Limits...
Biodegradable biomatrices and bridging the injured spinal cord: the corticospinal tract as a proof of principle.

Joosten EA - Cell Tissue Res. (2012)

Bottom Line: These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract.The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord.The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Pain Management and Research Center, Maastricht University Medical Hospital, Maastricht, The Netherlands. b.joosten@maastrichtuniversity.nl

ABSTRACT
Important advances in the development of smart biodegradable implants for axonal regeneration after spinal cord injury have recently been reported. These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract. The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord. The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair. Based on the findings summarized in this review, the future development of smart biodegradable bridges for CST regrowth and regeneration in the injured spinal cord is discussed.

Show MeSH

Related in: MedlinePlus

Corticospinal and ascending sensory tract tracing at 12 weeks. Parasagittal sections, with rostral cord oriented toward top, ventral surface toward left. a Biotin dextran amine (BDA) anterograde tracing of the corticospinal tract (cst) in a F-DS-NT-3 (1,000 ng/mL) treated cord. The CST extends from the rostral intact cord toward the lesion site. The CST is located just dorsal to the gray matter (gm, indicated by dotted line), in the most ventral part in the white matter (wm) of the dorsal funiculus. In all groups, as fibers approached the lesion (l, border indicated by line), the fibers were truncated or diverted to more dorsal white matter (arrow). Infrequently, CST-positive fibers were seen in the spared dorsal matter encircling the rostral lesion cavity (arrowhead). b Tracing of ascending sensory neurons with cholera toxin B (CTB) in F-DS-NT-3 (1,000 ng/mL) treated cord. In all groups, CTB staining ended abruptly at the lesion border with the intact cord (lc). Adapted from Taylor and Sakiyama-Elbert (2006), with permission
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3375422&req=5

Fig3: Corticospinal and ascending sensory tract tracing at 12 weeks. Parasagittal sections, with rostral cord oriented toward top, ventral surface toward left. a Biotin dextran amine (BDA) anterograde tracing of the corticospinal tract (cst) in a F-DS-NT-3 (1,000 ng/mL) treated cord. The CST extends from the rostral intact cord toward the lesion site. The CST is located just dorsal to the gray matter (gm, indicated by dotted line), in the most ventral part in the white matter (wm) of the dorsal funiculus. In all groups, as fibers approached the lesion (l, border indicated by line), the fibers were truncated or diverted to more dorsal white matter (arrow). Infrequently, CST-positive fibers were seen in the spared dorsal matter encircling the rostral lesion cavity (arrowhead). b Tracing of ascending sensory neurons with cholera toxin B (CTB) in F-DS-NT-3 (1,000 ng/mL) treated cord. In all groups, CTB staining ended abruptly at the lesion border with the intact cord (lc). Adapted from Taylor and Sakiyama-Elbert (2006), with permission

Mentions: As already discussed (see “Matrigel”), the additional use of fibrin scaffolding is needed in order to stimulate the regrowth of injured CST fibers after use and in combination with various transplantation paradigms in the lesioned rat spinal cord (Guest et al. 1997a). Furthermore, fibronectin mats or fibrin scaffolds in themselves can be used to deliver neurotrophins (or growth factors) in a controlled manner and at the same time act as a physical bridge for regeneration. Fibrin-based tissue engineering scaffolds not only enhance neural fiber sprouting but at the same time delay the accumulation of reactive astrocytes at the lesion in a subacute model of spinal cord injury (Johnson et al. 2010). For optimal delivery of drugs into the lesioned spinal cord, it is required that the delivery system (DS) sequesters and protects the protein (or growth factor) until the appropriate time of release and, furthermore, that the release allows the drug to be available to regenerating neurons or axons over a longer period of time. An affinity-based delivery system based on fibrin scaffolds has been developed to provide sustained release of neurotrophins (Wood et al. 2010). Affinity-based delivery systems allow the release of growth factors to be controlled related to the degradation of the delivery system and surrounding fibrin matrix (Sakiyama-Elbert and Hubbell 2000). The delivery of NGF and GDNF from fibrin matrices containing the affinity-based delivery system has been shown to promote peripheral nerve regeneration in short-term in vivo studies and in particular the GDNF DS demonstrated superior functional recovery as compared to autograft controls (Wood et al. 2009, 2010). Also, an affinity-based delivery system to release NT-3 in a controlled manner from fibrin gels has been developed (Taylor et al. 2004): NT-3 was immobilized within fibrin gels via non-covalent interactions in order to slow the diffusion release. Then, the release of NT-3 is mediated through the cell-activated degradation of fibrin (Taylor et al. 2004). The immediate implantation of NT-3 containing fibrin scaffolds into the lesioned spinal cord enhanced the initial regenerative response (9 days after the lesion) by increasing neuronal fiber sprouting and cell migration into the lesion. This cellular response was, however, not accompanied by functional improvements (Taylor et al. 2006). In a follow-up study, the effect of controlled delivery of NT-3 from fibrin scaffolds acutely after spinal cord injury was evaluated at the chronic stages. At 12 weeks after injury and treatment, the animals treated with NT-3 fibrin scaffolds did not show functional improvements and, despite the fact that neuronal fibers were present inside the lesion, anterogradely traced CST fibers (where these fibers were truncated or diverted to the more dorsal white matter; Fig. 3; Taylor and Sakiyama-Elbert 2006) and dorsal sensory tract axons did not regrow into the lesion (Taylor and Sakiyama-Elbert 2006). In this context, a major disadvantage of the fibronectin mats as well as fibrin glue acting as bridge implants is their relatively rapid (1–2 weeks) degradation. Hence, an alternative approach would be to perform this treatment in the chronic phase after the lesion has stabilized.Fig. 3


Biodegradable biomatrices and bridging the injured spinal cord: the corticospinal tract as a proof of principle.

Joosten EA - Cell Tissue Res. (2012)

Corticospinal and ascending sensory tract tracing at 12 weeks. Parasagittal sections, with rostral cord oriented toward top, ventral surface toward left. a Biotin dextran amine (BDA) anterograde tracing of the corticospinal tract (cst) in a F-DS-NT-3 (1,000 ng/mL) treated cord. The CST extends from the rostral intact cord toward the lesion site. The CST is located just dorsal to the gray matter (gm, indicated by dotted line), in the most ventral part in the white matter (wm) of the dorsal funiculus. In all groups, as fibers approached the lesion (l, border indicated by line), the fibers were truncated or diverted to more dorsal white matter (arrow). Infrequently, CST-positive fibers were seen in the spared dorsal matter encircling the rostral lesion cavity (arrowhead). b Tracing of ascending sensory neurons with cholera toxin B (CTB) in F-DS-NT-3 (1,000 ng/mL) treated cord. In all groups, CTB staining ended abruptly at the lesion border with the intact cord (lc). Adapted from Taylor and Sakiyama-Elbert (2006), with permission
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375422&req=5

Fig3: Corticospinal and ascending sensory tract tracing at 12 weeks. Parasagittal sections, with rostral cord oriented toward top, ventral surface toward left. a Biotin dextran amine (BDA) anterograde tracing of the corticospinal tract (cst) in a F-DS-NT-3 (1,000 ng/mL) treated cord. The CST extends from the rostral intact cord toward the lesion site. The CST is located just dorsal to the gray matter (gm, indicated by dotted line), in the most ventral part in the white matter (wm) of the dorsal funiculus. In all groups, as fibers approached the lesion (l, border indicated by line), the fibers were truncated or diverted to more dorsal white matter (arrow). Infrequently, CST-positive fibers were seen in the spared dorsal matter encircling the rostral lesion cavity (arrowhead). b Tracing of ascending sensory neurons with cholera toxin B (CTB) in F-DS-NT-3 (1,000 ng/mL) treated cord. In all groups, CTB staining ended abruptly at the lesion border with the intact cord (lc). Adapted from Taylor and Sakiyama-Elbert (2006), with permission
Mentions: As already discussed (see “Matrigel”), the additional use of fibrin scaffolding is needed in order to stimulate the regrowth of injured CST fibers after use and in combination with various transplantation paradigms in the lesioned rat spinal cord (Guest et al. 1997a). Furthermore, fibronectin mats or fibrin scaffolds in themselves can be used to deliver neurotrophins (or growth factors) in a controlled manner and at the same time act as a physical bridge for regeneration. Fibrin-based tissue engineering scaffolds not only enhance neural fiber sprouting but at the same time delay the accumulation of reactive astrocytes at the lesion in a subacute model of spinal cord injury (Johnson et al. 2010). For optimal delivery of drugs into the lesioned spinal cord, it is required that the delivery system (DS) sequesters and protects the protein (or growth factor) until the appropriate time of release and, furthermore, that the release allows the drug to be available to regenerating neurons or axons over a longer period of time. An affinity-based delivery system based on fibrin scaffolds has been developed to provide sustained release of neurotrophins (Wood et al. 2010). Affinity-based delivery systems allow the release of growth factors to be controlled related to the degradation of the delivery system and surrounding fibrin matrix (Sakiyama-Elbert and Hubbell 2000). The delivery of NGF and GDNF from fibrin matrices containing the affinity-based delivery system has been shown to promote peripheral nerve regeneration in short-term in vivo studies and in particular the GDNF DS demonstrated superior functional recovery as compared to autograft controls (Wood et al. 2009, 2010). Also, an affinity-based delivery system to release NT-3 in a controlled manner from fibrin gels has been developed (Taylor et al. 2004): NT-3 was immobilized within fibrin gels via non-covalent interactions in order to slow the diffusion release. Then, the release of NT-3 is mediated through the cell-activated degradation of fibrin (Taylor et al. 2004). The immediate implantation of NT-3 containing fibrin scaffolds into the lesioned spinal cord enhanced the initial regenerative response (9 days after the lesion) by increasing neuronal fiber sprouting and cell migration into the lesion. This cellular response was, however, not accompanied by functional improvements (Taylor et al. 2006). In a follow-up study, the effect of controlled delivery of NT-3 from fibrin scaffolds acutely after spinal cord injury was evaluated at the chronic stages. At 12 weeks after injury and treatment, the animals treated with NT-3 fibrin scaffolds did not show functional improvements and, despite the fact that neuronal fibers were present inside the lesion, anterogradely traced CST fibers (where these fibers were truncated or diverted to the more dorsal white matter; Fig. 3; Taylor and Sakiyama-Elbert 2006) and dorsal sensory tract axons did not regrow into the lesion (Taylor and Sakiyama-Elbert 2006). In this context, a major disadvantage of the fibronectin mats as well as fibrin glue acting as bridge implants is their relatively rapid (1–2 weeks) degradation. Hence, an alternative approach would be to perform this treatment in the chronic phase after the lesion has stabilized.Fig. 3

Bottom Line: These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract.The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord.The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Pain Management and Research Center, Maastricht University Medical Hospital, Maastricht, The Netherlands. b.joosten@maastrichtuniversity.nl

ABSTRACT
Important advances in the development of smart biodegradable implants for axonal regeneration after spinal cord injury have recently been reported. These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract. The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord. The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair. Based on the findings summarized in this review, the future development of smart biodegradable bridges for CST regrowth and regeneration in the injured spinal cord is discussed.

Show MeSH
Related in: MedlinePlus