HYDROGEL: RESPONSIVE STRUCTURES FOR DRUG DELIVERY
DOI:
https://doi.org/10.22159/ijap.2021v13i1.39507Keywords:
Stimuli-responsive, Smart hydrogel, Triggers, Environment-sensitive, Biocompatibility, BiodegradabilityAbstract
Hydrogels are water-swollen 3D networks made of polymers, proteins, small molecules, or colloids. They are porous in structure and entrap/encapsulate large amounts of therapeutic agents and biopharmaceuticals. Their unique properties like biocompatibility, biodegradability, sensitivity to various stimuli, and the ability to be easily conjugated with hydrophilic and hydrophobic drugs with a controlled-release profile make hydrogels a smart drug delivery system. Smart hydrogel systems with various chemically and structurally responsive moieties exhibit responsiveness to external stimuli including temperature, pH, ionic concentration, light, magnetic fields, electrical fields, and chemical and biological stimuli with selected triggers includes polymers with multiple responsive properties have also been developed elegantly combining two or more stimuli-responsive mechanisms. This article emphasized the types, features, and various stimuli systems that produce responsive delivery of drugs.
Downloads
References
Shivani PS, Ajeet G, Shilpa B, Pankaj G. Hydrogels: introduction, preparation, characterization, and applications. Int J Res Methodol 2015;1:47-71.
Sowjanya P, Boddu VK, Ajay BP. A review article on hydrogels. Int J Res Pharm Nano Sci 2013;2:548-53.
Navarra MA, Dal Bosco C, Serra Moreno J, Vitucci FM. Synthesis and characterization of cellulose-based hydrogels to be used as gel electrolytes. Membranes 2015;5:810-23.
Shen X, Shamshina JL, Berton P, Gurau G, Rogers RD. Hydrogels based on cellulose and chitin: fabrication, properties, and applications. Green Chemical 2016;18:53-75.
Colombo P. Swelling-controlled release in hydrogel matrices for oral route. Adv Drug Delivery Rev 1993;11:37-57.
Ahn S, Kasi RM, Kim SC, Sharma N, Zhou Y. Stimuli-responsive polymer gels. Soft Matter 2008;4:1151-7.
Peppas N, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm 2000;50:27-46.
Sun L, Huang WM, Ding Z, Zhao Y, Wang CC, Purnawali. Stimulus-responsive shape-memory materials. A review. Mater Des 2012;33:577-640.
Lin CC, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Delivery Rev 2006;58:1379-408.
Zaman M, Siddique W, Waheed S, Muhammad SS. A review: hydrogels, their applications, and polymers used for hydrogels. Int J Biol Pharm Allied Sci 2015;4:6581-603.
Zhu J, Marchant RE. Design properties of hydrogel tissue-engineering scaffolds: expert Rev Med Devices 2011;8:607-26.
Zhu J. Bioactive modification of poly (ethylene glycol) hydrogels for tissue engineering.Biomaterials 2010;31:4639-56.
Chung HK, Park TG. Self-assembled and nanostructured hydrogels for drug delivery and tissue engineering. Nano Today 2009;4:429-37.
Liu SQ, Tay R, Khan M, Ee PLR, Hedrick JL, Yang YY. Synthetic hydrogels for controlled stem cell differentiation. Soft Matter 2010;6:67-81.
Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA. Hydrogels in regenerative medicine. Adv Mater 2009;21:3307-29.
Nguyen TK, West JL. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials 2002;23:4307-14.
Hoffman AS. Hydrogels for biomedical applications. Adv Drug Delivery Rev 2002;43:3-12.
Kharkar PM, Kiick KL, Kloxin AM. Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem Soc Rev 2013;42:7335-72.
Bajpai AK, SK Shukla, S Bhanu, S Kankane. Responsive polymers in controlled drug delivery. Prog Polym Sci 2008;33:1088-118.
Gupta P, K Vermani, S Garg. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discovery Today 2002;7:569-79.
Anal KA. Stimuli-induced pulsatile or triggered release delivery systems for bioactive compounds. Recent Patents Endocrine Metab Immune Drug Discovery 2007;1:83–90.
Onofrei MD, Filimon A. Cellulose-based hydrogels: designing concepts, properties, and perspectives for biomedical and environmental applications. Material Science;2016. p. 108-20.
Jarry C, Leroux JC, Haeck J, Chaput C. Irradiating or autoclaving chitosan/polyol solutions: effect on thermogelling chitosan-β-glycerophosphate systems. Chem Pharm Bull 2002;50:1335-40.
GilES, SMHudson. Stimuli-responsive polymers and their bioconjugates.Prog Polym Sci 2004;29:1173–222.
Qiu Y, K Park. Environment-sensitive hydrogels for drug delivery. Adv Drug Delivery Rev 2012;64:49-60.
Chaterji S, IK Kwon, K Park. Smart polymeric gels: redefining the limits of biomedical devices. Prog Polym Sci 2007;32:1083-122.
Cheng X, Y Jin, T Sun, R Qi, B Fan, H Li. Oxidation-and thermo-responsive poly (N-isopropylacrylamide-co-2-hydroxyethyl acrylate) hydrogels cross-linked via diselenides for controlled drug delivery. RSC Adv 2015;5:4162-70.
Nagam SP, Jyothi AN, Poojitha J, Aruna S, Nadendla RR. A comprehensive review on hydrogels. Int J Curr Pharm Res2016;8:19-23.
Z Zhang, J Ni, L Chen, L Yu, J Xu, J Ding. Biodegradable and thermoreversible PCLA–PEG–PCLA hydrogel as a barrier for prevention of postoperative adhesion. Biomaterials 2011;32:4725–36.
Chatterjee, Sudipta, Hui, Patrick. Stimuli-responsive hydrogels. An Interdisciplinary Overview; 2019. p. 7-17.
Serra L, Domenech J, Peppas NA. Drug transport mechanisms and release kinetics from molecularly designed poly (acrylic acid-g-ethylene glycol) hydrogels. Biomaterials 2006;27:5440-51.
N Sood, A Bhardwaj, S Mehta, A Mehta. Stimuli-responsive hydrogels in drug delivery and tissue engineering. Drug Delivery 2016;23:748-70.
J Wiedemair, MJ Serpe, J Kim, JF Masson. In-situ AFM studies of the phase-transition behavior of single thermoresponsive hydrogel particles. Langmuir 2007;23:130-7.
Auge A, Zhao Y. What determines the volume transition temperature of UCST acrylamide–acrylonitrile hydrogels. RSC Adv 2016;6:70616-23.
SannaR, Fortunati E,AlzariV, NuvoliD, TerenziA. Poly (N-vinylcaprolactam) nanocomposites containing nanocrystalline cellulose. a green approach to thermoresponsive hydrogels. Cellulose 2013;20:2393-402.
Kumar A, Srivastava A, Galaev IY, Mattiasson B. Smart polymers: physical forms and bioengineering applications. Prog Polym Sci 2007;32:1205-37.
Ge J, Neofytou E, Cahill TJ, Beygui R. Drug release from electric-field-responsive nanoparticles. ACS Nano 2012;6:227-33.
Shang J, Shao Z, Chen X. Electrical behavior of a natural polyelectrolyte hydrogel: chitosan/carboxymethylcellulose hydrogel. Biomaterials 2008;9:1208-13.
Kim J, Wang N, Chen Y, Lee SK, Yun GY. The electroactive-paper actuator is made with cellulose/NaOH/urea and sodium alginate. Cellulose 2007;14:217-23.
Zhao W, Odelius K, Edlund U, Zhao C, Albertsson AC. In situ synthesis of magnetic field-responsive hemicellulose hydrogels for drug delivery. Biomacromolecules 2015;16:2522-8.
Hua MY, Liu HL, Yang HW, Chen. The effectiveness of a magnetic nanoparticle-based delivery system for BCNU in the treatment of gliomas. Biomaterials 2011;32:516-27.
Liu, Zhongyang, Liu, Jianheng, Cui, Xiang, Wang. Recent advances on magnetic sensitive hydrogels in tissue engineering.Frontiers Chem 2020;8:124.
Cai K, Luo Z, Hu Y, Chen X, Liao. Magnetically triggered reversible controlled drug delivery from microfabricated polymeric multi-reservoir devices. Adv Materials 2009;21:4045-9.
AlvarezLorenzo C, Bromberg L, Concheiro A. Light-sensitive intelligent drug delivery systems. Photochem Photobiol 2009;85:848-60.
Zhao YL, Stoddart JF. Azobenzene-based light-responsive hydrogel system.Langmuir 2009;25:8442-6.
Suzuki T Tanaka. Phase transition in polymer gels induced by visible light. Nature 1990;346:345-7.
Suzuki T Ishii, Y Maruyama. Optical switching in polymer gels. J Appl Phys 1996;80:131-6.
T Manouras, M Vamvakaki. Field responsive materials: photo-, electro-, magnetic-and ultrasound-sensitive polymers. Polym Chem 2017;8:74-96.
Boissenot T, Bordat A, Fattal E, Tsapis N. Ultrasound triggered drug delivery for cancer treatment using drug delivery systems. From theoretical considerations to practical applications. J Controlled Release 2016;241:144-63.
Ahmadi F, McLoughlin IV, Chauhan S. Bioeffects and safety of low-intensity, low-frequency ultrasonic exposure.Prog Biophys Mol Biol 2012;108:119-38.
Huang D, Sun M, Bu Y, Luo F, Lin C, Lin Z, et al. Microcapsule-embedded hydrogel patches for ultrasound responsive and enhanced transdermal delivery of diclofenac sodium. J Mater Chem B 2019;7:2330-7.
Pereira TA, Ramos DN, Lopez RFV. Hydrogel increases localized transport regions and skin permeability during low-frequency ultrasound treatment. Sci Rep 2017;7:1-10.
Taghizadeh B, S Taranejoo, SA Monemian, ZS. Classification of stimuli-responsive polymers as anticancer drug delivery systems. Drug Delivery 2015;22:145-55.
Jianqi F, Lixia G. PVA/PAA thermo-crosslinking hydrogel fiber: preparation and pH-sensitive properties in an electrolyte solution. Eur Polymer J 2002;38:1653-8.
Podual K, FJ Doyle, NA Peppas. Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase.Polymer 2000;41:3975-83.
Lalita Devi, Punam Gaba. Hydrogel: an updated primer. J Crit Rev 2019;6:1-10.
Risbud MV, AA Hardikar, SV Bhat. pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as a controlled release system for antibiotic delivery.J Controlled Release 2000;68:23-30.
Oishi M, Nagasaki Y. Synthesis, characterization, and biomedical applications of core shell-type stimuli-responsive nanogels nanogel composed of poly [2-(N, N-diethylamino) ethyl methacrylate] core and PEG tethered chains. React Function Polymer 2007;67:1311-29.
V Stadler, R Kirmse, M Beyer, F Breitling. PEGMA/MMA copolymer graftings: generation, protein resistance, and a hydrophobic domain. Langmuir 2008;24:8151-7.
L Rivas, SA Pooley, ED Pereira, A Maureira. Water-soluble polyelectrolytes with metal ion removal ability by using the liquid phase based retention technique. Macromolecular. Symp 2006;116:245-6.
Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discovery Today 2002;7:569-79.
Peppas NA, KM Wood, JO Blanchette. Hydrogels for oral delivery of therapeutic proteins. Expert Opinion Biol Ther 2004;4:881-7.
Cevik O, D Gidon, S Kizilel. Visible-light-induced synthesis of pH-responsive composite hydrogels for controlled delivery of the anticonvulsant drug pregabalin. Acta Biomaterialia 2015;11:151-61.
L Xu,L Qiu,Y Sheng, Y Sun, L Deng, X Li. Biodegradable pH-responsive hydrogels for controlled dual-drug release. J Mater Chem B 2018;6:510–7.
E Cabane, X Zhang, K Langowska, CG Palivan. Stimuli-responsive polymers and their applications in nanomedicine.Biointerphases 2012;7:9.
P Li, S Wang, H Chen, S Zhang, S Yu Y. A novel ion-activated in situ gelling ophthalmic delivery system based on κ-carrageenan for acyclovir.Drug Dev Ind Pharm 2018;44:829-36.
Bawa P, Pillay V, Choonara YE, du Toit LC. Stimuli-responsive polymers and their applications in drug delivery. Biomed Mater 2009;4:022001.
R Chandrawati. Enzyme-responsive polymer hydrogels for therapeutic delivery. Exp Biological Med 2016;241:972-9.
Podual K, Doyle F, Peppas N. Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase. Polymer 2000;41:3975–83.
Ehrick JD, Luckett MR, Khatwani S, Wei Y. Glucose responsive hydrogel networks based on protein recognition.Macromolecular Biosci 2009;9:864-8.
Kim JJ, Park K. Modulated insulin delivery from glucose-sensitive hydrogel dosage forms. J Controlled Release 2001;77:39-47.
Traitel T, Cohen Y, Kost J. Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions. Biomaterials 2000;21:1679-87.
T Miyata, N Asami, T Uragami. A reversibly antigen-responsive hydrogel. Nature 1999;399:766-9.
T Miyata, T Uragami, K Nakamae. Biomolecule sensitive hydrogels. Adv Drug Delivery Rev 2002;54:79-98.
Lim SH, Kathuria H, Tan JJY, Kang L. 3D printed drug delivery and testing systems a passing fad or the future. Adv Drug Delivery Rev 2018;132:139-68.
Al-Kinani AA, Zidan G, Elsaid N, Seyfoddin A. Ophthalmic gels: past, present and future. Adv Drug Delivery Rev 2018;126:113-26.
Wang X, Qin XH, Hu C, Terzopoulou A. 3D printed enzymatically biodegradable soft helical microswimmers. Adv Funct Mater 2018;28:1-8.
Daly AC, Freeman FE, Gonzalez Fernandez T. 3D bioprinting for cartilage and osteochondral tissue engineering. Adv Healthcare Mater 2017;6:1-20.
Peppas NA, Lowman AM. Hydrogels: In.Controlled drug delivery. Mathiowitz E. editor. Encyclopedia; 1999. p. 397-418.
Vo TN, Kasper FK, Mikos AG. Strategies for controlled delivery of growth factors and cells for bone regeneration. Adv Drug Delivery Rev 2012;64:1292-309.
Ebara M, Kotsuchibashi Y, Hoffman JM. Smart biomaterials. Berlin: Springer NIMS Monographs; 2014. p. 1-7.
Surojeet Das, Vivek Kumar. Recent advances in hydrogels for biomedical applications. Asian J Pharm Clin Res2018;11:62-8.
Vihola H, Laukkanen A, Tenhu H, Hirvonen J. Drug release characteristics of physically cross-linkedthermosensitive poly(N-vinylcaprolactam) hydrogel particles. J Pharm Sci 2008;97:4783-93.
Tan R, She Z, Wang M, Fang Z, Liu Y. Thermo-sensitive alginate-based injectable hydrogel fortissue engineering. Carbohydr Polym 2012;87:1515-21.
Gong C, Qi T, Wei X, Qu Y. Thermosensitive polymeric hydrogels as drug delivery systems. Curr Med Chem 2013;20:79-94.
Ge J, Neofytou E, Cahill TJ, Beygui RE, Zare RN. Drug release from electric-field-responsive nanoparticles. ACS Nano 2012;6:227-33.
Liu Y, Servant A, Guy OJ, Al-Jamal. An electric-field responsive microsystem for controllable miniaturized drug delivery applications. Procedia Eng 2011;25:984-7.
Anca Onaciu, Raluca. Hydrogels based drug delivery synthesis, characterization and administration.Pharmaceutics 2019;11:432.
Zhao W, Odelius K, Edlund U, Zhao. In situ synthesis of magnetic field-responsive hemicellulose hydrogels for drug delivery. Biomacromolecules 2015;16:2522-8.
Araujo Custodio S, Gomez Florit M, Toma. Injectable and magnetic responsive hydrogels with bioinspired ordered structures. ACS Biomater Sci Eng 2019;5:1392-404.
Filipcsei G, Csetneki I, Szilagyi. Magnetic field-responsive smart polymer composites in oligomers-polymer composites-molecular imprinting. Springer Berlin/Heidelberg 2007;206:137–89.
El-Leithy ES, Shaker DS, Ghorab MK. Evaluation of mucoadhesive hydrogels loaded with diclofenac sodium-chitosan microspheres for rectal administration. AAPS PharmSciTech 2010;11:1695-702.
Liu Q, Liu L. Novel light-responsive hydrogels with antimicrobial and antifouling capabilities. Langmuir 2019;35:1450-7.
Li L, Scheiger JM, Levkin PA. Design and applications of photoresponsive hydrogels. Adv Mater 2019;1807333:1-17.
Mathiowitz E, Cohen MD. Polyamide microcapsules for controlled release: characterization of the membranes.J Membr Sci 1989;40:1–26.
Mathiowitz E, Cohen MD. Polyamide microcapsules for controlled release: II release characteristics of the micro capsules. J Membr Sci1989;40:27-41.
Ninan N, Forget A, Shastri VP, Voelcker. Antibacterial and anti-inflammatory pH-responsive tannic acid-carboxylated agarose composite hydrogels for wound healing. ACS Appl Mater Interfaces 2016;8:28511-21.
Nesrinne S, Djamel A. Synthesis, characterization and rheological behavior of pH sensitive poly (acrylamide-co-acrylic acid) hydrogels. Arab J Chem 2017;10:539-47.
Ohmine I, Tanaka T. Salt effects on the phase transition of ionic gels. J Chem Phys 1982;77:5725.
Ozmen MM, Okay O. Superfast responsive ionic hydrogels: effect of the monomer concentration. J Macromol Sci Part A 2006;43:1215-25.
Zhou X, Wang J, Nie J, Du B. Poly (N-isopropylacrylamide)-based ionic hydrogels: synthesis, swelling properties, interfacial adsorption and release of dyes. Polymer J 2016;48:431-8.
Lim Y, Kim SM, Lee Y, Lee W, Yang. Cationic hyperbranched poly (amino ester): a novel class of DNA condensing molecule with cationic surface, biodegradable three-dimensional structure, and tertiary amine groups in the interior.J Am Chem Soc 2001;123:2460-1.
Matsumoto A, Ikeda S, Harada A. Glucose-responsive polymer bearing a novel phenylborate derivative as a glucose-sensing moiety operating at physiological pH conditions.Biomacromolecules 2003;4:1410-6.
Prabaharan M, Mano JF. Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials. Macromol Biosci 2006;6:991-1008.
Miyata T, Asami N, Uragami T. A reversibly antigen-responsive hydrogel.Nature 1999;399:766-9.
Zelzer M, Todd SJ, Hirst. Enzyme responsive materials: design strategies and future developments. Biomater Sci Royal Soc Chem 2013;1:11-39.
Huabing Chen, Xueling Chang. Microemulsion-based hydrogel formulation of ibuprofen for topical delivery. Epub 2006;315:52-8.
Sabale V, Vora S. Formulation and evaluation of microemulsion-based hydrogel for topical delivery. Int J Pharma Investig 2012;2:140-9.
Srinivas Hebbar, Akhilesh Dubey, Ravi G. Studies on cross-linked chitosan hydrogel for matrix tablets of montelukast sodium. Int JAppl Pharm 2017;9:22-9.
Gina SEl-feky, Gamal MZayed. Plga nanoparticles loaded mucoadhesive and thermosensitive hydrogel as a potential platform for the treatment of oral mucositis. Int JAppl Pharm 2019;11:106-12.
Eunhee Cho, Ken Webb. Formulation and characterization of poloxamine-based hydrogels as tissue sealants. Acta Biomaterialia 2012;8:2223-32.
Guoming Sun, Xian Zheng Zhang. Formulation and characterization of chitosan-based hydrogel films having both temperature and pH sensitivity. J Mater Sci Mater Med 2007;18:1563-77.
Suguna Selvakumaran, Ida Idayu Muhamad. Optimization of formulation of floating hydrogels containing gas forming agent using response surface methodology. Int J Pharm Pharm Sci 2013;6:526-30.
Basavaraj K Nanjwade, Rucha V. Formulation and evaluation of micro hydrogel of moxifloxacin hydrochloride. Eur J Drug Metab Pharmacokinet 2012;37:117-23.
Pulatova Nilufar Ubaydullaevna, Maksumova Oytura Sitdikovna. Physico-chemical polymer and hydrogel on the basis of 1-chloro-3-piperidine-2-propyl acrylate. J Crit Rev 2020;7:287-93.
Biswajit Biswal, Nabin Karnal. Formulation and evaluation of microemulsion based topical hydrogel containing lornoxicam. J Appl Pharm Sci 2014;4:77-84.
Devi Lalitha Gatiganti, Madhavi Harika Srimathkandala. Formulation and evaluation of oral natural polysaccharide hydrogel microbeads of Irbesartan. Anal Chem Lett 2016;6:334-44.
Emmanuel O Akala. Novel pH-sensitive hydrogels with adjustable swelling kinetics. Biomaterials 1998;19:1037-47.
Hu Yang, Weiyuan John Kao. Thermoresponsive gelatin/Monomethoxy poly (Ethylene Glycol)–poly (D, L-lactide) hydrogels: formulation, characterization, and antibacterial drug delivery. Pharm Res 2006;23:205-14.
Azizullah, Nisar-ur-Rehman. Novel gelatin-polyoxometalate based self-assembled pH responsive hydrogels. Formulation and in vitro characterization: Des Monomers Polym 2016;19:697-705.
Sun Namkung, Chih Chang Chu. Partially biodegradable temperature and pH-responsive poly (N-isopropyl acrylamide)/dextran-maleic acid hydrogels: formulation and controlled drug delivery of doxorubicin. J Biomater Sci Polymer Edition 2007;18:901-24.
Lihui Weng. Rheological characterization of in situ crosslinkable hydrogels formulated from oxidized dextran and n-carboxyethyl chitosan. Biomacromolecules 2007;8:1109-15.
Aka Any Grah. Formulation of mucoadhesive vaginal hydrogels insensitive to dilution with vaginal fluids. Eur J Pharm Biopharm 2010;76:296-303.
Torres Lugo, Peppas. Molecular design and in vitro studies of novel pH-sensitive hydrogels for the oral delivery of calcitonin. Macromolecules 1999;32:6646-51.
Das S Pal. Dextrin/poly (HEMA): pH responsive porous hydrogel for controlled release of ciprofloxacin. Int J Biol Macromol 2014;72:171-8.
N Vishal Gupta, HG Shivakumar. Preparation and characterization of superporous hydrogels as pH sensitive drug delivery system for pantoprazole sodium. Curr Drug Delivery 2009;6:505-10.
Bindu Sri M, Ashok V, Arkendu Chatterjee. A review on hydrogels as drug delivery in the pharmaceutical field. Int J Pharm Chem Sci 2012;1:642-61.
Kalshetti PP, Rajendra V, Dixit DP, Parekh PP. Hydrogels as a drug delivery system and applications: a review. Int J Pharm Pharm Sci 2012;4:1-7.
Enrica C, Vitaliy VK. Biomedical applications of hydrogels: a review of patents and commercial products.Eur Polymer J 2015;65:252-67.
Xu J, Tam M, Samaei S, Lerouge. Mucoadhesive chitosan hydrogels as rectal drug delivery vessels to treat ulcerative colitis. Acta Biomater 2017;48:247-57.
Syed KHG, Saphwan AA, Glyn OP. Hydrogels: methods of preparation, characterisation, and applications. Prog Mol Environ Bioeng: Anal Model Technol Appl 2011;51:118-20.
Anisha Singh, Pramod Kumar Sharma. A comprehensive review of hydrogels: Int J Pharm Sci Rev Res 2010;4:97-105.
M Amiji, R Tailor, MK Ly J. Gelatin poly (ethylene oxide) semi-interpenetrating polymer network with pH-sensitive swelling and enzyme-degradable properties for oral drug delivery. Drug Dev Ind Pharm 1997;23:575-82.
Liu M, Zeng X, Ma C, Yi H, Ali X. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res 2017;5:1-20.