Biodegradable Thermogels

Abstract

All living creatures respond to external stimuli. Similarly, some polymers undergo conformational changes in response to changes in temperature, pH, magnetic field, electrical field, or the wavelength of light. In one type of stimuli-responsive polymer, thermogel polymers, the polymer aqueous solution undergoes sol-to-gel transition as the temperature increases. Drugs or cells can be mixed into the polymer aqueous solution when it is in its lower viscosity solution state. After injection of the solution into a target site, heating prompts the formation of a hydrogel depot in situ, which can then act as a drug releasing system or a cell growing matrix. In this Account, we describe key materials developed in our laboratory for the construction of biodegradable thermogels. We particularly emphasize recently developed polypeptide-based materials where the secondary structure and nanoassembly play an important role in the determining the material properties. This Account will provide insights for controlling parameters, such as the sol-gel transition temperature, gel modulus, critical gel concentration, and degradability of the polymer, when designing a new thermogel system for a specific biomedical application. By varying the stereochemistry of amino acids in polypeptides, the molecular weight of hydrophobic/hydrophilic blocks, the composition of the polypeptides, the hydrophobic end-capping of the polypeptides, and the microsequences of a block copolymer, we have controlled the thermosensitivity and nanoassembly patterns of the polymers. We have investigated a series of thermogel biodegradable polymers. Polymers such as poly(lactic acid-co-glycolic acid), polycaprolactone, poly(trimethylene carbonate), polycyanoacrylate, sebacic ester, polypeptide were used as hydrophobic blocks, and poly(ethylene glycol) and poly(vinyl pyrrolidone) were used as hydrophilic blocks. To prepare a polymer sensitive to pH and temperature, carboxylic acid or amine groups were introduced along the polymer backbone. The sol-gel transition mechanism involves changes in the secondary structures of the hydrophobic polypeptide and in the conformation of the hydrophilic block. The polypeptide copolymers were stable in the phosphate buffered saline, but the presence of proteolytic enzymes such as elastase, cathepsin B, cathepsin C, and matrix metallopreoteinase accelerated their degradation. We also describe several biomedical applications of biogradable thermogel polymers. One subcutaneous injection of the insulin formulation of thermogel polypeptide copolymers in diabetic rats provided hypoglycemic efficacy for more than 16 days. The thermogels also provided a compatible microenvironment for chondrocytes, and these cells produced biomarkers for articular cartilage such as sulfated glucoaminoglycan (sGAG) and type II collagen. The thermogels were also used as a fixing agent for in situ cell imaging, and cellular activities such as endocytosis were observed by live cell microscopy.

Role of Side-Chain Molecular Features in Tuning Lower Critical Solution Temperatures (LCSTs) of Oligoethylene Glycol Modified Polypeptides

“…[1][2][3] Double hydrophilic block copolymers containing a thermoresponsive segment, i.e. possessing a lower critical solution temperature (LCST), are able to transform from solutions in water into hydrogels 4,5 or suspensions of nanoparticles 6,7 upon heating to above the LCST. In recent years there has been considerable development of new polymers that possess LCSTs in water, primarily based on repeats bearing short oligoethylene glycol (OEG) side-chains.…”

“…Here, we have utilized a recently developed synthetic methodology that allows facile modification of polypeptide sidechains 24,25 to prepare a series of thermoresponsive OEG containing polypeptides, where the number of EG repeats, EG terminal groups, and linkage groups were all systematically varied in order to obtain insights on how these molecular features affect LCST behavior ( Figure 1). Using this family of polypeptides with side-chain diversity, we show that adjustment of each of these molecular features can be used to predictably adjust LCST, 4 allowing for an understanding of how different molecular components influence polypeptide solution properties. …”

Stimuli‐responsive polypeptide materials prepared by ring‐opening polymerization of α‐amino acid N‐carboxyanhydrides

“…19 Combining polypeptides with hydrophilic PEG can form thermo-responsive hydrogels. [20][21][22][23] For those ionic polypeptides, they can undergo solubility and conformation change upon solution pH change. Representative examples include poly-L-lysine and poly-L-glutamic acid.…”

Extraction of Oil from Oil Sands Using Thermoresponsive Polymeric Surfactants

“…It was this latter line of thoughts that was followed in the present study that investigates how an aqueous solution of a thermoresponsive polymeric surfactant would, in the presence of a small amount of organic thinner, affect the efficiency of oil extraction from oil sands. Considering the large body of work found in the scientific literature on block copolymers where the heat-induced insolubility of a selected block results in the formation of block copolymer micelles, 14,15 we selected a poly(ethylene-glycol)-b-poly(2-(2-methoxyethoxy)ethyl methacrylate] diblock copolymer (PEG-b-PMEO2MA) as a thermo-responsive polymeric surfactant. 16 While PEG is watersoluble between 0 and 98 o C, PMEO2MA has an LCST of 26 o C. 17 Consequently, PEG-b-PMEO2MA was expected to be completely water-soluble or form block copolymer micelles with a PMEO2MA core below or above the LCST of the PMEO2MA block, respectively.…”