?Tissuegen has developed proprietary technology that allows the release of growth factors from biodegradable fibers. These fibers, commercially available as elute(r) biodegradable drug- loaded fibers (www.tissuegen.com), can be used in microfluidic spaces to form three- dimensional gradients using variable pitch coils. The elute fibers are coiled along the lumen of the microchannels with a variable pitch angle, such that when the pitch angle is small and the fiber coils are very close together the concentration of the neurotrophic factor in the lumen is high, and conversely when the fiber coils are far apart the concentration within the lumen of the microchannel drops. By choosing both the concentration of the appropriate neurotrophic factor in the fiber as well as the rate at which the pitch angle changes we have the ability to "dial---in" a wide range of concentration gradients. Here, we will take advantage of these growth factor gradients in microchannels to improve peripheral nerve regeneration. The elute fibers can release protein for periods ranging from weeks to several months depending on how the fiber is fabricated. Therefore, the concentration gradient will be maintained within the lumen for prolonged periods. The rate at which the elute fibers release the protein decreases with time, and hence the concentration of growth factor at a particular point within the lumen will likewise decrease with time; however, the slope and shape of the gradient will be maintained as long as the fiber continues to release the protein. In other words, the ratio of the concentration at the high end to the concentration at the low end will remain constant throughout the entire time course of drug release. The first specific aim of this research is to determine an appropriate concentration gradient by investigating various neurotrophic concentrations within the elute fiber as determined by in vitro assays involving explanted dorsal root ganglion (drg) cells from neonatal rats. After we have verified that a specific gradient concentration within the microchannels eluting a specific gradient induces directional growth of axons from drgs we will be prepared to move to specific aim 2, which is to create a long gap (4cm) in a rabbit peroneal nerve injury model. The gap will be filled with an appropriate sized elute bni (or control). The endpoints will include both histological evidence and functional recovery. If successful, this technology can be beneficial to other areas or nerve repair both in the peripheral and central nervous systems.
Public Health Relevance Statement: Public Health Relevance: tissue gen has developed proprietary technology that allows the release of growth factors from biodegradable fibers. These fibers can be wound into a variable pitch coil, thereby creating a 3- dimensional concentration gradient within the coil. This technology can be applied to the repair of the nervous system, as nerve cells are known to follow growth factor concentration gradients during development and after injury. This study will provide the necessary in vivo evidence that a stable, three- dimensional concentration gradient of appropriate neural growth factors can be incorporated reliably into nerve guides, improving the outcome of nerve repair. This is important, as it is also known that if neurons are uniformly exposed by growth factors, they will begin grow, but with no specific direction. However, if they are exposed to a gradient, meaning an ever-increasing concentration of growth factors as they move towards their target they will constantly be motivated to migrate in the preferred direction. To an injured patient, this means that the speed and accuracy of functional recovery might be increased. If successful, this technology can be beneficial to other areas or nerve repair both in the peripheral and central nervous systems.
NIH Spending Category: bioengineering; injury (total) accidents/adverse effects; neurosciences; regenerative medicine
Project Terms: 3-dimensional; adult; afferent neurons; area; autologous transplantation; axon; axon growth; axon regeneration; axonal guidance; base; behavior test; biocompatible; biodegradable polymer; biological; cells; crows; defect; density; design; development; device designs; drops; environment; evaluation; fiber; fibroblasts; ganglion cell; glial cell-line derived neurotrophic factor; growth; growth factor; hydrogels; immune; implant; implantable device; improved; in vitro; in vitro assay; in vivo; inflammation; injured; injury; injury and repair; legal patent; length; marketing; mediating; medical; meetings; methodology; methods; microfluidics; microspheres; modeling; molecular; motor; natural regeneration; neonatal; nerve; nerve injury; nerve regeneration; nervous system structure; neural growth; neuraxis; neuronal injury; neurons; neurotrophic factor; novel; oryctolagus cuniculus; outcome; patients; peripheral; peripheral nerve injury; peripheral nerve regeneration; peroneal nerve; pharmaceutical preparations; physiological; physiological processes; polymers; process; property; proteins; prototype; public health relevance; rattus; recovery of function; reinnervation; repaired; reporting; research; research design; role; scaffold; sensory; shapes; site; speed (motion); spinal cord; spinal ganglia; sterilization; stimulus; technology; testing; texas; time; tissues; universities; ursidae family; variant; wound; wound healing
