Chapter 5: Summary and Future prospects
2.1 Introduction
which acts as an impene reaching the synaptic target.
Fig 2.1: Changes in CNS environments after maturation and injury.
development, unmyelinated axons with motile growth cones can extend, retract and
to various trophic and guidance molecules. This dynamic process allows the neural circuitry to be fine-tuned (a). As the nervous system matures after birth, myelination is finalized with oligodendrocytes ensheathing axons to prevent aberrant sprout
chondroitin sulphate proteoglycans (CSPGs) to further limit structural plasticity in the adult (b). After CNS injury, axons become transected and reactive astrocytes further upregulate their secretion of CSPGs. The distal endin
and become exposed to CSPGs from the glial scar, as well as myelin from oligodendrocytes and myelin debris (
plasticity in the adult and lon
influences might not only enhance the regeneration of severed axons, but might also promote compensatory sprouting. EphA4, the cognate neuronal receptor for ephrin B3;
MAG, myelin-associated glycoprotein; NgR, Nogo myelin glycoprotein; Trk, tyrosine receptor kinase. ( 2006)
which acts as an impenetrable barrier inhibiting the regenerating neurons from target.
Changes in CNS environments after maturation and injury.
development, unmyelinated axons with motile growth cones can extend, retract and
to various trophic and guidance molecules. This dynamic process allows the neural circuitry ). As the nervous system matures after birth, myelination is finalized with oligodendrocytes ensheathing axons to prevent aberrant sprouting and astrocytes secreting chondroitin sulphate proteoglycans (CSPGs) to further limit structural plasticity in the adult ). After CNS injury, axons become transected and reactive astrocytes further upregulate their secretion of CSPGs. The distal endings of severed axons form dystrophic growth cones and become exposed to CSPGs from the glial scar, as well as myelin-associated inhibitors from oligodendrocytes and myelin debris (c). As similar mechanisms prevent short
plasticity in the adult and long-distance axon repair after injury, relieving these inhibitory influences might not only enhance the regeneration of severed axons, but might also promote compensatory sprouting. EphA4, the cognate neuronal receptor for ephrin B3;
lycoprotein; NgR, Nogo-66 receptor; OMgp, oligodendrocyte myelin glycoprotein; Trk, tyrosine receptor kinase. (Adapted with permission from Yiu
trable barrier inhibiting the regenerating neurons from
Changes in CNS environments after maturation and injury. During embryonic development, unmyelinated axons with motile growth cones can extend, retract and respond to various trophic and guidance molecules. This dynamic process allows the neural circuitry ). As the nervous system matures after birth, myelination is finalized with ing and astrocytes secreting chondroitin sulphate proteoglycans (CSPGs) to further limit structural plasticity in the adult ). After CNS injury, axons become transected and reactive astrocytes further upregulate gs of severed axons form dystrophic growth cones associated inhibitors ). As similar mechanisms prevent short-range distance axon repair after injury, relieving these inhibitory influences might not only enhance the regeneration of severed axons, but might also promote compensatory sprouting. EphA4, the cognate neuronal receptor for ephrin B3;
66 receptor; OMgp, oligodendrocyte Adapted with permission from Yiu et al,
This unfavourable cellular milieu for neural regeneration makes even minor injuries/tissue damage in the CNS fatal. Fig 2.1 describes the changes in CNS environment after nerve injury. However, the glial cells in the peripheral nervous system (PNS) i.e the Schwann cells play a much more constructive role in nerve regeneration than their CNS counterparts. Upon nerve damage, the Schwann cells shed their myelin sheath and release cytokines which triggers macrophages and monocytes to rush to the site of injury and clear the debris. Such phagocytic infiltration is aided by the easy physiological access to the peripheral nerves as compared to the heavily guarded CNS. The axonal sprouts arising from the Nodes of Ranvier in the proximal end are guided by the neurotrophins secreted by the Schwann cells towards the distal end at a rate of 2-5mm/day (Schmidt, 2003). Thus injuries resulting in small gaps in the peripheral nerves can be healed by regeneration. However, in case of gaps larger than 5mm, surgical intervention becomes essential (Cunha et al, 2011).
Neural tissue engineering (NTE) provides promising alternative therapeutic solutions to achieve functional regeneration in severe traumatic injuries which lead to large nerve gaps. NTE involves fabrication of tubular shaped scaffolds called nerve guides/nerve conduits which upon implantation in a nerve gap provide topographical guidance and biochemical cues by maintaining appropriate concentration of cells and growth factors in the lumen thereby facilitating axonal regeneration.
2.1.2 Components of an artificial nerve conduit
Artificial nerve conduits generally comprises of three components – Scaffolds, Support cells and Growth factors.
The scaffold is a template which provides a framework and initial support for the cells to attach, proliferate and differentiate and form an extra cellular matrix (ECM). The scaffolds are developed from a special class of materials called Biomaterials using carefully chosen fabrication method depending on the native architecture of the target tissue. A biomaterial can be described as a substance (other than a drug) or combination of substances synthetic or natural in origin, which can be used for any period of time, as a whole or part of a system to treat, augments, or replace tissue, organ, or its biological function (Williams DF, 2004). Biomaterials generally can be
subdivided to fall under different categories like metals, ceramics, polymers and composites (Williams DF, 2004).
Like any other tissue engineered graft, nerve conduits also should contain cells that are seeded over scaffold and grown in 3D to form the native extracellular matrix of the target tissue thereby making the regenerated tissue functional. Support cells may be autologous, allogeneic, xenogeneic or immortalised cell lines specific to the target tissue.
An ideal nerve conduit should be incorporated with biomolecules to provide biochemical cues to the regenerating axons. Such molecules are generally growth factors, hormones etc and can be delivered through scaffold functionalization or secreted by genetically engineered support cells.
Extensive in vivo studies are essential to establish the clinical significance of artificial nerve conduits. The importance of designing the animal experimentation with appropriate injury model is discussed in the following sections.