Micropatterned polymer substrates control alignment of proliferating Schwann cells to direct neuronal regeneration

Schmalenberg, Kristine E.; Uhrich, Kathryn E.

doi:10.1109/cne.2003.1196804

Cited by 15 publications

(28 citation statements)

References 15 publications

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“…While it is important to demonstrate that decellularization does not affect structural parameters, we hypothesized that the small size of endoneurial tubes does not permit efficient penetration of cells. This is supported by studies on several substrates (PDMS (Goldner et al, 2006;Schmalenberg and Uhrich, 2005), chitosan (Hu et al, 2009), collagen (Bozkurt et al, 2009)) that report a pore size of 20-60µm to be optimal for maximum axon penetration with minimum axon misdirection . Furthermore, a direct comparison between decellularized sensory and motor nerves resulted in better regeneration and higher nerve fiber count through motor nerves, primarily due to the larger size of endoneurial tubes in motor compared to sensory nerves (Moradzadeh et al, 2008).…”

Section: Discussionmentioning

confidence: 78%

Decellularized grafts with axially aligned channels for peripheral nerve regeneration

Sridharan

Reilly

Buckley

2015

Journal of the Mechanical Behavior of Biomedical Materials

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At least 2 million people worldwide suffer annually from peripheral nerve injuries (PNI), with estimated costs of $7 billion incurred due to paralysis alone. The current "gold" standard for treatment of PNI is the autograft, which poses disadvantages such as high fiscal cost, possible loss of sensation at donor site and the requirement of two surgeries. Allografts are viable alternatives; however, intensive immunosuppressive treatments are often necessary to prevent host rejection. For this reason, significant efforts have been made to remove cellular material from allografts. These decellularized nerve grafts perform better than other clinically available grafts but not as well as autografts; therefore, current research on these grafts includes the incorporation of additional components such as growth factors and cells to provide chemical guidance to regenerating axons. However, effective cellular and axonal penetration is not achieved due to the small pore size (5-10μm) of the decellularized grafts.The overall objective of this study was to induce axially aligned channels in decellularized nerve grafts to facilitate enhanced cell penetration. The specific aims of this study were to optimize a decellularization method to enhance cellular removal, to induce axially aligned pore formation in decellularized grafts through a novel unidirectional freeze drying method, to study the bulk mechanical properties of these modified decellularized grafts and to assess cell penetration into these grafts. To this end we modified an existing decellularization protocol to improve cellular removal while preserving matrix structure in rat sciatic nerve sections. Standard freeze drying and unidirectional freeze drying were employed to impart the necessary pore architecture, and our results suggest that unidirectional freezing is a pertinent modification to the freeze drying process to obtain axially aligned channels. These highly porous scaffolds obtained using unidirectional freeze-drying possessed similar tensile properties to native nerve tissue and exhibited enhanced cellular penetration after 14 days of culture when compared to non-freeze dried and standard freeze-dried scaffolds. The results of this study not only highlight the importance of aligned pores of diameters ~20-60μm on cellular infiltration, but also presents unidirectional freeze drying as a viable technique for producing this required architecture in decellularized nerves. To the best of our knowledge, this study represents the first attempt to manipulate the physical structure of decellularized nerves to enhance cell penetration which may serve as a basis for future peripheral nerve regenerative strategies using decellularized allografts.

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Section: Discussionmentioning

confidence: 78%

Decellularized grafts with axially aligned channels for peripheral nerve regeneration

Sridharan

Reilly

Buckley

2015

Journal of the Mechanical Behavior of Biomedical Materials

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“…40 Alignment of proliferating Schwann cells was obtained by patterning surfaces, which was able to direct neuronal growth. 41,42 Recently, in vitro studies indicated that 100 mm channel patterns are able to attain linear and guided neuronal extensions more effectively than 250 mm channel patterns. 21 Further, the 150 mm channel design allowed for an increase in number of channels from 7 channels (250 mm channel design) to 20 channels.…”

Section: Discussionmentioning

confidence: 99%

Multiple Channel Bridges for Spinal Cord Injury: Cellular Characterization of Host Response

Yang

Laporte

Zelivyanskaya

et al. 2009

Tissue Engineering Part A

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Bridges for treatment of the injured spinal cord must stabilize the injury site to prevent secondary damage and create a permissive environment that promotes regeneration. The host response to the bridge is central to creating a permissive environment, as the cell types that respond to the injury have the potential to secrete both stimulatory and inhibitory factors. We investigated multiple channel bridges for spinal cord regeneration and correlated the bridge structure to cell infiltration and axonal elongation. Poly(lactide-co-glycolide) bridges were fabricated by a gas foaming=particulate leaching process. Channels within the bridge had diameters of 150 or 250 mm, and the main body of the bridge was highly porous with a controllable pore size. Upon implantation in a rat spinal cord hemisection site, cells infiltrated into the bridge pores and channels, with the pore size influencing the rate of infiltration. The pores had significant cell infiltration, including fibroblasts, macrophages, S-100b-positive cells, and endothelial cells. The channels of the bridge were completely infiltrated with cells, which had aligned axially, and consisted primarily of fibroblasts, S-100b-positive cells, and endothelial cells. Reactive astrocytes were observed primarily outside of the bridge, and staining for chondroitin sulfate proteoglycans was decreased in the region surrounding the bridge relative to studies without bridges. Neurofilament staining revealed a preferential growth of the neural fibers within the bridge channels relative to the pores. Multiple channel bridges capable of supporting cellular infiltration, creating a permissive environment, and directing the growth of neural fibers have potential for promoting and directing spinal cord regeneration.

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“…This partial alignment of cells may be the reason behind the similar gene expression changes observed in the two fibrous scaffolds. In contrast, Schwann cells cultured on PCL film, in the absence of topographical signals, adopted a random orientation and spread-out morphology similar to that observed on other two-dimensional smooth substrates [34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…Alignment of Schwann cells by microgrooves or micropatterned ECM molecules [15][16][17] are ways to imitate the formation of bands of Büngner in vitro. In vivo, nerve conduits seeded with aligned Schwann cells have been used [18,19].…”

Section: Discussionmentioning

confidence: 99%

The effect of the alignment of electrospun fibrous scaffolds on Schwann cell maturation

et al. 2008

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Peripheral nerve regeneration can be enhanced by the stimulation of formation of bands of Büngner prior to implantation. Aligned electrospun poly(ε-caprolactone) (PCL) fibers were fabricated to test their potential to provide contact guidance to human Schwann cells. After 7 days of culture, cell cytoskeleton and nuclei were observed to align and elongate along the fiber axes, emulating the structure of bands of Büngner. Microarray analysis revealed a general down-regulation in expression of neurotrophin and neurotrophic receptors in aligned cells as compared to cells seeded on twodimensional PCL film. Real-time-PCR analyses confirmed the up-regulation of early myelination marker, MAG, and the down-regulation of NCAM-1, a marker of immature Schwann cells. Similar gene expression changes were also observed on cells cultured on randomly-oriented PCL electrospun fibers. However, up-regulation of the myelin-specific gene, P0, was observed only on aligned electrospun fibers, suggesting the propensity of aligned fibers in promoting Schwann cell maturation.

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Micropatterned polymer substrates control alignment of proliferating Schwann cells to direct neuronal regeneration

Cited by 15 publications

References 15 publications

Decellularized grafts with axially aligned channels for peripheral nerve regeneration

Decellularized grafts with axially aligned channels for peripheral nerve regeneration

Multiple Channel Bridges for Spinal Cord Injury: Cellular Characterization of Host Response

The effect of the alignment of electrospun fibrous scaffolds on Schwann cell maturation

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