Please wait a minute...
Friction  2022, Vol. 10 Issue (2): 232-246    doi: 10.1007/s40544-020-0437-5
Research Article     
Gelatin-based composite hydrogels with biomimetic lubrication and sustained drug release
Kuan ZHANG1,2,Jielai YANG3,4,Yulong SUN1,Yi WANG1,Jing LIANG4,Jing LUO5,Wenguo CUI4,Lianfu DENG4,Xiangyang XU3,*(),Bo WANG2,*(),Hongyu ZHANG1,*()
1 State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing 100084, China
2 School of Chemical and Biological Engineering, Shandong University of Science and Technology, Qingdao 266590, China
3 Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
4 Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
5 Beijing Research Institute of Automation for Machinery Industry Co., Ltd., Beijing 100120, China
Download: PDF (30664 KB)      HTML
Export: BibTeX | EndNote (RIS)      

Abstract  

The occurrence of osteoarthritis is closely related to progressive and irreversible destruction of the articular cartilage, which increases the friction significantly and causes further inflammation of the joint. Thus, a scaffold for articular cartilage defects should be developed via lubrication restoration and drug intervention. In this study, we successfully synthesized gelatin-based composite hydrogels, namely GelMA-PAM-PMPC, with the properties of biomimetic lubrication and sustained drug release by photopolymerization of methacrylic anhydride modified gelatin (GelMA), acrylamide (AM), and 2-methacryloyloxyethyl phosphorylcholine (MPC). Tribological test showed that the composite hydrogels remarkably enhanced lubrication due to the hydration lubrication mechanism, where a tenacious hydration shell was formed around the zwitterionic phosphocholine headgroups. In addition, drug release test indicated that the composite hydrogels efficiently encapsulated an anti-inflammatory drug (diclofenac sodium) and achieved sustained release. Furthermore, the in vitro test revealed that the composite hydrogels were biocompatible, and the mRNA expression of both anabolic and catabolic genes of the articular cartilage was suitably regulated. This indicated that the composite hydrogels could effectively protect chondrocytes from inflammatory cytokine-induced degeneration. In summary, the composite hydrogels that provide biomimetic hydration lubrication and sustained local drug release represent a promising scaffold for cartilage defects in the treatment of osteoarthritis.



Key wordshydrogel      articular cartilage      zwitterionic polymer      hydration lubrication      drug delivery     
Received: 12 June 2020      Published: 17 January 2022
Fund:  National Natural Science Foundation of China(51675296);Shanghai Municipal Science Foundation(SYXF011803);Tsinghua University- Peking Union Medical College Hospital Initiative Scientific Research Program(20191080593);National Key R&D Program of China(2017YFC1103800);Foshan-Tsinghua Innovation Special Fund (FTISF), Research Fund of State Key Laboratory of Tribology, Tsinghua University, China(SKLT2020C11);Ng Teng Fong Charitable Foundation(202-276-132-13)
Corresponding Authors: Xiangyang XU,Bo WANG,Hongyu ZHANG     E-mail: xu664531@163.com;wb@sdust.edu.cn;zhanghyu@tsinghua.edu.cn
About author: Kuan ZHANG. He received his B.S. in chemical engineering and technology in 2016 from Hainan University. He is currently a joint master student in Tsinghua University. His research interests include biotribology and soft materials.|Jielai YANG. He is a Ph.D. student at Department of Orthopedics & Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine. His research focuses on the novel biomaterials for osteochondral regeneration and osteoarthritis management.|Xiangyang XU. He is director of foot and ankle surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. He is deputy director of foot and ankle surgery, Chinese Medical Association. He got his Ph.D. degree from Shanghai Medical University. His research focuses on diagnosis and treatment of diseases of the foot and ankle, with expertise in ankle instability and ankle osteoarthritis.|Bo WANG. He is a professor at College of Chemical and Biological Engineering, Shandong University of Science and Technology, China. He received his B.S. degree in Hainan University and Ph.D. degree in Zhejiang University, China. His research covers green chemistry, bio-catalysis, and asymmetric synthesis.|Hongyu ZHANG. He received his B.S. degree from Tianjin University, China (2005) and Ph.D. degree from University of Huddersfield, UK (2009). He is an associate professor at the State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, China. His research interests focus on the development of lubricating biomaterials such as nanoparticles, coatings, hydrogels, and electrospun nanofibers, which integrate the multi-disciplinary knowledge including biotribology, chemistry, materials science, and medicine to address clinical issues, e.g., osteoarthritis, anti-tissue/cell/ bacteria adhesion, bone tissue engineering, etc.
Cite this article:

Kuan ZHANG,Jielai YANG,Yulong SUN,Yi WANG,Jing LIANG,Jing LUO,Wenguo CUI,Lianfu DENG,Xiangyang XU,Bo WANG,Hongyu ZHANG. Gelatin-based composite hydrogels with biomimetic lubrication and sustained drug release. Friction, 2022, 10(2): 232-246.

URL:

http://friction.tsinghuajournals.com/10.1007/s40544-020-0437-5     OR     http://friction.tsinghuajournals.com/Y2022/V10/I2/232

GenesForward sequenceReverse sequence
Aggrecan5’-TGCAGGACCAGACCGTCAGATAC-3’5’-CGAGGCGTGTGGCGAAGAAC-3’
COL2A15’-TACTGGAGTGACTGGTCCTAAG-3’5’-AACACCTTTGGGACCATCTTTT-3’
MMP135’-AACACCTTTGGGACCATCTTTT-3’5’-GTCACACTTCTCTGGTGTTTTG-3’
ADAMTS55’-GGCAAATGTGTGGACAAAACTA-3’5’-GAGGTGCAGGGTTATTACAATG-3’
β-actin5’-CTACCTCATGAAGATCCTGACC-3’5’-CACAGCTTCTCTTTGATGTCAC-3’
Table 1 The primer sequences of the genes used in the study.
Fig. 1 Schematic illustration of gelatin-based composite hydrogels for the treatment of osteoarthritis with biomimetic lubrication and sustained drug release. (a) Synthesis of the composite hydrogels through photopolymerization. (b) Lubrication enhancement and chondroprotective potential of the hydrogels.
Fig. 2 Characterization of the composite hydrogels. 1H NMR spectrum of (a) gelatin and (b) GelMA. (c) FTIR spectrum of PMPC, GelMA, and GelMA-PAM-PMPC. (d) TGA curve, (e) relative volume, (f) swelling ratio of GelMA and GelMA-PAM-PMPC. Water contact angle, SEM image, pore distribution, EDS spectrum of (g, i, k, m) GelMA and (h, j, l, n) GelMA-PAM-PMPC. (o) Compression stress, and (p) drug release profile of GelMA and GelMA-PAM-PMPC.
Fig. 3 Lubrication property of composite hydrogels. (a) Schematic diagram showing the setup of the tribological test. Surface topography contour of (b) GelMA-PAM and (c) GelMA-PAM-PMPC. (d) COF of GelMA-PAM-PMPC with different MPC contents. COF of GelMA-PAM and GelMA-PAM-PMPC with (e) various normal loads, rotation frequency: 5 Hz and (f) various rotation frequencies, normal load: 0.5 N. (g) Schematic diagram showing the deformation of the hydrogels under applied normal load. Surface topography contour of (h) steel ball and (i) PDMS ball. COF-cycle curve for (j) steel contact pair and (k) PDMS contact pair. Inset figure shows the average COF calculated from different cycle intervals.
Fig. 4  In vitro cell viability and proliferation of the chondrocytes incubated with the GelMA and GelMA-PAM-PMPC hydrogels for 1, 3, and 5 days. Blank group: untreated chondrocytes. (a) Representative fluorescence images of the chondrocytes in live/dead cell staining assay. (b, c) Quantitative data of the (b) live and (c) dead cells summarized from the live/dead cell staining assay. (d) Phalloidin staining showing the fibrous actin of the cytoskeleton of the cells. (e) Cell cytotoxicity of the hydrogels examined with CCK-8 assay. The hydrogels are biocompatible with the chondrocytes. NS: no significance.
Fig. 5 RT-qPCR analysis showing the mRNA expression levels of anabolic genes (a, e) Aggrecan, (b, f) COL2A1, and catabolic genes (c, g) MMP13, (d, h) ADAMTS5 in IL-1β and TNF-α treated chondrocytes, which are incubated with the GelMA and GelMA-PAM-PMPC hydrogels. n = 3, *P < 0.05, **P < 0.01, compared with the blank group.
[1]   Ji X, Yan Y, Sun T, Zhang Q, Wang Y, Zhang M, Zhang H, Zhao X. Glucosamine sulphate-loaded distearoyl phosphocholine liposomes for osteoarthritis treatment: combination of sustained drug release and improved lubrication. Biomater Sci 7: 2716-2728 (2019)
[2]   Zheng Y, Yang J, Liang J, Xu X, Cui W, Deng L, Zhang H. Bioinspired hyaluronic acid/phosphorylcholine polymer with enhanced lubrication and anti-inflammation. Biomacromolecules 20: 4135-4142 (2019)
[3]   Wan L, Wang Y, Tang X, Sun Y, Luo J, Zhang H. Biodegradable lubricating mesoporous silica nanoparticles for osteoarthritis therapy. Friction 10(1): 68-79 (2022)
[4]   Tan X, Sun Y, Sun T, Zhang H. Mechanised lubricating silica nanoparticles for on-command cargo release on simulated surfaces of joint cavities. Chem Commun 55: 2593-2596 (2019)
[5]   Pan Y, Xiao C, Tan H, Yuan G, Li J, Li S, Jia Y, Xiong D, Hu X, Niu X. Covalently injectable chitosan/chondroitin sulfate hydrogel integrated gelatin/heparin microspheres for soft tissue engineering. Int J Polym Mater 70: 149-157 (2021)
[6]   Wang M, Chen J, Li W, Zang F, Liu X, Qin S. Paclitaxel- nanoparticles-loaded double network hydrogel for local treatment of breast cancer after surgical resection. Mater Sci Eng C Mater Biol Appl 114: 111046 (2020)
[7]   Liu Y, Xiong D. Self-healable polyacrylic acid-polyacrylamide- ferric ion dual-crosslinked hydrogel with good biotribological performance as a load-bearing surface. J Appl Polym Sci 137: 48499 (2019)
[8]   Chen K, Chen G, Wei S, Yang X, Zhang D, Xu L. Preparation and property of high strength and low friction PVA-HA/PAA composite hydrogel using annealing treatment. Mater Sci Eng C Mater Biol Appl 91: 579-588 (2018)
[9]   Gong J, Katsuyama Y, Kurokawa T, Osada Y. Double- network hydrogels with extremely high mechanical strength. Adv Mater 15: 1155-1158 (2003)
[10]   Han L, Liu K, Wang M, Wang K, Fang L, Chen H, Zhou J, Lu X. Mussel-inspired adhesive and conductive hydrogel with long-lasting moisture and extreme temperature tolerance. Adv Funct Mater 28: 1704195 (2018)
[11]   Gan D, Xu T, Xing W, Ge X, Fang L, Wang K, Ren F, Lu X. Mussel-inspired contact-active antibacterial hydrogel with high cell affinity, toughness, and recoverability. Adv Funct Mater 29: 1805964 (2019)
[12]   Liu K, Han L, Tang P, Yang K, Gan D, Wang X, Wang K, Ren F, Fang L, Xu X, et al. An anisotropic hydrogel based on mussel-inspired conductive ferrofluid composed of electromagnetic nanohybrids. Nano Lett 19: 8343-8356 (2019)
[13]   Wang J, Lin L, Cheng Q, Jiang L. A strong bio-inspired layered pnipam-clay nanocomposite hydrogel. Angew Chem Int Ed 51: 4676-4680 (2012)
[14]   Dai X, Zhang Y, Gao L, Bai T, Wang W, Cui Y, Liu W. A mechanically strong, highly stable, thermoplastic, and self- healable supramolecular polymer hydrogel. Adv Mater 27: 3566-3571 (2015)
[15]   Wang H, Zhou L, Liao J, Ning C, Tan G. Cell-laden photocrosslinked gelma-dexma copolymer hydrogels with tunable mechanical properties for tissue engineering. J Mater Sci Mater Med 25: 2173-2183 (2014)
[16]   Visser J, Gawlitta D, Benders K E, Malda J. Endochondral bone formation in gelatin methacrylamide hydrogel with embedded cartilage-derived matrix particles. Biomaterials 37: 174-182 (2015)
[17]   Yue K, Santiago G T, Alvarez M M, Tamayol A, Annabi N, Khademhosseini A. Synthesis, properties, and biomedical applications of gelatin methacryloyl (gelma) hydrogels. Biomaterials 73: 254-271 (2015)
[18]   Elomaa L, Keshi E, Sauer I M, Weinhart M. Development of GelMA/PCL and dECM/PCL resins for 3D printing of acellular in vitro tissue scaffolds by stereolithography. Mater Sci Eng C Mater Biol Appl 112: 110958 (2020)
[19]   Su R, Zihlmann C, Akbari M, Tang X, Khademhosseini A. Reduced graphene oxide-gelma hybrid hydrogels as scaffolds for cardiac tissue engineering. Small 12: 3677-3689 (2016)
[20]   Yuk H, Zhang T, Lin S, Parada G A, Zhao X. Tough bonding of hydrogels to diverse non-porous surfaces. Nat Mater 15: 190-196 (2016)
[21]   Hu X, Vatankhah-Varnoosfaderani M, Zhou J, Li Q, Sheiko S S. Weak hydrogen bonding enables hard, strong, tough, and elastic hydrogels. Adv Mater 27: 6899-6905 (2016)
[22]   Jahn S, Seror J, Klein J. Lubrication of articular cartilage. Annu Rev Biomed Eng 18: 235-258 (2016)
[23]   Seror J, Merkher Y, Kampf N, Collinson L, Day A J, Maroudas A, Klein J. Normal and shear interactions between hyaluronan-aggrecan complexes mimicking possible boundary lubricants in articular cartilage in synovial joints. Biomacromolecules 13: 3823-3832 (2012)
[24]   Wang Y, Sun Y, Gu Y, Zhang H. Articular cartilage-inspired surface functionalization for enhanced lubrication. Adv Mater Interfaces 6: 1900180 (2019)
[25]   Klein J. Hydration lubrication. Friction 1: 1-23 (2013)
[26]   Moro T, Takatori Y, Ishihara K, Konno T, Takigawa Y, Matsushita T, Chung U, Nakamura K, Kawaguchi H. Surface grafting of artificial joints with a biocompatible polymer for preventing periprosthetic osteolysis. Nat Mater 3: 829-836 (2004)
[27]   Kyomoto M, Moro T, Saiga K, Miyaji F, Kawaguchi H, Takatori Y, Nakamura K, Ishihara K. Lubricity and stability of poly(2-methacryloyloxyethyl phosphorylcholine) polymer layer on Co-Cr-Mo surface for hemi-arthroplasty to prevent degeneration of articular cartilage. Biomaterials 31: 658-668 (2010)
[28]   Kyomoto M, Moro T, Yamane S, Hashimoto M, Takatori Y, Ishihara K. Poly(ether-ether-ketone) orthopedic bearing surface modified byself-initiated surface grafting of poly(2- methacryloyloxyethyl phosphorylcholine). Biomaterials 34: 7829-7839 (2013)
[29]   Daniele M A, Adams A A, Naciri J, North S H, Ligler F S. Interpenetrating networks based on gelatin methacrylamide and PEG formed using concurrent thiol click chemistries for hydrogel tissue engineering scaffolds. Biomaterials 35: 1845-1856 (2014)
[30]   Liu B, Wang Y, Miao Y, Zhang X, Fan Z, Singh G, Zhang X, Xu K, Li B, Hu Z, et al. Hydrogen bonds autonomously powered gelatin methacrylate hydrogels with super-elasticity, self-heal and underwater self-adhesion for sutureless skin and stomach surgery and E-skin. Biomaterials 171: 83-96 (2018)
[31]   Brown L, Zhang H, Blunt L, Barrans S. Reproduction of fretting wear at the stem-cement interface in total hip replacement. Proc Inst Mech Eng Part H-J Eng Med 221: 963-971 (2007)
[32]   Zhang H, Zhang S, Luo J, Liu Y, Qian S, Liang F, Huang Y. Investigation of protein adsorption mechanism and biotribological properties at simulated stem-cement interface. J Tribol-Trans ASME 135: 032301 (2013)
[33]   Livak K J, Schmittgen T D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25: 402-408 (2001)
[34]   Yan Y, Sun T, Zhang H, Ji X, Sun Y, Zhao X, Deng L, Jin Q, Cui W, Santos H, et al. Euryale ferox seed-inspired superlubricated nanoparticles for treatment of osteoarthritis. Adv Funct Mater 29: 1807559 (2019)
[35]   Lin P, Zhang R, Wang X, Zhou F. Articular cartilage inspired bilayer tough hydrogel prepared by interfacial modulated polymerization showing excellent combination of high load-bearing and low friction performance. ACS Macro Lett 5: 1191-1195 (2016)
[36]   Shoaib T, Heintz J, Lopez-Berganza J A, Muro-Barrios R, Egner S A, Espinosa-Marzal R. Stick-slip friction reveals hydrogel lubrication mechanisms. Langmuir 34: 756-765 (2018)
[37]   Gombert Y, Simic R, Roncoroni F, Dubner M, Geue T, Spencer N D. Structuring hydrogel surfaces for tribology. Adv Mater Interfaces 6: 1901320 (2019)
[38]   Zhang X, Wang J, Jin H, Wang S, Song W. Bioinspired supramolecular lubricating hydrogel induced by shear force. J Am Chem Soc 140: 3186-3189 (2018)
[39]   Liu G, Cai M, Zhou F, Liu W. Charged polymer brushes- grafted hollow silica nanoparticles as a novel promising material for simultaneous joint lubrication and treatment. J Phys Chem B 118: 4920-4931 (2014)
[40]   Chen H, Sun T, Yan Y, Ji X, Sun Y, Zhao X, Qi J, Cui W, Deng L, Zhang H. Cartilage matrix-inspired biomimetic superlubricated nanospheres for treatment of osteoarthritis. Biomaterials 242: 119931 (2020)
[41]   Seror J, Zhu L, Goldberg R, Day A J, Klein J. Supramolecular synergy in the boundary lubrication of synovial joints. Nat Commun 6: 6497 (2015)
[42]   Ma S, Scaraggi M, Wang D, Zhou F. Stick-slip friction reveals hydrogel lubrication mechanisms. Adv Func Mater 25: 7366-7374 (2016)
[1] Jiawei LI,Luyao GAO,Rongnian XU,Shuanhong MA,Zhengfeng MA,Yanhua LIU,Yang WU,Libang FENG,Meirong CAI,Feng ZHOU. Fibers reinforced composite hydrogels with improved lubrication and load-bearing capacity[J]. Friction, 2022, 10(1): 54-67.
[2] Li WAN,Yi WANG,Xiaolong TAN,Yulong SUN,Jing LUO,Hongyu ZHANG. Biodegradable lubricating mesoporous silica nanoparticles for osteoarthritis therapy[J]. Friction, 2022, 10(1): 68-79.
[3] Weijun LI,Hao LIU,Yuanyuan MI,Miaoran ZHANG,Jinmiao SHI,Ming ZHAO,Melvin A. RAMOS,Travis Shihao HU,Jianxiong LI,Meng XU,Quan XU. Robust and conductive hydrogel based on mussel adhesive chemistry for remote monitoring of body signals[J]. Friction, 2022, 10(1): 80-93.
[4] JinJing LIAO,David W. SMITH,Saeed MIRAMINI,Bruce S. GARDINER,Lihai ZHANG. Investigation of role of cartilage surface polymer brush border in lubrication of biological joints[J]. Friction, 2022, 10(1): 110-127.
[5] Chaobao WANG,Xiuqin BAI,Conglin DONG,Zhiwei GUO,Chengqing YUAN,Anne NEVILLE. Designing soft/hard double network hydrogel microsphere/ UHMWPE composites to promote water lubrication performance[J]. Friction, 2021, 9(3): 551-568.
[6] Teruo MURAKAMI,Seido YARIMITSU,Kazuhiro NAKASHIMA,Yoshinori SAWAE,Nobuo SAKAI. Influence of synovia constituents on tribological behaviors of articular cartilage[J]. Friction, 2013, 1(2): 150-162.
[7] Jacob KLEIN. Hydration lubrication[J]. Friction, 2013, 1(1): 1-23.