A functionalizable reverse thermal gel based on a polyurethane/PEG block copolymer

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Biomaterials (Impact Factor: 8.56). 10/2010; 32(3):777-86. DOI: 10.1016/j.biomaterials.2010.09.044
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Injectable reverse thermal gels have great potentials as biomaterials for tissue engineering and drug delivery. However, most existing gels lack functional groups that can be modified with biomolecules that can guide cell/material interactions. We created an amine-functionalized ABA block copolymer, poly(ethylene glycol)-poly(serinol hexamethylene urethane), or ESHU. This reverse thermal gel consists of a hydrophobic block (B): poly(serinol hexamethylene urethane) and a hydrophilic block (A): poly(ethylene glycol). The polymer was characterized by GPC, FTIR and (1)H FTNMR. Rheological study demonstrated that ESHU solution in phosphate-buffered saline initiated phase transition at 32 °C and reached maximum elastic modulus at 37 °C. The in vitro degradation tests performed in PBS and cholesterol esterase solutions revealed that the polymer was hydrolyzable and the presence of cholesterol esterase greatly accelerated the hydrolysis. The in vitro cytotoxicity tests carried out using baboon smooth muscle cells demonstrated that ESHU had good cytocompatibility with cell viability indistinguishable from tissue culture treated polystyrene. Subcutaneous implantation in rats revealed well tolerated accurate inflammatory response with moderate ED-1 positive macrophages in the early stages, which largely resolved 4 weeks post-implantation. We functionalized ESHU with a hexapeptide, Ile-Lys-Val-Ala-Val-Ser (IKVAVS), which gelled rapidly at body temperature. We expect this new platform of functionalizable reverse thermal gels to provide versatile biomaterials in tissue engineering and regenerative medicine.

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    • "Serinol is a rather new building-block for the preparation of PUs. This serine derivative has two–OH groups for reaction with a suitable diisocyanate, and one–BOC protected NH 2 group that, after polymerization and deprotection, is available for further chemical functionalization (Park et al., 2011). "
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    ABSTRACT: Polyurethanes (PUs) are formed by a reaction between isocyanates and diols to yield polymers with urethane bonds (-NH-COO-) in their main chain. A great variety of building blocks is commercially available that allows the chemical and physical properties of PUs to be tailored to their target applications, particularly for the biomedical and pharmaceutical fields. This article reviews the synthesis and characterization of PUs and PU-copolymers, as well as their in vitro and in vivo biodegradability and biocompatibility. Particular emphasis is placed on the use of PUs for the controlled release of drugs and for the (targeted) delivery of biotherapeutics.
    International Journal of Pharmaceutics 04/2013; 450(1). DOI:10.1016/j.ijpharm.2013.04.063 · 3.65 Impact Factor
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    • "Temperaturesensitive hydrogels, which exist in the sol state at low temperatures but turn into a gel state at physiological temperature (37 °C), have attracted considerable attention. Typical examples of temperature-sensitive hydrogels are as listed: poly(N-isopropylacrylamide ) [26], Pluronic and its derivative [27] [28], triblock copolymers consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic block including poly(caprolactone-co-lactide) (PCLA–PEG–PCLA), poly(caprolactone) (PCL–PEG–PCL), poly(lactide-co-glycolide ) (PLGA–PEG–PLGA), poly(phosphazene) [29] [30] [31] [32] [33] [34] and natural polymers [8]. However, temperature-sensitive hydrogels are normally neutral, which limits their application to the delivery of ionic drugs/proteins. "
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    ABSTRACT: An injectable biodegradable pH/temperature-sensitive oligo(β-amino ester urethane) (OAEU) was synthesized. The OAEU was synthesized by addition polymerization between the isocyanate groups of 1,6-diisocyanato hexamethylene and the hydroxyl groups of a synthesized monomer piperazine dihydroxyl amino ester (monomer PDE) in chloroform in the presence of dibutyltin dilaurate as a catalyst. The synthesized OAEU was characterized by (1)H NMR spectroscopy, Fourier transform infrared spectroscopy and gel permeation chromatography. The aqueous solutions of OAEU showed a sol-to-gel-to-sol phase transition as a function of temperature and pH. The gel window covered the physiological conditions (37°C, pH 7.4) and could be controlled by changing the OAEU concentration. After a subcutaneous injection of the OAEU solution into Sprague-Dawley rats, a gel formed rapidly in situ and remained in the body for more than 2 weeks. The in vitro cytotoxicity test and in vitro degradation showed that the OAEU hydrogel was non-cytotoxic and biodegradable. The in vitro release of doxorubicin from this OAEU hydrogel was sustained for more than 10 days. This injectable biodegradable pH/temperature-sensitive OAEU hydrogel is a potential candidate as a drug/protein carrier and in biomedical applications.
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