controlling the decomposition time by increasing water inflow to the biodegradable polymer. In addition, the sebacic acid serves to impart hydrophobicity and improve the mechanical strength of the polymer. In addition, the diacrylate imparts hydrophobicity and can control the decomposition time by controlling the biodegradable ester-based molecular weight and chemical constituents.
The polyethyleneglycol-sebacic acid-diacrylate polymer may be prepared by adjusting the molecular weight of the polymer, the composition, the relative ratio of the hydrophilic and hydrophobic molecules, the ratio and concentration of the drug to be injected and the biodegradable polymer, Microgel can be produced. Preferably, polyethylene glycol-sebacic acid-diacrylate containing polyethylene glycol having a molecular weight of 1,000 to 10,000 Da and having a molecular weight of 100,000 Da or less is emulsion-polymerized to prepare a microgel according to the present invention can do.
The microgel is not only degradable biodegradable in vivo but also exhibits beneficial properties such as fluidity, roughness, shear stability, and thickening effect.
The microgel according to the present invention has an average particle size in micrometer (탆), preferably 10 to 500 탆, more preferably 50 to 200 탆.
In addition, the microgel according to the present invention has a drug impregnation efficiency of 60% or more, which can minimize the use of the drug, and is biodegradable in the body. In addition, the type and concentration of the chemically bound drug, the physical strength of the gel, And can be effectively used as a drug delivery system that can control the delivery rate of the delivery material in the body and exhibit beneficial properties such as fluidity, roughness, shear stability, thickening effect, and the like.
(A) dissolving a polyethylene glycol-sebacic acid-diacrylate polymer in a buffer solution; (b) dissolving the radical initiator in the solution obtained in step (a); (c) dropping the solution obtained in step (b) on an oil phase; And (d) stirring the solution obtained in the step (c).
More specifically, in order to prepare the microgel, a solution of a solution of polyethylene glycol-sebacic acid-diacrylate polymer in a buffer solution may be prepared, and phosphate buffered saline may be used as a buffer solution. But is not limited to.
A mixed solution was prepared by dissolving a radical initiator capable of generating oxidation-reduction in the prepared mixed buffer solution, and this mixed solution was dispersed in a hydrophobic solvent and emulsion-polymerized by a water-in-oil type method to obtain polyethylene glycol-sebacic acid- The microgel may be prepared by crosslinking the polymer with a covalent bond, hydrogen bond, van der Waals bond, ionic bond, crystallites, etc. The radical initiator may be ascorbic acid or ammonium persulfate. But is not limited to.
The microgel may be used as a drug delivery system by supporting a delivery drug, and the drug delivery system may be constructed such that the biodegradable polymer is impregnated in a solvent mixed with a delivery drug and supported on a microgel by a physicochemical method And can be used as a drug delivery system. Whereby the delivery drug can be bound by a microgel on the surface or in a reticulated tissue, and can deliver the drug into the body in its combined state, from which it can be released back to the body under certain conditions.
Accordingly, the present invention provides a method for producing a protein DNA, RNA, PNA, oligonucleotide, etc., such as antibiotics, anticancer agents, antiinflammatory agents, antiviral agents, antimicrobial agents, hormones, cytokines, enzymes, antibodies, growth factors, transcription factors, Cells such as fibroblasts, vascular endothelial cells, smooth muscle cells, neurons, chondrocytes, bone cells, skin cells, Schwann cells, stem cells, heparin, heparan sulfate, keratan sulfate, dermatan sulfate, chondroitin sulfate , Hyaluronic acid, or other extracellular matrix materials such as collagen, fibronectin, gelatin, laminin, and bitonectin may be used alone or in combination, and the resulting drug may be effectively used in a drug delivery system .
In addition, adult stem cells such as human mesenchymal stem cells (hMSCs) are cultured inside or outside the cells using the above-mentioned microgel as a matrix or as an extracellular matrix (ECM) Can be used to measure various cell functions such as cell proliferation, cell migration, cell proliferation, or differentiaton.
Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. The examples and test examples provided are merely concrete examples of the present invention and are not intended to limit the scope of the present invention.
Example 1. Preparation of microgel containing PEGSDA
(1) Synthesis of PEGSDA
Polyethylene glycol (PEG) and sebacoyl chloride having molecular weights of 1000, 2000 and 3400 Da were reacted at 0 ° C under triethylamine (TEA) catalyst to produce polyethylene glycol-sebacic acid , PEGS) were synthesized. Polyethylene glycol-sebacic acid-diacrylate (PEGSDA) was synthesized by reacting synthesized PEGS and acryloyl chloride under the same conditions as PEGS. The obtained PEGSDA was precipitated with petroleum ether and dried with a rotary evaporator to obtain a PEGSDA polymer powder.
(2) Identification and molecular weight determination of synthesized PEGSDA polymer
Proton nuclear magnetic resonance spectroscopy ( 1 H-NMR) and Fourier transform infrared (FTIR) spectroscopy were performed to identify the synthesized PEGSDA polymer.
From the results of the FTIR spectra, it was confirmed that a characteristic peak of an ester group appeared near 1730 cm -1 (not shown). From the 1 H-NMR analysis result of FIG. 1, characteristic peaks at 5.9, 6.2 and 6.4 ppm And it was confirmed that PEGSDA, a biodegradable polymer, was successfully synthesized.
Gel permeation chromatography (GPC) was performed to measure the molecular weight of the synthesized PEGSDA polymer. As a result, it was confirmed that the molecular weight of the synthesized PEGSDA polymer was about 10,000 Da.
(3) Preparation of microgel containing PEGSDA polymer
PEGSDA aqueous solution (25 wt%) was prepared by dissolving the synthesized PEGSDA polymer in phosphate buffered saline (PBS), and a redox radical initiator (0.3 M ammonium persulfate and 0.3 M Of ascorbic acid) was dissolved in an aqueous PEGSDA solution. The resultant solution was stirred for about 30 minutes at a stirring speed of 300 rpm while dropping one drop into the mineral oil to proceed cross-linking. The mineral oil used was one containing 1.5% of sorbitan monooleate and 0.5% of polyoxyethylene sorbitan monooleate. The prepared PEGSDA microgels were washed with cold acetone and lyophilized.
(4) Morphological characterization of microgels
A microscope image of the PEGSDA microgel particle was shown in FIG. 2 (a) to analyze the morphological characteristics of the prepared PEGSDA microgel particle. In addition, the average particle size and particle size distribution of the PEGSDA microgel particles were measured by a microscopic image analysis method and are shown in FIG. 3 (a).
The average particle size of the PEGSDA microgel was found to be about 83 탆, and as shown in Fig. 3 (a), it was confirmed that the particles having an average particle size of less than 60 탆 accounted for about 40% of the PEGSDA microgel (Fig. 4 (a)).
Comparative Example 1. Preparation of microparticles using PLGA
PLGA microparticles were prepared by copolymerization using a double-emulsion polymerization method (water-in-oil-in-water, W-O-W) using a poly (lactic-co-glycolic acid)
In order to analyze the morphological characteristics of the prepared PLGA microparticles, a microscope image of PLGA microparticles is shown in FIG. 2 (b). In addition, the average particle size and particle size distribution of PLGA microparticles were measured by a microscopic image analysis method and are shown in FIG. 3 (b).
It was confirmed that the PLGA microparticles (Fig. 3 (b)) had an average particle size of about 85 탆 (as shown in Fig. 2 (b) (Fig. 3 (b)).
Comparative Example 2. Preparation of PEGSDA hydrogel
PEGSDA, which is the same biodegradable polymer as in Example 1, was mixed with
Test Example 1. Analysis of Drug Impregnation Efficiency of PEGSDA Microgel
In order to analyze the drug impregnation efficiency and drug release efficiency of the PEGSDA microgel prepared, 500 mg of Texas red dextran (TRD), a model drug, and recombinant human bone morphogenetic protein-2, rhBMP-2 ) Was impregnated with 1 mL of PEGSDA microgel aqueous solution and 1 mL of PEGSDA hydrogel aqueous solution at room temperature, respectively. Then, the same amount of TRD and rhBMP-2 were impregnated into 1 mL of PLGA microparticle aqueous solution, respectively.
In order to measure the dissolution rate of the drug, the drug-impregnated aqueous solution was placed in an incubator at 37 ° C and the drug concentration was measured. In the case of TRD impregnation, TRD concentration was measured using a spectrophotometer for 4 weeks. When rhBMP-2 was impregnated, rhBMP-2 was infused for 3 weeks using an enzyme-linked immunospecific assay (ELISA) -2 was measured.
As shown in FIG. 4, the drug impregnation efficiency shows that the PEGSDA microgel particle, the PLGA microparticle, and the PEGSDA hydrogel particle show a high impregnation rate of 60% or more, and the PEGSDA microgel can efficiently carry the drug It can be confirmed that it is useful for biotherapy.
Test Example 2. Analysis of Drug Distribution of PEGSDA Microgel
In addition, confocal laser microscope images of TRD-impregnated PEGSDA microgels were photographed to confirm the distribution of the impregnated drug in the PEGSDA microgel particles and are shown in FIG.
As shown in FIG. 5, it can be seen that the TRD is uniformly distributed throughout the PEGSDA microgel particle, and thus the PEGSDA microgel particle is a non-uniform drug, which is one of the disadvantages of the existing drug system (for example, absorbed collagen sponge Distribution can be solved.
Test Example 3. Analysis of Drug Release Efficiency of PEGSDA Microgel
In order to analyze the drug release efficiency of PEGSDA microgel, drug release rate of PEGSDA microgel, PLGA microparticle and PEGSDA hydrogel impregnated with TRD and rhBMP-2 over time was measured and shown in FIG.
As shown in FIG. 6, when TRD was impregnated, it was found that initial burst release was larger than rhBMP-2 as a whole. In the case of PEGSDA hydrogel, swelling It was found that the initial release rate was remarkably reduced due to the low swelling ratio (Non-Patent Document 4). In addition, when the PEGSDA microgel of Example 1 was used, it was confirmed that the initial release rate can be further reduced, and thus it can be effectively used as a drug delivery system in a sustained-release preparation requiring sustained drug release.
Claims (8)
(b) dissolving the radical initiator in the solution obtained in step (a);
(c) dropping the solution obtained in step (b) on an oil phase; And
(d) stirring the mixture obtained in step (c)
≪ / RTI >
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150045636A KR20160117050A (en) | 2015-03-31 | 2015-03-31 | Microgel comprising biodegradable polymer and method for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150045636A KR20160117050A (en) | 2015-03-31 | 2015-03-31 | Microgel comprising biodegradable polymer and method for preparing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20160117050A true KR20160117050A (en) | 2016-10-10 |
Family
ID=57146302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150045636A KR20160117050A (en) | 2015-03-31 | 2015-03-31 | Microgel comprising biodegradable polymer and method for preparing the same |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20160117050A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190082133A (en) * | 2017-12-29 | 2019-07-09 | 서울대학교산학협력단 | Photo-crosslinked microgel for protein drug delivery and fabrication method thereof |
| KR20200095157A (en) | 2019-01-31 | 2020-08-10 | 부산대학교 산학협력단 | Radioisotope-labelled photo-crosslinkable hydrogels and fabrication method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20050058291A (en) | 2002-06-28 | 2005-06-16 | 마크로메드 인코퍼레이티드 | Biodegradable block copolymeric compositions for drug delivery |
| KR20050092795A (en) | 2003-01-31 | 2005-09-22 | 짐머 오르쏘바이올로직스 인코포레이티드 | Hydrogel compositions comprisign nucleus pulposus tissue |
| KR20070035592A (en) | 2004-06-30 | 2007-03-30 | 더 보오드 오브 트러스티스 오브 더 유니버시티 오브 일리노이즈 | Polyethylene glycol-diacrylate-PEGDA-crosslinked hydrogels comprising adipogenic mesenchymal stem cells |
| KR20140109415A (en) | 2011-12-05 | 2014-09-15 | 인셉트, 엘엘씨 | Medical organogel processes and compositions |
-
2015
- 2015-03-31 KR KR1020150045636A patent/KR20160117050A/en not_active Application Discontinuation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20050058291A (en) | 2002-06-28 | 2005-06-16 | 마크로메드 인코퍼레이티드 | Biodegradable block copolymeric compositions for drug delivery |
| KR20050092795A (en) | 2003-01-31 | 2005-09-22 | 짐머 오르쏘바이올로직스 인코포레이티드 | Hydrogel compositions comprisign nucleus pulposus tissue |
| KR20070035592A (en) | 2004-06-30 | 2007-03-30 | 더 보오드 오브 트러스티스 오브 더 유니버시티 오브 일리노이즈 | Polyethylene glycol-diacrylate-PEGDA-crosslinked hydrogels comprising adipogenic mesenchymal stem cells |
| KR20140109415A (en) | 2011-12-05 | 2014-09-15 | 인셉트, 엘엘씨 | Medical organogel processes and compositions |
Non-Patent Citations (4)
| Title |
|---|
| Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J.11:471-91, 2011. |
| Greenward AS, Boden SD, Barrak RL, Bostrom MPG, Goldberg VM, Yaszemski MJ, et al. The evloving role of bone-graft substitutes. American academy of orthopaedic surgeons 77th annual meeting. New Orleans, LA, 2010. |
| Kim J, Lee K-W, Hefferan TE, Currier BL, et al. Synthesis and Evaluation of Novel Biodegradable Hydrogels Based on Poly(ethylene glycol) and Sebacic Acid as Tissue Engineering Scaffolds. Biomacromolecules. 9:149-157, 2008. |
| Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med.158:877-89, 2013. |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190082133A (en) * | 2017-12-29 | 2019-07-09 | 서울대학교산학협력단 | Photo-crosslinked microgel for protein drug delivery and fabrication method thereof |
| KR20200095157A (en) | 2019-01-31 | 2020-08-10 | 부산대학교 산학협력단 | Radioisotope-labelled photo-crosslinkable hydrogels and fabrication method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ooi et al. | Thiol–ene alginate hydrogels as versatile bioinks for bioprinting | |
| US20230404936A1 (en) | Injectable preformed macroscopic 3-dimensional scaffolds for minimally invasive administration | |
| Vega et al. | Recent advances in hydrogels for cartilage tissue engineering | |
| Xu et al. | Highly elastic biodegradable single-network hydrogel for cell printing | |
| Yang et al. | In situ-forming injectable hydrogels for regenerative medicine | |
| Li et al. | Water soluble polyhydroxyalkanoates: future materials for therapeutic applications | |
| Lee et al. | Hydrogels for tissue engineering | |
| Chiu et al. | The role of pore size on vascularization and tissue remodeling in PEG hydrogels | |
| Zulkifli et al. | In vitro degradation study of novel HEC/PVA/collagen nanofibrous scaffold for skin tissue engineering applications | |
| EP2370115B1 (en) | Hydrogel sponges, methods of producing them and uses thereof | |
| Tan et al. | Development of alginate-based hydrogels: Crosslinking strategies and biomedical applications | |
| Abed et al. | Influence of polysaccharide composition on the biocompatibility of pullulan/dextran‐based hydrogels | |
| Petrov et al. | Novel electrically conducting 2-hydroxyethylcellulose/polyaniline nanocomposite cryogels: Synthesis and application in tissue engineering | |
| Lü et al. | Thermoresponsive injectable hydrogel for three-dimensional cell culture: chondroitin sulfate bioconjugated with poly (N-isopropylacrylamide) synthesized by RAFT polymerization | |
| Shi et al. | Cell-compatible hydrogels based on a multifunctional crosslinker with tunable stiffness for tissue engineering | |
| US20150337121A1 (en) | Multifunctional tunable biomaterials for tissue engineering | |
| Jeong et al. | Supramolecular injectable hyaluronate hydrogels for cartilage tissue regeneration | |
| Pan et al. | One-step cross-linked injectable hydrogels with tunable properties for space-filling scaffolds in tissue engineering | |
| Bakaic et al. | Injectable and degradable poly (oligoethylene glycol methacrylate) hydrogels with tunable charge densities as adhesive peptide-free cell scaffolds | |
| Patil et al. | Alginate/poly (amidoamine) injectable hybrid hydrogel for cell delivery | |
| Chen et al. | Hyaluronic acid-based biphasic scaffold with layer-specific induction capacity for osteochondral defect regeneration | |
| Khiabani et al. | A review of hydrogel systems based on poly (N-isopropyl acrylamide) for use in the engineering of bone tissues | |
| Nguyen et al. | Oxidation-mediated scaffold engineering of hyaluronic acid-based microcarriers enhances corneal stromal regeneration | |
| Gupta et al. | Graphene oxide–carbamoylated chitosan hydrogels with tunable mechanical properties for biological applications | |
| KR20160117050A (en) | Microgel comprising biodegradable polymer and method for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E601 | Decision to refuse application |