Recently, there has been a great deal of research activity in the development of stimulus-responsive polymeric hydrogels. These hydrogels are responsive to external or internal stimuli and the response can be observed through abrupt changes in the physical nature of the network. This property can be favorable in many drug delivery applications. The external stimuli can be temperature, pH, ionic strength, ultrasonic sound, electric current, etc. A majority of the literature related to the development of stimulus-responsive drug delivery systems deals with temperature-sensitive poly(N-isopropyl acrylamide) (pNIPAAm) and its various derivatives. However, acrylic-based pH-sensitive systems with weakly acidic/basic functional groups have also been widely studied. Quite recently, glucose-sensitive hydrogels that are responsive to glucose concentration have been developed to monitor the release of insulin. The present article provides a brief introduction and recent developments in the area of stimulus-responsive hydrogels, particularly those that respond to temperature and pH, and their applications in drug delivery.

Stimulus-Responsive “Smart” Hydrogels as Novel Drug Delivery Systems

https://www.foodeng.wisc.edu/images/publications/2007-9.pdf

Use of whey proteins for encapsulation and controlled delivery applications

Covalently cross-linked whey protein microgels (WPM) were produced without the use of a chemical cross-linking agent. The hierarchical structure of WPM is formed by a complex interplay of heat denaturation, aggregation, electrostatic repulsion, and formation of disulfide bonds. Therefore, well-defined spherical particles with a diameter of several hundreds of nanometers and with relatively low polydispersity are formed in a narrow pH regime (5.8–6.2) only. WPM production was carried out on large scale by heating a protein solution in a plate-plate heat exchanger. Thereafter, the microgels were concentrated by microfiltration and spray dried into a powder. The spherical structure of the WPM was conserved in the powder. After re-dispersion, the microgel dispersions fully recovered their initial structure and size distribution. Due to the formation of disulfide bonds the particles were internally covalently cross-linked and were remarkably stable in a large pH range. Because of the pH dependent charge of the constituents the particles underwent significant size changes upon shifting the pH. Small angle X-ray scattering experiments were used to reveal their internal structure, and we report on the pH-induced structural changes occurring on different length scale. Our experiments showed that close analogies could be drawn to internally cross-linked and pH-responsive microgels based on weak polyelectrolytes. WPM also exhibited a pronounced swelling at pH values below the isoelectric point (IEP), and a collapse at the IEP. However, in contrast to classical microgels, WPM are not build up by simple polymer chains but possess a complex hierarchical structure consisting of strands formed by clusters of aggregated denatured proteins that act as primary building blocks. They were flexible enough to respond to changes of the environment, and were stable enough to tolerate pH values where the proteins were highly charged and the strands were stretched.

/pdf/internal-structure-and-colloidal-behaviour-of-covalent-whey-5axxytt2e0.pdf

Internal structure and colloidal behaviour of covalent whey protein microgels obtained by heat treatment

Thermosensitive polymers as carriers for DNA delivery

https://escholarship.org/content/qt1gx881n4/qt1gx881n4.pdf?t=p0t11i

Swelling properties of acrylamide-based ampholytic hydrogels : comparison of experiment with theory

A combined capillary drop viscometer-pH cell has been constructed and used to study the solution properties of some polymeric weak acids, bases, and ampholytes containing methacrylic acid (MAA), dimethylaminoethyl methacrylate (DMAEMA), and 2-hydroxyethyl methacrylate (HEMA). The behavior of polyelectrolytes based on MAA or DMAEMA is consistent with established thinking, and is dominated by the chain expansions which accompany ionization of acidic (MAA) or protonation of basic (DMAEMA) functionality. The solution behavior of the polyampholytes is complex and was studied as a preliminary to investigations of crosslinked hydrogel analogues. Briefly, it was found that changes in polymer coil dimensions were dictated by the formation or “breakage” of intramolecular salt bridges by, for example, lowering the solution pH to protonate weakly acidic, or raising the pH to deprotonate weakly basic functionality. Similar effects were observed on adding counterions which preferentially complex with one of the bound ions. The pH “sensitivity” of polymer coil dimensions increased with the concentration of charged functionality in the polymer. Chemically crosslinked polyampholytes were prepared and equilibrium water contents were measured as a function of pH. In contrast, due to network constraints, the pH “sensitivity” of the hydrogels, as measured by changes in equilibrium water uptake, increased with a decrease in the level of charged functionality in the polymer.

S. Wen

Papers

Synthetic pH sensitive polyampholyte hydrogels: A preliminary study