Intelligent copolymers based on poly (N-isopropilacrylamide). Part ii: Grafts polysaccharide to obtain new biomaterials for biomedical and pharmacological applications

Main Article Content

Marcos Antonio Sabino
Maria Gabriela Carrero
Carlos Julio Rodriguez


Biopolymers such as polysaccharides are compounds that have functional groups and they are very susceptible to be used in chemical modifications and also allows them to synthesizer of new copolymers (used as graft-like chains). Poly (N-Isopropylacrylamide) PNIPAm, is a thermosensitive synthetic polymer widely used in the preparation of intelligent gels for the biomedical field, but have some limitations in use as biodegradable matrix or scaffolds. In this research wered the synthesis and characterization of copolymers their PNIPAm grafted with the polysaccharides: chitosan (CS) or hyaluronic acid (HA), were performed to obtain new biodegradable and biocompatible biomaterials that conserve the intelligent character (thermosensitivity).The PNIPAm was in first chemically modified with 3-butenoic acid in order to generate carboxyl end groups on the graft-polymer chain (PNIPAm-co-COOH) which serve as anchor points and then covalently graft the polysaccharides. For the specific case of grafting with hyaluronic acid, it was necessary to perform a second modification using piperazine (PIP) and obtain the graft-polymers PNIPAm-co-COO-g-PIP. All this modification process was previously reported (Carrero et al, 2018). In this case, the polysaccharides used as grafts-like chains were: (1) chitosan oligomers obtained by acid degradation and (2) hyaluronic acid. The characterization of all copolymers obtained was follow by infrared spectroscopic (FT-IR); the differential scanning calorimetric (DSC) technique was used to determine the lower critical solution transition temperature (LCST), resulting in the range of 29-34 °C. Its morphology was studied using scanning electron microscopy (SEM), but previously was simulate an inject process, for the reversible gel character presented by these novel copolymers; resulting a high porosity and interconnection between pores (scaffold-like micrometric structures). Hemocompatibility assays were performed on agar/blood systems, showing non cytotoxicity. All these results give these graftcopolymers a high potentiality of use as scaffolds in tissue engineering and also for pharmacological applications.


Download data is not yet available.

Article Details

How to Cite
Sabino, M. A., Carrero, M. G., & Rodriguez, C. J. (2019). Intelligent copolymers based on poly (N-isopropilacrylamide). Part ii: Grafts polysaccharide to obtain new biomaterials for biomedical and pharmacological applications. International Journal of Advances in Medical Biotechnology - IJAMB, 2(1), 17-26.
Special Edition Submission: "3D Printing for Medicine: biomaterials, processes and techniques"
Author Biographies

Marcos Antonio Sabino, Simon Bolivar University

Departamento de Química

Maria Gabriela Carrero, Simon Bolivar University


Carlos Julio Rodriguez, Simon Bolivar University



Fu G and Soboyejo W, Swelling and diffusion characteristics of modified poly (N-isopropylacrylamide) hydrogels, Materials Science and Engineering C. 30: 8-13 (2010).

Haq MA, Su Y, Wang D. Mechanical properties of PNIPAm based hydrogels: A review. Materials Science and Engineering C, 70: 842–55 (2017).

Alvarez-Lorenzo C, Concheiro A, Dubovik A, Grinberg N, Burova T, Grinberg V. Temperature-sensitive chitosan-poly(N-isopropylacrylamide) interpenetrated networks with enhanced loading capacity and controlled release properties. Journal of Controlled Release, 102: 629-641 (2005).

Guo H, Brûlet A, Rajamohanan P, Marcellan A, Sanson N, Hourdet D. Influence of topology of LCST-based graft copolymers on responsive assembling in aqueous media. Polymer, 60: 164.175 (2015).

Zhang W, Shi L, Wu K, An Y. Thermoresponsive Micellization of Poly (ethylene glycol)-b-poly (N-isopropylacrylamide) in Water. Macromolecules,38 (13): 5743–5747 (2005).

Conzatti G, Cavalie S, Combes C, Torrisani J, Carrere N, Tourrette A. PNIPAm grafted surfaces through ATRP and RAFT polymerization: Chemistry and bioadhesion, Colloids and Surfaces B: Biointerfaces. 151: 143–55 (2017).

Davis K, Matyjaszewski K. Statistical, Gradient and Segmented Copolymers by Controlled/Living Radical polymerizations. In: Advances in polymer Science. Springer-Verlag Berlin Heidelberg (2002).

Feng C, Li Y, Yang D, Hu J, Zhang X, Huang X, Well-defined graft copolymers: from controlled synthesis to multipurpose applications, The Royal Society of Chemistry, 40: 1282–1295 (2011).

Malviya R, Sharma PK, Dubey SK, Modification of polysaccharides: Pharmaceutical and tissue engineering applications with commercial utility (patents). Materials Science & Engineering C, 68: 929-938 (2016).

Pino V, Meléndez H, Ramos A, Bucio E. Radiation Grafting of Biopolymers and Synthetic Polymers: Synthesis and Biomedical Applications. In: Biopolymer Grafting: Applications, Elsevier Inc (2018).

Le P, Huynh C, Tran N. Advances in thermosensitive polymer-grafted platforms for biomedical applications. Materials Science and Engineering: C, 92: 1016-1030 (2018).

Soni S, Ghosh A. (2018). Grafting Onto Biopolymers: Application in Targeted Drug Delivery. In: Biopolymer Grafting: Applications, Elsevier Inc (2018).

Bhavsar C, Momin M, Gharat S, Omri A. Functionalized and graft copolymers of chitosan and its pharmaceutical applications. Expert Opinion on Drug Delivery, 14(10):1189-1204 (2017).

Ohya S, Kidoaki S, Matsuda T. Poly(N-isopropylacrylamide) (PNIPAM)-grafted gelatin hydrogel surfaces: interrelationship between microscopic structure and mechanical property of surface regions and cell adhesiveness. Biomaterials, 26(16):3105-3111 (2005).

Işıklan N and Tokmak S. Microwave based synthesis and spectral characterization of thermo-sensitive poly(N,N-diethylacrylamide) grafted pectin copolymer. International Journal of Biological Macromolecules, 113: 669-680 (2018).

Ciocoiu O,Staikos G, Vasile C. Thermoresponsive behavior of sodium alginate grafted with poly(N-isopropylacrylamide) in aqueous media. Carbohydrate Polymers, 184: 118-126 (2018).

Conzattia G, Cavalie S, Gayet F, Torrisani J, Carrère N, Tourrette A. Elaboration of a thermosensitive smart biomaterial: From synthesis to the ex vivo bioadhesion evaluation. Colloids and Surfaces B: Biointerfaces, 175: 91-97 (2019).

Vihola H, Laukkanen A, Valtola L, Tenhu H, Hirvonen J. Cytotoxicity of thermosensitive polymers poly(N-isopropylacrylamide), poly(N-vinylcaprolactam) and amphiphilically modified poly(N-vinylcaprolactam). Biomaterials, 26(16): 3055-3064 (2005).

Cooperstein M and Canavan H. Assessment of cytotoxicity of (N-isopropyl acrylamide) and Poly(N-isopropyl acrylamide)-coated surfaces. Biointerphases, 8(19): 1-12 (2013).

Tsitsilianis C, Lencina S, Iatridi Z, Villar M, Thermoresponsive hydrogels from alginate-based graft copolymers. European Polymer Journal, 61: 33-44 (2014).

Rueda J, Zschoche S, Komber H, Schmaljohann D, Voit B, Síntesis y caracterización de hidrogeles termosensibles. Revista de QUÍMICA, 41-46 (2006).

Rejinold NS, Sreerekha PR, Chennazhi KP, Nair SV, Jayakumar R, Biocompatible, biodegradable and thermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drug delivery. Macromolecules, 49: 161-172 (2011).

Isıklan N and Küçükbalcı G, Microwave-induced synthesis of alginate–graft-poly(N-isopropylacrylamide) and drug release properties of dual pH- and temperature-responsive beads. European Journal of Pharmaceutics and Biopharmaceutics. 82:316-331 (2012).

Stile R, Burghardt W, Healy K, Synthesis and Characterization of Injectable Poly(N-isopropylacrylamide)-Based Hydrogels That Support Tissue Formation in Vitro. Macromolecules. 32: 7370-7379 (1999).

Vieira J, Posada J, Rezende R, Sabino M, Starch and chitosan oligosaccharides as interpenetrating phases in poly(N-isopropylacrylamide) injectable gels. Materials Science and Engineering C. 37: 20-27 (2014).

Benrebouh A, Avoce D, Zhu X, Thermo- and pH-sensitive polymers containing cholic acid derivatives. Polymer. 42: 4031-4038 (2001).

Zhu J and Marchant R, Design properties of hydrogel tissue-engineering scaffolds. Expert Rev. Med. Devices. 8(5): 607-626 (2011).

Carrero M, Posada J, Sabino M, Intelligent copolymers based on poly (N-isopropylacrylamide) PNIPAm with potential use in biomedical applications. Part I: PNIPAm functionalization with 3-butenoic acid and piperazine. International Journal Of Advances In Medical Biotechnology. 1(1):23-31 (2018).

Coronado R, Pekerar S, Lorenzo A, Sabino M, Characterization of thermo-sensitive hydrogels based on poly (N-isopropylacrylamide)/hyaluronic acid. Polymer Bulletin, 67: 101-124 (2011).

Brugnerotto J, Lizardi J, Goycoolea FM, Argüelles-Monal W, Desbrieres J, Rinaudo M, An infrared investigation in relation with chitin and chitosan characterization. Polymer. 42: 3569-3580 (2001).

Povea M, Argüelles-Monal W, Cauich-Rodriguez J, May A, Badas N, Peniche C, Interpenetrated chitosan-poly(acrylic acid-co-acrylamide) hydrogels. Synthesis, characterization and sustained protein release studies. Materials Sciences and Applications. 2: 509-520 (2011).

Sestak J, Mullins M, Northrup L, Thati S, Forrest ML, Siahaan TJ, Berkland C. Single-step grafting of aminooxy-peptides to hyaluronan: A simple approach to multifunctional therapeutics for experimental autoimmune encephalomyelitis. Journal of Controlled Release. 168: 334–340 (2013).

Chang KH, Liao HT, Chen JP, Preparation and characterization of gelatin/hyaluronic acid cryogels for adipose tissue engineering: In vitro and in vivo studies. Acta Biomater. 9(11): 9012-9026 (2013).

Jagadeeswara R, and Karunakaran K, Purification and characterization of hyaluronic acid produced by Streptococcus zooepidemicus strain 3523-7. J. BioSci. Biotech., 2(3): 173-179 (2013).

Khanmohammadi M, Baradar A, Eskandarnezhad S, Feyze N, Ebrahimi S, Sequential optimization strategy for hyaluronic acid extraction from eggshell and its partial characterization. Journal of Industrial and Engineering Chemistry, 20(6): 4371–4376 (2014).

Zhang J, Ma X, Fan D, Zhu C, Deng J, Hui J, Ma P, Synthesis and characterization of hyaluronic acid/human-like collagen hydrogels. Materials Science and Engineering C. 43:547–554 (2014).

Ha D, Lee S, Chong M, Lee Y, Preparation of Thermo-Responsive and Injectable Hydrogels Based on Hyaluronic Acid and Poly(N-isopropylacrylamide) and Their Drug Release Behaviors. Macromolecular Research, 14(1): 87-93 (2006).

Chang B, Ahuja N, Ma C, Liu X, Injectable scaffolds: Preparation and application in dental and craniofacial regeneration. Materials Science and Engineering R, 111: 1-26 (2017).

Xiang Y, Peng Z, Chen D, A new polymer/clay nano-composite hydrogel with improved response rate and tensile mechanical properties. European Polymer Journal, 42(9): 2125–2132 (2006).

Koo H, Jin G, Kang H, Lee Y, Nam H, Jang H, Park J, A new biodegradable crosslinked polyethylene oxide sulfide (PEOS) hydrogel for controlled drug release. International Journal of Pharmaceutics, 374: 58-65 (2009).

|] Coronado R, Pekerar S, Lorenzo A, Sabino M, Obtención y caracterización de hidrogeles inteligentes del tipo red interpenetrada basados en Poli(N-Isopropilacrilamida). Suplemento de la Revista Latinoamericana de Metalurgía y Materiales, S2(1): 65-66 (2009).

Mao Y, Pravansu M, Gargi G, Morphology and properties of poly vinyl alcohol (PVA) scaffolds: Impact of process variables. Materials Science and Engineering, 42: 289-294 (2004).

Khademhosseini A, Langer R, Microengineered hydrogels for tissue engineering. Biomaterials, 28: 5087-5092 (2007).

Sabino M, Feijoo J, Nuñez O, Ajami D, Interaction of Fibroblast with Poly(p-dioxanone) and its degradation products. Journal of Materials Science, 37(1): 35–40 (2002).

Khan A, Husain T, Ahamed M, Mohamed A, Aldalbahi A, Alam J, Ahamad T. Temperature-Responsive Polymer Microgel-Gold Nanorods Composite Particles: Physicochemical Characterization and Cytocompatibility. Polymers, 10(1): 1-13 (2018).

Rodríguez E, Gamboa M, Hernández F, García J, Bacteriología General: Principios y Prácticas de Laboratorio. Universidad de Costa Rica, pp. 498-499 (2005).

Most read articles by the same author(s)