CN1446590A - New type cement with composite polypeptide/calcium phosphate being as framework - Google Patents
New type cement with composite polypeptide/calcium phosphate being as framework Download PDFInfo
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- CN1446590A CN1446590A CN 03115008 CN03115008A CN1446590A CN 1446590 A CN1446590 A CN 1446590A CN 03115008 CN03115008 CN 03115008 CN 03115008 A CN03115008 A CN 03115008A CN 1446590 A CN1446590 A CN 1446590A
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Abstract
A polypeptide reinforced calcium phosphate bone cemkent for repairing hard tissue of human body and treating diseases is prepared from the biocompatible and degradable polypeptide or its grafted block copolymer, calcium phosphate bone cemkent, active factor and medicine. Its advantages are self solidifying, high compression strength and controlled release of medicine.
Description
Technical field
The invention belongs to field of medical materials, relate to a kind of damaged novel organic/inorganic composite material of human body hard tissue that is used to fill, repair.
Background technology
Human body is different according to structure and effect, requires also inequality to the damaged required repair materials of corresponding site.The reparation that bone is damaged is the thorny problem that perplexs the orthopedist for a long time, through the joint efforts of medical circle and material educational circles, has developed multiple material and technology.As autologous bone transplanting, allograph bone, polymethyl methacrylate bone cement, bio-vitric, bioactive ceramics etc., but all there is in various degree defective, limited its clinical being extensive use of.Autologous bone transplanting is a bone renovating material with the most use clinically at present, that effect is best, but is subjected to the source restriction from body bone quantity, can cause the second operation misery, and is difficult to according to the accurate plastotype of defect; Though the restriction of allogenic bone transplantation on the source is improved, and has antibody one antigen-reactive in various degree, also might bring adverse consequencess such as source of disease propagation; The molding of polymethyl methacrylate bone cement is easy, but its solidification process heat release, can cause the necrosis of surrounding tissue, the polymethyl methacrylate biocompatibility is poor simultaneously, absorbed by human body by foreign matters in vivo, after finishing function, need second operation to take out, increased patient's the painful success rate that also reduces operation simultaneously.
Calcium phosphate bone cement (Calcium Phosphate Cenent is called for short CPC) is a kind of novel hard tissue repairing material, can reconcile into pastel, and is moulding arbitrarily according to defect.Its good biocompatibility, under the environment of human body and temperature conditions, solidify voluntarily, its aquation composition finally is converted into hydroxyapatite (hydroxyapatite HAP), can guide osteogenesis, progressively be organized and absorb and generation bone regeneration effect present orthopaedics clinical practice result satisfactory (old system first-class, Chinese wound magazine, 1999,15 (3): 184-86).CPC is used for non-heavy burden and hangs down the damaged filling effect of heavy burden position bone obtaining certainly clinically at present.But the intensity of material also has distance for the requirement at the position that is applied to bear a heavy burden.Material fragility is big in addition, the toughness deficiency, thus make its application be subjected to certain limitation.Must strengthen CPC for this reason, toughness reinforcing so that satisfy intensity and the toughness reguirements that is used for support function in clinical better.
It is a lot of at present cement class material to be strengthened toughness reinforcing method, strengthens fiber reinforcement etc. as granule.CPC is strengthened toughness reinforcing some reports that also have:
1.Xu Deng adopting carbon fiber respectively, glass fibre, silicon nitride fiber and silicon carbide fibre etc. strengthen calcium phosphate bone cement, can improve strength of cement significantly, reach 20-78MPa by original 10MPa, but the increase rate of intensity and kinds of fibers, length, content and interface are in conjunction with relevant, particularly length requirement is longer, this has increased difficulty (Xu H.H. to clinical manipulation, ReinforCement of a Self-setting Calcium Phosphate Cement with differentfibers., J.Biomed Mat.Res., 2000,52 (1): 107-114);
2.Santos adopt polyamide to strengthen CPC respectively Deng with Xu, also can make the bigger raising of intensity (Santos L.A., Fiber Reinforced Calcium Phosphate Cement, Artif, Organs, 2000,24 (3): 212-216);
3.Gonten adopt fleece to strengthen bone cement, try hard to reach the instructions for use of heavy burden position.
The enhancing body that said method adopted is not all degraded in human body, remains in after the operation in the human body and can produce adverse influence to human body; If by operation taking-up once more, then increased patient's misery, also increase the operation burden simultaneously and infected probability.Seek a kind of new reinforced effects good, can vivo degradation and the enhancing body of good biocompatibility just become the key of enhancing modified CPC.
Mainly comprise polyester and poly-peptide two big classes at good biocompatibility, degradable macromolecular material, the polyesters biodegradable polymer comprises polylactic acid, pla-pcl etc., wherein extensive with polylactic acid-based research, but polylactic acid pair cell affinity is relatively poor, degradation in vivo can produce the acids catabolite, make a certain proportion of patient produce aseptic inflammation, vivo degradation procedural strength attenuation process is too fast simultaneously, is difficult to control.
Poly-peptide is the material that is polymerized by a plurality of aminoacid, and good biocompatibility and degradation property are arranged.Its degradation speed can be controlled by changing molecular backbone and side-chain structure; Poly-peptide also has good mechanical property simultaneously, for example exceeds 1 times (Kim H., Tehan Hwahakhoe Chi1990,34,203) with the intensity of the fine protein glue of the enhanced blood of synthesize polypeptide than the intensity of the fine protein glue of simple blood; In addition, poly-peptide has also obtained using more widely aspect sustained release pharmaceutical formulation, change the chemical constitution of the poly-γ-benzyl of poly-peptide main chain-L-glutamate by the method for copolymerization as the people such as Markland of the U.S., thereby obtain the poly-peptide carrier (MarklandP. of different slow release effects, Int.J.Pharm.1999,178,183); Poly-in addition peptide can form the core-shell structure of micellelike under certain condition, its size about 0.1 micron, shell with check medicine different suctions, slow releasing function arranged, can be used as slow releasing pharmaceutical carrier use (Cho C., Polymer 1999,40,6769).
Excellent biological compatibility, degradability and biomechanical property that poly-peptide is had, and the characteristics such as core-shell structure that can form micellelike under certain condition make poly-peptide can perform well in the enhancing modified of calcium phosphate bone cement CPC, are that a kind of calcium phosphate up-and-coming, function admirable strengthens body.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of novel poly-peptide/calcium phosphate composite bone cement and preparation method thereof, to overcome existing in human body, not the degrading that body exists that strengthen, remain in the interior meeting of human body after the operation to the defective that human body has a negative impact, can satisfy the operation instructions for use better.
Design of the present invention is such:
The present invention develop and the calcium phosphate inorganic-bone cement basis of extensive use on, according to bionical natural structure, to have good biocompatibility and degradability, to have the synthetic graininess of certain biomechanical property, Powdered and thread poly-peptide and a calcium phosphate bone cement compound, thereby realize that organic-inorganic is compound, improve the strength of materials.Behind composite implant into body corresponding site, can partly satisfy of the requirement of human body heavy burden position to intensity.
According to clinical use to the different requirements in degradation rate ground, regulate degradation speed by the chemical constitution that changes poly-peptide molecule main chain, side chain, simultaneously can also be written into active factors or medicine, numerator self-assembly technique by under certain condition makes supermolecule nano core-shell structure material, make its embedding bioactie agent or medicine, reach the purpose of filling reparation, induced osteogenesis and Drug therapy.And regulate by master chain chemical constitution, solved the nano combined interface problem of material, become the toughness reinforcing organic/inorganic composite material of the enhancing with special performance, have the application prospect that the very wide scope of application is become reconciled.
The detailed technical scheme of the present invention is as described below:
The said poly-peptide/calcium phosphate composite bone cement of the present invention comprises the compound phosphoric acid calcium salt and strengthens the poly-peptide enhancing body of toughness reinforcing effective dose.
Its preferred ingredients and weight percent content comprise:
Conventional calcium phosphate bone cement 80～99.9%
Poly-peptide strengthens body 0.1～20%
According to the present invention, also can in poly-peptide, add the medicine and the active factors of treatment effective dose, the addition of active factors or medicine is counted with poly-peptide total amount:
Medicine 0.5～10%
Active factors 0.01～5%
Said compound phosphoric acid calcium salt is by the blended by a certain percentage mixture of several calcium phosphate, can be by (US5525148, US5545254) disclosed method preparation, can be a kind of in calcium phosphate (α type or the β type) tetracalcium phosphate (TECP) or both mixture, contain OCP in addition, calcium hydrogen phosphate (has water of crystallization or does not have water of crystallization, DCPD or DCPA), hydroxyapatite, fluor-apatite, a kind of in the calcium pyrophosphate or their mixture, wherein synthos particles of powder size should be less than 10 microns, generally at 0.01～10 micron.
Said poly-peptide strengthens body and is meant granule, powder or thread poly-peptide, block copolymer and graft copolymer that poly-peptide is made up of stiff backbone and flexible side-chains.The poly-peptide segment of the rigidity of being addressed is selected poly-γ-benzyl-L-glutamate, poly-β-phenethyl-L-aspartic acid, poly-γ-ester group-L-glutamate for use; Wherein γ-benzyl-the L-glutamate is good to gather; The soft segment of being addressed is selected water miscible polyethylene glycol oxide (PEO), polylactic acid etc. for use, is good with polyethylene glycol oxide wherein;
The bioactie agent of being addressed is meant bone morphogenetic protein (BMP), the inverting biological factor (TGF-β), basic fibroblast growth factor (bFGF), BMP (OGP); Be good wherein with BMP.
Said medicine comprises one or more in antineoplastic agent or the antibiotic.
The preparation method of novel poly-peptide/calcium phosphate composite bone cement of the present invention comprises the steps:
(1) preparation of granule, powder or thread poly-peptide: the initiator of selecting different molecular weight for use, adopt active anionic polymerization, poly-(the r-benzene methyl-L-glutamic acid) of synthetic different molecular weight (PBLG) and the grafting or the block copolymer of PBLG and polyethylene glycol oxide (PEO), this copolymer can be self-assembled into nano-micelle in aqueous solution.The shell that the macromolecule flexible chain is formed makes micelle have water solublity, and the poly-peptide nuclear of internal layer has hydrophobic property, can be used as the carrier of medicine, active factors, obtains granule or Powdered poly-peptide after the polymer drying.Also can again PEO be grafted on the PBLG earlier with the spinning of PBLG fluid;
(2) then with granule, powder or thread poly-peptide and compound phosphoric acid calcium salt mixing and stirring, be poly-peptide/calcium phosphate composite bone cement of the present invention.
Poly-peptide of the present invention/calcium phosphate composite bone cement can implant after adding firming agent.
The firming agent of being addressed is normal saline or other saline solution, and ratio and poly-peptide/calcium phosphate composite bone cement mix homogeneously in solid-to-liquid ratio 2: 1～5: 1 (weight) reconcile into pastel, can implant.Pastel also can solidify the firming body that the back forms in external 37 ℃, 100% humidity environment.
Said other saline solution comprise aqueous phosphatic.
Poly-peptide nano-micelle modification CPC of the present invention has very significant advantage:
Introduce poly-peptide in complex calcium phosphate, do not change the solidified voluntarily characteristic of calcium phosphate bone cement, be 3 to 20 minutes hardening time; Do not change and solidify the composition that the back hydrated product is mainly hydroxyapatite; Improved the comprcssive strength of solidifying the back calcium phosphate bone cement, comprcssive strength is greater than 80MPa, and bending strength is greater than 20MPa.Because the self assembly core-shell structure of poly-peptide, can be written into active factors and medicine, improve the controlled release properties and the induced osteogenesis activity of material, the organic/inorganic composite material of Gou Jianing can be degraded simultaneously, new bone formation is followed in the degraded of material, so have fabulous application prospect.
Description of drawings
Fig. 1 is drug microcapsule/CPC bone cement slow release figure.
The specific embodiment
Further illustrate content of the present invention below in conjunction with example, but these examples do not limit protection scope of the present invention.
Embodiment 1
Take by weighing the particle diameter that contains calcium hydrogen phosphate, tetracalcium phosphate and hydroxyapatite compound phosphoric acid calcium salt powder 10g less than 10 μ m, poly-peptide powder 1g composition mixture, add normal saline 5 grams with its furnishing pasty state, making batten solidifies, be 15min setting time, comprcssive strength reaches 95MPa, satisfies the part requirement of strength at human body heavy burden position.
Embodiment 2
Take by weighing the particle diameter that contains calcium hydrogen phosphate, tetracalcium phosphate and hydroxyapatite mixed phosphate calcium salt powder 10g less than 10 μ m, poly-peptide suspension 1 composition mixture, add normal saline 4 grams with its furnishing pasty state, making batten solidifies, be 20min setting time, comprcssive strength reaches 90MPa, satisfies the part requirement of strength at human body heavy burden position.
Embodiment 3
Take by weighing the particle diameter that contains calcium hydrogen phosphate, tetracalcium phosphate and hydroxyapatite mixed phosphate calcium salt powder 10g less than 10 μ m, thread poly-peptide 1g composition mixture, add normal saline 3 grams with its furnishing pasty state, making batten solidifies, be 17min setting time, comprcssive strength reaches 120MPa, satisfies the part requirement of strength at human body heavy burden position.
Embodiment 4
Take by weighing the particle diameter that contains calcium hydrogen phosphate, tetracalcium phosphate and hydroxyapatite mixed phosphate calcium salt powder 10g less than 10 μ m, poly-peptide particles 1g composition mixture, add aqueous phosphatic 5 grams with its furnishing pasty state, making batten solidifies, be 17min setting time, comprcssive strength reaches 100MPa, satisfies the part requirement of strength at human body heavy burden position.
Embodiment 5
Take by weighing and contain calcium hydrogen phosphate, the particle diameter of tetracalcium phosphate and hydroxyapatite is less than the mixed phosphate calcium salt powder 10g of 10 μ m, the poly-peptide micelle 1g composition mixture that contains the antibiotic cefradine, add normal saline 5 grams with its furnishing pasty state, making batten solidifies, be 17min setting time, comprcssive strength reaches 100MPa, satisfy the part requirement of strength at human body heavy burden position, material is loaded with antibiotic simultaneously, can in human body, continue slow release valid density medicine in 8 weeks, see Fig. 1, realize keeping partial high concentration and lower in the concentration of whole body, reduce toxic and side effects, improve therapeutic effect.Obvious for treatment, effect after the chronic osteomyelitis processing.
Embodiment 6
Take by weighing the particle diameter that contains calcium hydrogen phosphate, tetracalcium phosphate and hydroxyapatite mixed phosphate calcium salt powder 10g less than 10 μ m, contain the recombinate poly-peptide micelle 1g composition mixture of BMP-2 of active factors people, add normal saline 5 grams with its furnishing pasty state, making batten solidifies, be 17min setting time, comprcssive strength reaches 80MPa, satisfies the part requirement of strength at human body heavy burden position.Material is implanted the back because induced osteogenesis effect, the material degradation speed of BMP are obviously accelerated simultaneously, has quickened the formation of new bone.The implantation rabbit femoral had in interior 3 months clearly measures the callus generation, and material degradation is fairly obvious during half a year, and material is degraded substantially in the time of 1 year, new osteogenesis.
Embodiment 7
Take by weighing and contain calcium hydrogen phosphate, the particle diameter of tetracalcium phosphate and hydroxyapatite is less than the mixed phosphate calcium salt powder 10g of 10 μ m, with the poly-peptide micelle 1g composition mixture that contains antitumor drug Ismipur (6-MP) medicine, add normal saline 4 grams with its furnishing pasty state, making batten solidifies, be 22min setting time, comprcssive strength reaches 95MPa, satisfy the part requirement of strength at human body heavy burden position, main is to implant this composite behind the bone tumour resection, can make 6-MP concentration around the osseous tissue higher and systemic concentrations is lower, reduce toxic and side, improved local use position therapeutic effect, thereby effectively suppressed the recurrence of tumor.
Claims (13)
1. a poly-peptide/calcium phosphate composite bone cement is characterized in that being made up of the calcium phosphate bone cement of routine and the poly-peptide of poly-peptide enhancing body of the toughness reinforcing effective dose of enhancing.
2. cement according to claim 1 is characterized in that its component and weight percent content comprise:
Conventional bone cement 80～99.9%
Poly-peptide strengthens body 0.1～20%
3. cement according to claim 2 is characterized in that also comprising the medicine and the active factors for the treatment of effective dose in the poly-peptide enhancing body.
4. cement according to claim 3 is characterized in that the addition of active factors or medicine is counted with poly-peptide total amount:
Medicine 0.5～10%
Active factors 0.01～5%
5. according to claim 1,2,3 or 4 described cement, it is characterized in that said compound phosphoric acid calcium salt is by the blended by a certain percentage mixture of several ultra-fine calcium phosphate.
6. cement according to claim 5 is characterized in that, said compound phosphoric acid calcium salt is calcium phosphate, tetracalcium phosphate, OCP, calcium hydrogen phosphate, hydroxyapatite, fluor-apatite, a kind of in the calcium pyrophosphate or and composition thereof.
7. cement according to claim 1 is characterized in that, said poly-peptide strengthens body and is meant granule, powder or thread poly-peptide, block copolymer and graft copolymer that poly-peptide is made up of stiff backbone and flexible side-chains.
8. cement according to claim 7 is characterized in that, the poly-peptide segment of the rigidity of being addressed is selected poly-γ-benzyl-L-glutamate, poly-β-phenethyl-L-aspartic acid, poly-γ-ester group-L-glutamate for use; Wherein γ-benzyl-the L-glutamate is good to gather; The soft segment of being addressed is selected water miscible polyethylene glycol oxide (PEO), polylactic acid etc. for use, is good with polyethylene glycol oxide wherein;
9. cement according to claim 1, it is characterized in that the bioactie agent of being addressed is meant bone morphogenetic protein (BMP) series, the inverting biological factor (TGF-β), basic fibroblast growth factor (bFGF), BMP (OGP), insulin like growth factor (IGF).
10. cement according to claim 4 is characterized in that, bioactie agent is BMP series, TGF-β, bFGF, OGP, IGF.
11. cement according to claim 4 is characterized in that, said medicine comprises one or more in antineoplastic agent or the antibiotic.
12. the preparation method according to claim 1,2 or 3 described cement is characterized in that, comprises the steps:
(1) preparation of granule, powder or thread poly-peptide: in aqueous solution, will gather the peptide self-assembled nano micelle or the calendering spinning obtain thread poly-peptide;
(2) then with granule, powder or thread poly-peptide and compound phosphoric acid calcium salt, firming agent mixing and stirring, be poly-peptide/calcium phosphate composite bone cement of the present invention.
13. the preparation method according to each described cement of claim 4～11 is characterized in that, comprises the steps:
(1) preparation of granule, powder or thread poly-peptide: will gather that the peptide self assembly contains medicine or/and the nano-micelle of active factors or calendering spinning obtain thread poly-peptide;
(2) then with granule, powder or thread poly-peptide and compound phosphoric acid calcium salt, firming agent mixing and stirring, be poly-peptide/calcium phosphate composite bone cement of the present invention.
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| CN 03115008 CN1446590A (en) | 2003-01-21 | 2003-01-21 | New type cement with composite polypeptide/calcium phosphate being as framework |
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| CN 03115008 CN1446590A (en) | 2003-01-21 | 2003-01-21 | New type cement with composite polypeptide/calcium phosphate being as framework |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100366302C (en) * | 2006-09-14 | 2008-02-06 | 清华大学 | Mineralized polypeptide material in use for repairing bones, and preparation method |
| CN101053673B (en) * | 2007-04-20 | 2010-11-10 | 西安交通大学 | High strength and tenacity degradable strontium calcium superphosphate composite bone cement and its preparation method |
| CN101613524B (en) * | 2009-07-14 | 2011-03-16 | 中国科学院上海硅酸盐研究所 | Triblock copolymer PEO-PPO-PEO/calcium phosphate nanometer composite material and preparation method thereof |
| CN101623266B (en) * | 2009-07-24 | 2012-08-08 | 中国科学院上海硅酸盐研究所 | Calcium phosphate/block copolymer composite porous nanoparticles and preparation method thereof |
| CN103025360A (en) * | 2010-05-24 | 2013-04-03 | 犹他大学研究基金会 | Reinforced adhesive complex coacervates and methods of making and using thereof |
| CN103179992A (en) * | 2010-11-12 | 2013-06-26 | 犹他大学研究基金会 | Simple adhesive coacervates and methods of making and using thereof |
| US9272069B2 (en) | 2008-01-24 | 2016-03-01 | University Of Utah Research Foundation | Adhesive complex coacervates and methods of making and using thereof |
| TWI601536B (en) * | 2016-09-22 | 2017-10-11 | 國立清華大學 | Sequentially decomposable polypeptide-based nanocarriers with shell and preparation thereof |
| US9913926B2 (en) | 2008-01-24 | 2018-03-13 | University Of Utah Research Foundation | Adhesive complex coacervates and method of making and using thereof |
| US9913927B2 (en) | 2014-07-14 | 2018-03-13 | University Of Utah Research Foundation | In situ solidifying complex coacervates and methods of making and using thereof |
| US10077324B2 (en) | 2013-02-06 | 2018-09-18 | Kci Licensing, Inc. | Polymers, preparation and use thereof |
| CN115350326A (en) * | 2022-10-20 | 2022-11-18 | 四川大学华西医院 | Anti-infection function enhanced antibiotic bone cement and preparation method and application thereof |
| US11896234B2 (en) | 2018-01-26 | 2024-02-13 | Fluidx Medical Technology, Llc | Apparatus and method of using in situ solidifying complex coacervates for vascular occlusion |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100366302C (en) * | 2006-09-14 | 2008-02-06 | 清华大学 | Mineralized polypeptide material in use for repairing bones, and preparation method |
| CN101053673B (en) * | 2007-04-20 | 2010-11-10 | 西安交通大学 | High strength and tenacity degradable strontium calcium superphosphate composite bone cement and its preparation method |
| US9272069B2 (en) | 2008-01-24 | 2016-03-01 | University Of Utah Research Foundation | Adhesive complex coacervates and methods of making and using thereof |
| US10517987B2 (en) | 2008-01-24 | 2019-12-31 | University Of Utah Research Foundation | Adhesive complex coacervates and methods of making and using thereof |
| US9913926B2 (en) | 2008-01-24 | 2018-03-13 | University Of Utah Research Foundation | Adhesive complex coacervates and method of making and using thereof |
| CN101613524B (en) * | 2009-07-14 | 2011-03-16 | 中国科学院上海硅酸盐研究所 | Triblock copolymer PEO-PPO-PEO/calcium phosphate nanometer composite material and preparation method thereof |
| CN101623266B (en) * | 2009-07-24 | 2012-08-08 | 中国科学院上海硅酸盐研究所 | Calcium phosphate/block copolymer composite porous nanoparticles and preparation method thereof |
| US9867899B2 (en) | 2010-05-24 | 2018-01-16 | University Of Utah Research Foundation | Reinforced adhesive complex coacervates and methods of making and using thereof |
| CN103025360A (en) * | 2010-05-24 | 2013-04-03 | 犹他大学研究基金会 | Reinforced adhesive complex coacervates and methods of making and using thereof |
| US10653813B2 (en) | 2010-05-24 | 2020-05-19 | University Of Utah Research Foundation | Reinforced adhesive complex coacervates and methods of making and using thereof |
| CN103179992A (en) * | 2010-11-12 | 2013-06-26 | 犹他大学研究基金会 | Simple adhesive coacervates and methods of making and using thereof |
| US9999700B1 (en) | 2010-11-12 | 2018-06-19 | University Of Utah Research Foundation | Simple coacervates and methods of use thereof |
| US9421300B2 (en) | 2010-11-12 | 2016-08-23 | University Of Utah Research Foundation | Simple coacervates and methods of use thereof |
| US9173971B2 (en) | 2010-11-12 | 2015-11-03 | University Of Utah Research Foundation | Simple adhesive coacervates and methods of making and using thereof |
| US10077324B2 (en) | 2013-02-06 | 2018-09-18 | Kci Licensing, Inc. | Polymers, preparation and use thereof |
| US9913927B2 (en) | 2014-07-14 | 2018-03-13 | University Of Utah Research Foundation | In situ solidifying complex coacervates and methods of making and using thereof |
| US10369249B2 (en) | 2014-07-14 | 2019-08-06 | University Of Utah Research Foundation | In situ solidifying complex coacervates and methods of making and using thereof |
| US10729807B2 (en) | 2014-07-14 | 2020-08-04 | University Of Utah Research Foundation | In situ solidifying solutions and methods of making and using thereof |
| US11471557B2 (en) | 2014-07-14 | 2022-10-18 | University Of Utah Research Foundation | In situ solidifying solutions and methods of making and using thereof |
| TWI601536B (en) * | 2016-09-22 | 2017-10-11 | 國立清華大學 | Sequentially decomposable polypeptide-based nanocarriers with shell and preparation thereof |
| US11896234B2 (en) | 2018-01-26 | 2024-02-13 | Fluidx Medical Technology, Llc | Apparatus and method of using in situ solidifying complex coacervates for vascular occlusion |
| CN115350326A (en) * | 2022-10-20 | 2022-11-18 | 四川大学华西医院 | Anti-infection function enhanced antibiotic bone cement and preparation method and application thereof |
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