Written by: Fei Chen (Chair), Ashley Clarke (Clerk), and Laura McKiel (Editor)
Polymers that respond sharply to small changes in physical or chemical conditions with relative large phase or property changes are termed “stimuli-responsive”. Smart biomaterials may be:
- Dissolved in or phase-separated out of aqueous solutions
- Adsorbed onto aqueous-solid interfaces
- Chemically grafted onto aqueous-solid interfaces
- Chemically crosslinked, H-bonded, and/or physically entangled as hydrogels.
Figure 1: Examples of stimuli triggers for polymers. Source: Journal of Controlled Release 194 (2014) 1–19
Temperature Responsive Polymers
Poly(N-isopropylacrylamide) (PNIPAAm) is one of the most popular and well-studied temperature responsive polymers. It is soluble in organic solvents, such as chloroform and acetone, as well as cold water. Heating an aqueous PNIPAAm solution past 32 °C instantly coverts the clear solution into a milky suspension. PNIPAAm remains the leader for biomedical applications because of the sharpness of the transition, a transition temperature that is close to physiological temperature, and the availability of information on the polymer and its phase transition. The mechanism of phase separation at lower critical solution temperature (LCST) is large entropy gain caused by release of the hydrophobically-bound water molecules around the isopropyl groups.
Figure 2: Stimuli-responsive behaviour of PNIPAAm. Source: Material Matters 2010, 5.3, 56
One of the main applications of temperature responsive polymers is used as smart cell culture surfaces. Basically, using an electron beam to polymerize PNIPAAm from a solution of NIPAAm monomer in 2-propanol can coat a layer of PNIPAAm on TCPS surface. The thickness of the PNIPAAm layer can be adjusted by the intensity, length of irradiation of electron beam, or monomer concentration. Cells adhere to the hydrophobic PNIPAAm surface during cell culture, then you use a temperature change from 37oC to room temperature to cause a phase transition in PNIPAAm to free the cells, which then are floating in solution. The smart cell culture surface could be advantageous over requiring a degradable scaffold for cell culture.
Figure 3: PNIPAAm for use as a smart culture surface. Source: Material Matters 2010, 5.3, 56
Another biomedical application of temperature responsive polymers is for drug delivery. Since high molecular weight PNIPAAm can’t be degraded or excreted, so there is research into other polymers such as poly(lactide co-glycoide) (PLGA)-polyethylene glycol (PEG)-PLGA block copolymers, the idea is that self-assembled micelles containing the drug collapse into gels (thermo-gelling behaviour) at 37 °C, resulting in a long-acting drug release.
pH Responsive Polymers
pH responsive polymers normally possess a functional group that can donate or accept protons, such as acidic groups (-COO, SO3H) or basic group (NH2). One example is poly(methyl methacrylate-methacrylic acid) (MMA-MAA), which can change its hydrophobicity in terms of change in pH. When pH is lower than pKa of carboxyl group, it is hydrophobic, and if pH is above pKa of carboxyl group it is hydrophilic. One of the clinical application is for enteric coatings being applied to drugs.
Figure 4: Poly(MMA-MAA) chemical structure.
Enzyme responsive Polymers
Enzyme responsive polymers are a new class of smart materials that undergo macroscopic transitions triggered by selective catalytic actions of enzymes. The use of enzymes as stimuli to trigger properties change opens up many possible applications in biology and medicine. One example discussed during the session was that a matrix metalloprotease (MMP) cleavable crosslinker was used to tune the mechanical and chemical environment of a hyaluronic acid hydrogel, to elucidate the role of the microenvironment in cancer cell invasion.
Figure 5: MMP cleavable crosslinker used to alter the chemical and mechanical environment of a hydrogel. Source: Adv. Funct. Mater. 2015 , 25, 7163 −7172
Photo-responsive polymers can change their physicochemical properties or degrade in response to light irradiation of appropriate wavelength and intensity. Light is a readily available trigger and is often inexpensive (i.e. lamps), while being able to be remotely applied and allowing for spatiotemporal control.
One example was discussed based on presenter’s own work under the supervision of Dr. Amsden (Biomacromolecules 2016, 17, 208−214). By copolymerizing a trimethylene carbonate with a pendant acrylate group (AC) with L-lactide (LLA) and e-caprolactone (CL) to form a copolymer, the copolymer can be printed by Melt Electrospinning Writing (MEW) process and then crosslinked by UV irradiation. The crosslinked fibers had significantly improved mechanical properties compared to non-crosslinked fibers, with the crosslinked hydrated fibers possessing elastic moduli of 370 MPa compared to about 40 MPa for the noncrosslinked materials. This high modulus was retained even after 10 000 strain-relaxation cycles, with the samples remaining intact after 200 000 cycles. Such photo-crosslinked scaffold could avoid the creep effect upon hydration of commonly used thermoplastics, such as PCL.
Question 1: Why are there so few smart polymers which have made it into clinic?
- Potential cellular toxicity of the smart polymers is a main concern especially for applications involving intracellular delivery of biomolecular drugs
- Many of the smart polymers are not hydrolytically degradable
- PNIPAAm and polyacrylic acid (PAAc) are not readily excreted by kidneys and tend to accumulate in the body
- Smart polymer drug delivery systems have rarely been used in the clinic may be simple injection of biomolecular drug without a carrier is just a simple and well-accepted drug delivery method for now. Benefits from using a smart polymer device need to be proven to justify the time and money spent developing the materials
- It used to be a lot easier to get materials approved – today there are more regulations to meet and tests to perform
Question 2: Which applications of smart polymers will likely succeed in clinic and why?
- Greatly depends on application
- Tissue Engineering
- Harder to simulate bodily environment for tests
- Also, difficult to assess performance of grafts/scaffolds/other devices in vivo
- May be developed for longer-term applications, so in turn it will take longer to test materials
- Depends on whether you want to implant polymer scaffold with cells or wait for scaffold to degrade before implantation
- Drug delivery
- Short-term operation, so it may take less time to complete testing
- Simple methods available to study release rate in vitro and able to test drug concentration for in vivo tests
- Smart diagnostic applications
- Testing material, if not in body the regulations are much easier to meet/test (e.g. Immunoassay)
- Tissue Engineering