Neural tissue engineering: A self-organizing collagen guidance conduit
Neural Tissue Engineering: A Self-Organizing Collagen Guidance Conduit
James B. Phillips, Stephen C.J. Bunting, Susan M. Hall, Robert A. Brown. Tissue Engineering. September 1, 2005, 11(9-10): 1611-1617. doi:10.1089/ten.2005.11.1611.
Nerve autografts are currently widely used to bridge gaps in transected peripheral nerves. However, this practice is not ideal as it involves harvesting donor tissue which might cause donor site morbidity. So far, numerous compounds have been used in order to produce tissue-engineered conduits but only empty tubes have been approves for human use. The guidance provided by empty tubes on the tissue level is, however, limited and a better device would effectively be multilayerd to provide guidance at the cellular level.
This paper reports on an implantable device which delivers aligned collagen guidance conduit into a peripheral nerve injury site. The conduit contains Schwann cells. These cells, which were in tethered rectangular gels were observed to result in uniaxial alignment. The practical use of this methodology was tested in 3-D culture where it demonstrated the ability to guide neurite extension from dissociated dorsal root ganglia. Rectangular tethered gels were seeded with Schwann cells and allowed to contract and axonal growth was detected after 3 days by fluorescence immunostaining. Neurons seeded extended neurites parallel to the axis of tension in the central region of the gel which was known to contain aligned Schwann cells. No cells growth was seen at the stress-shielded delta zones at the ends.
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For an implantable construct, a silicon tube was incorporated within the tethering site which aided the uniaxial cell generation to form a bridge of aligned collagen fibrils with Schwann cells. The device was tested for surgical nerve regeneration in a rat sciatic nerve model with a 5mm defect. The implanted aligned Schwann cell collagen constructs tethered in silicon tubes were implanted into short gaps in transected rat sciatic nerves where they supported axonal outgrowth. This outgrowth generation was greater than observed in controls: 1)nerves across empty conduits of plain silicon tubes with no self aligned collagen and 2) no device.
The significance of this paper is that it describes a protocol for producing a novel device to deliver a self-aligning cell-seeded conduit for use in neural tissue engineering. The relative simplicity and robustness of this new device compared to current procedures can make it an alternative to nerve autografts. Moreover, the application shown here can be applied to create 3-D engineered tissue models.
7 comments:
I think the nerve tissue engineering research that this paper describes has a lot of promise and potential for the near future.
I was wondering what the main differences were between the guidance provided by empty tubes and the guidance provided by the new multi-layered device? Why would the latter be so much better?
The device proposed in this paper is very interesting because it is so simple. When implanted, this device repairs neural defects but does it lead to re-formation of the myelin sheath? Does the nerve need to retain both its ends for repair to occur? Did the paper talk about this device regenerating the axon of a nerve? Nerve regeneration has a lot of potential especially in neurodegenerative diseases. Very cool work.
The use of Schwann cells is interesting due to their role in the peripheral nervous system. These cells are the cells that make up the myelin sheath in the peripheral nervous system in a natural system. Does the paper mention regeneration of Schwann cells, or do the cells in the implanted device take on this function? Also: did the authors discuss the possibility of the use of these devices for specific diseases that cause neuronal degradation? This would be a very interesting topic to continue research on as it can provide an avenue for research where stem cell research is being considered, and may speed the process for the integration of the new information (stem cells) to the older technologies by providing a simple way to regrow nerve axons, and thus opening a door to further nerve repair.
This research is especially interesting to me because I cut a nerve in my finger a couple years ago and I've had the personal experience of a nerve regrowing in an extremity. I am curious if it was tested whether efficacy varied with distance and whether the device varied the growth rate of the nerve?
Hi Suruchi, we talked about stress shielding in BioE 102 in relation to bone impants, so it was interesting to see the same concept come up in the context of neural tissue. Did the paper go into more depth about what percentage of stress was "shielded," and was the stress mostly in shear or axial? It seems that shear stress might be the more important factor, but this is just my intuition so I don't know if it's correct.
Jason
Are the nerve clusters where these types of implants are grafted avascular? If they are vascular, does the paper talk about the bio compatibility of the conduit device? it seems that something Si based would cause a fibrogen response that will isolate the device from the body. Or is that beyond the scope of this article?
Dana: The paper describes that empty conduit tubes only provide a limited tissue level guidance, whereas the the multilayered device can provide guidance at the cellular level. Also, it gives the device control to manipulate the environment from within the conduit by seeding the walls or lumen with Schwann cells or components of the ECM. This can potentially enhance the outgrowth of regenerating axons.
Lavanya: The device does not re-form the myelin sheath, instead it utilizes the implanted Schwann cells to direct axonal regrowth. So the answer does appear to regenearte axons of a a nerve. Moreover, the nerves should retain both their ends as the repair system works by creating a bridge from the edges of the defect. That was a very acute observation on your part!
Sydney: The device, as I understand it, only directs axonal growth utilizing the aligned seeded Schwann cells so it does not promote the formation of new Schwann cells. And although the paper did not specifically talk about the role of this research in treatments for neurological diseases, it did discuss its potential role in revolutionizing nerve repair.
Dan: The device only promoted axonal regrowth directly above the aligned Schwann cell seeded collagen constructs. Moreover, the paper statistically expressed that axonal regrowth with the Schwann cell seeded device was significantly greater (p<.05, t-test)4 and 8 weeks after implantation. Although the growth rate itself was not directly discussed, it can potentially be collected from the data above that the device does regenerate axons at a higher rate than the control treatments.
Jason: The stress shielded areas tended to in the delta zones located at each end of the gel where no alignment of the contractile Schwann cells occurred. This uniaxial alignment is caused by a contractile stress so I suppose that you are right in proposing that the stress shielding is not due to axial stress. However, the regions under the axial stress were crucial for this experiment.
Luqiddis: You are justified in your concerns about the Si tubes. Although silicone tubes have been used clinically in nerve repair, they are not the material of choice for many clinical applications since they are not bioresorbable. The paper talks about preliminary experiments in which bioresorbable tubes are filled with the same cell-seeded aligned collagen gels. The material would be chosen from a range of materials with different degrees of stiffness as this is essential in accommodating the different mechanical properties of the nerves undergoing repair.
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