CANADIAN RESEARCH FOCUS
February 22, 2010
R.Chapanian and B.G.Amsden just published a new study
"Combined and sequential delivery of bioactive VEGF165 and HGF from poly(trimethylene carbonate) based photo-cross-linked elastomers”, Journal of Controlled Release (2009), doi:10.1016/j.jconrel.2009.11.025.
Interview with lead author, Prof. Brian Amsden
After obtaining his PhD in Chemical Engineering from Queen’s University, Dr. Amsden was an Assistant Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta (Edmonton, Alberta). A few years later he joined the Department of Chemical Engineering at Queen’s University (Kingston, Ontario) and is now full Professor. He currently heads a team of 16 students and researchers specializing in the development of polymer biomaterials for peptide/protein drug delivery or tissue engineering applications.
Dr. Amsden’s research interests include the development and characterization of biodegradable and biocompatible polymers for such biomedical applications as localized growth factor delivery, tissue engineering scaffolds, and ocular drug delivery. This research is multidisciplinary and requires frequent collaboration of his research team with colleagues in mechanical engineering and cell biology, as well as other fields when required. His most recent paper published in the Journal of Controlled Release, which will be discussed further below, saw some collaborative work with Drs. Tse and Pang of the Department of Cell Biology and Anatomy at Queen’s University.
Elastomeric-based systems are potentially suitable for a number of soft tissue applications, particularly in the fields of controlled drug delivery and tissue engineering where their properties can be designed to approximate those of the soft tissues involved (i.e. smooth muscle, articular cartilage, and vascular tissue). Trimethylene carbonate (TMC) based biodegradable elastomers are a relatively recent development in biomaterials. By co-polymerizing with such monomers as D, L-lactide (DLLA) and ε-caprolactone (ε -CL), the mechanical properties of the TMC system can be tailored. Photo-cross-linking is one of the more popular methods in literature of preparing these biodegradable elastomers as it is a rapid reaction and can effectively cross-link at low temperatures so that the probability of biological compound denaturation is reduced. This latter advantage is of particular interest in the delivery of drugs and bioactive growth factors.
Dr. Amsden is a leading authority on these materials and has published two recent authoritative reviews on the topic: “Biodegradable elastomers in drug delivery” (Expert Opinion on Drug Delivery, 5:2008) and “Curable, biodegradable elastomers: emerging biomaterials for drug delivery and tissue engineering” (Soft Matter, 3:2007). In his latest article in JCR he reports for the first time an elegant study on the ability of photo-cross-linked TMC-based elastomers to release VEGF and HGF by a mechanism of osmotic pressure driven release. Here the authors demonstrate that the osmotic release mechanism allows for a linear, sustained release with low initial burst such that the elastomers are able to release the growth factors throughout the release phase. The figure below shows an illustrative depiction of this mechanism. This study successfully demonstrated that the released growth factors were able to maintain a high bioactivity and that the elastomeric system was able to release combined growth factors at a similar rate, as well as in a controllable sequence.
cc-CRS:
Poly(trimethylene carbonate) based photo-cross-linked elastomers offer an interesting solution to the generation of acidic degradation products common with polyhydroxy acid esters. How difficult is it to balance mechanical properties while minimizing the acidity resulting from degradation?
Professor Amsden:
This is the central issue that needed to be resolved. Trimethylene carbonate forms excellent elastomers that do not generate acidic degradation products, but they are too elastic and do not generate cracks readily. To overcome this problem, the glass transition temperature of the elastomer needed to be increased. The glass transition temperature could be increased by decreasing the molecular weight of the prepolymer, but this in turn resulted in a much reduced elastomer degradation rate. As a compromise, lactide was copolymerized with the trimethylene carbonate to provide the appropriate tear properties, reasonable degradation rates, and limited production of acidic degradation products.
cc-CRS:
Could you please explain a little more about the osmotic release mechanism and how challenging it was for you to achieve staged release of two compounds? To what extent is the release dependent on the drug? Can it be tailored?
Professor Amsden:
The osmotic release mechanism relies on water penetration, initially by diffusion, into the polymer phase. The water moves into the polymer pretty much as a front. At some point, the water reaches a solid particle that has been embedded in the polymer. The water dissolves the particle, generating a concentrated solution. Now there is an enhanced driving force for water movement into the polymer, as the water activity gradient is increased (the water activity in the saturated solution is much lower than it is in the polymer). Water is now drawn from the exterior of the device toward the particle, and the saturated solution that is formed generates a pressure equal to the osmotic pressure of the saturated solution. This pressure causes the polymer to swell, and at some point, the ability of the polymer to resist this swelling is overcome, and cracks are formed in the polymer surrounding the swollen particle. The reduction in pressure forces the solution through the cracks, which are now connected to the surface, and thereby releases the contents of the solution into the environment surrounding the device. This occurs in a particle layer-by-particle layer fashion (each layer of distributed particles undergoes rupturing and crack formation before the next layer begins to swell), and so a prolonged, and nearly linear, release results. The release is driven by the osmotic pressure generated by the swelling particle, and we have shown previously that provided a physiologically innocuous compound, such as a sugar, was present in the highest amount, different proteins can be released at the same rate under the same loading conditions, and that the release rate was tailored by the amount of sugar initially present. Given that we knew that the release proceeded in a layer-by-layer fashion, it wasn't that difficult to conceive of having a device with different drugs in different layers to produce a staged release. It was more difficult to determine how to make the device into a geometry that could be easily implanted.
cc-CRS:
Regarding the elastomers, how long do they maintain their elastomeric behaviour during degradation? Do you think mechanical loading will also affect release kinetics?
Professor Amsden:
The change in elastic properties of the elastomers during degradation depends on the initial composition, and molecular weight of the prepolymers. In general, we have found that the mechanical properties remain unchanged, in vivo and in vitro, for between 4 to 6 weeks after implantation, after which time they begin to decrease. This time frame is sufficient to ensure that release by the osmotic pressure mechanism is complete, as it typically only lasts for from 2 - 4 weeks. I would expect that mechanical loading of the devices during release would affect the release kinetics, by adding an additional stress to the elastomers and likely increase the release rate.
cc-CRS:
What are the next steps for this work? Ultimately what application do you have in mind? What major hurdles remain to be overcome for this technology?
Professor Amsden:
The next steps are to demonstrate that the device can be effectively utilized in vivo. Applications we have considered include administration during coronary artery bypass grafting to generate blood vessels around blocked arteries that cannot be bypassed due to the location of the blockage or the lack of suitable donor tissue, and in the immunotherapeutic treatment of cancer. Major hurdles to overcome are to determine whether the inflammatory response around the implanted device results in impeded release of the drugs into the surrounding tissue, and to determine whether the concentrated solution that is released into the tissue produces an undesirable inflammatory response.
cc-CRS:
Thank you for this interview!