This post is the second of two covering the World Biomaterials Congress. To read my previous blog about the use of biomaterials to study cell behaviour and differentiation in vitro, please click here. This post will cover the use of biomaterials for in vivo delivery strategies.
Cartilage, despite its essential role in the movement of joints in our body, has a very limited ability to repair itself. Jason Burdick, from the University of Pennsylvania, is addressing this problem using a biomaterial implant to encourage meniscus repair. The strategy he presented is a unique, multi-polymer delivery system that meets a number of requirements for repair all contained within only one implant. By modifying the chemistry of each component of the delivery system, individual fibre degradation can be controlled, resulting in a separate release rate for each component to provide the proper timing of therapeutic action.
The foundation of the implant is a permanent scaffold of a polymer called polycaprolactone (PCL), which holds the implant together. The first therapeutic, of two, that gets released is collagenase, an enzyme that will degrade any necrotic tissue in the injury site, remodelling and priming it for repair. Collagenase release takes place in the first 12 hours following scaffold implantation. Next, over the course of weeks, a hyaluronan gel releases transforming growth factor-β1 (TGF- β1), a protein previously demonstrated to stimulate cartilage cell (known as chondrocytes) recruitment. Prof. Burdick’s lab injected this scaffold into a mouse subcutaneous implant meniscus model and analyzed the tissue four weeks later. They observed repair of the injury, as well as chondrocyte recruitment to the area, particularly when the implant contained both collagenase and the hyaluronan-TGF- β1 gel.
Moving from recruitment of the body’s cells to transplantation of new cells, Minna Chen, from the same lab, talked about ways to improve cell viability during the delivery process. Most cell delivery strategies, regardless of tissue, rely on injecting the cells through a needle into the location of interest. Unfortunately, this injection process is often associated with a significant amount of cell death due to the shear forces cells will experience as they squeeze through the small space of the needle.
To improve cell survival for injection of endothelial precursor cells into the heart, Ms. Chen discussed her work using hyaluronan, which is modified with two chemical compounds – adamantine and cyclodextrin – to form a self-assembling hydrogel. These two molecules can assemble and disassemble into a complex in a reversible reaction, so that when a force is applied to the hydrogel, the complex will disassemble to allow the hydrogel to be easily injected through a needle, after which it will reassemble.
Another important feature of this hydrogel is that many of its properties are easily customizable. By increasing the weight percentage of the hyaluronan, Ms. Chen was able to increase the viscosity of the gel and thus the injection force required to push it through a needle. She found that doing so caused more cell death, which was not unexpected considering more force is being exerted on the cells. Interestingly, something unexpected did happen when the speed that the cells were injected through the needle (i.e., the flow rate) was increased. There was no difference in cell survival, but the morphology and cell phenotype changed. This surprising finding may have an impact on the performance of the cells once they are delivered to the heart, and is an important consideration for future studies.
The last highlight was from David Nesbit, from the Australian National University in Canberra. His lab is using a peptide that will self-assemble into nanofibres through molecular interactions with itself to form a cell delivery vehicle to treat stroke. He investigated several peptides that could be attached to his nanofibre scaffold, including IKVAV, which is a small fragment of laminin, a protein found in the extracellular matrix of the brain, and RGD, a fragment of fibronectin, which is not commonly found in the brain.
When Dr. Nesbit’s lab delivered neurons encapsulated in their scaffold into the stroke-injured mouse brain, they found greater cell survival with the brain peptide IKVAV, as well as increased innervation of the cells. Dr. Nesbit also discussed a long-term survival study his lab conducted with this delivery system, in which they observed survival of transplanted cells up to nine months following transplantation, as well as behavioural improvements of treated mice. Cell survival in stroke transplantation studies is rarely tracked for so long after transplantation, and it is exciting that Dr. Nesbit’s lab was able to achieve such long-term survival.
These examples represent just some of the amazing work going on in the field of biomaterials and regenerative medicine to better direct repair by the cells of the body, and to improve delivery of healthy cells into the body. By using biomaterials to control cells, we can improve delivery strategies in a wide range of organs and tissues for eventual clinical translation.
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