Progress has been made in continuing research on scaffolds for the guided growth of nerves to replace damaged ones. The scaffolds contain pores that are approximately cylindrical and parallel, with nearly uniform widths ranging from tens to hundreds of microns. At the earlier stage of development, experimental scaffolds had been made from agarose hydrogel. Such a scaffold was made in a multistep process in which poly(methyl methacrylate) [PMMA] fibers were used as templates for the pores. The process included placement of a bundle of the PMMA fibers in a tube, filling the interstices in the tube with a hot agarose solution, cooling to turn the solution into a gel, and then immersion in acetone to dissolve the PMMA fibers. The scaffolds were typically limited to about 25 pores per scaffold, square cross sections of no more than about 1.5 by 1.5 mm, and lengths of no more than about 2 mm.
To be clinically relevant, the scaffolds must be scaled up: They are required to have typical cross-sectional dimensions of the order of 1 cm and to have lengths in the approximate range of 2 to 2.5 cm. For repairs of the central nervous system, there is an additional requirement that each scaffold contain between about 100 and about 1,000 pores; for repairs of peripheral nerves, there is a requirement for sustained or timed release of brain-derived neurotrophic factor (BDNF) or another suitable nerve-growth agent to enable growth to continue to the required lengths.
The work performed since the earlier stage has been oriented toward satisfying these and other requirements. The work has included development of a more-complex version of the prior multistep process that has made it possible to partly satisfy the scaling-up requirements in that scaffolds having cross sections exceeding 1 cm2 in area and lengths up to 1 cm have been fabricated. One notable feature of the present version of the process is a multistep subprocess in which a template of polystyrene (PS) fibers is made from a composite of polystyrene fibers surrounded by a continuous PMMA matrix. Another notable feature of the present version of the process is the use of centrifugation to ensure complete permeation of the template by the hot agarose solution.
To satisfy the requirement for sustained or timed release of nerve-growth agents, it has been proposed to incorporate, into scaffolds, reservoirs containing such agents. In cases in which the agent is BDNF, the proposal encompasses an alternative approach in which the reservoirs would be filled with genetically engineered cells that secrete BDNF. The figure illustrates the proposal as it might be implemented in a scaffold that would be attached to the severed ends of a peripheral nerve. Attached to the scaffold would be open-ended sleeves that would enable attachment to the severed nerve ends. The pores in the scaffold would serve as channels to guide the growth of the nerve ends toward each other. The reservoir containing the nerve-growth agent would be integrated into the outer wall of the scaffold. The nerve-growth agent would be delivered from the reservoir to the channels by diffusion through the agarose hydrogel matrix.
This work was done by Jeffrey Sakamoto of Caltech and Mark Tuszynski of UC San Diego for NASA’s Jet Propulsion Laboratory.
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