Peripheral nerve injuries Flashcards
Why are nerve injuries one of the most challenging in regenerative medicine?
CNS and PNS = different cell types! Composition of cells therefore very different
Epidemiology of nerve injuries ?
9000 per year in UK
Mainly younger population (car accidents etc)
Therefore large financial burden on society
ANATOMY OF NERVE
Axons are surrounded by myelinated schwann cells
They are enclosed by the endoneurium (surrounds axons)
These are bundled together into fascicles
Fascicles are enclosed by the perineurium. Mutiple fascicles = nerves!
Whole nerves are surrounded by the epineurium
INJURY TYPES?
Elongation –> only 10/20% extension of nerve is allowed before structural damage occurs
Laceration –> make up 30% of nerve injuries
Compression –> external mechanical pressure on conductive membrane of nerve
Wallerian degeneration - how long does the process take ? why does it take longer in the CNS?
1-3mm each day
In CNS, macrophages infiltrate much more slowly, inhibiting the removal of dead myelin
Role of reactive astrocytes in wallerian degeneration?
Reactive astrocytes produce glial scars –> this inhibits regeneration in the CNS and promotes it in the PNS!!!
Approaches to repair in the PNS?
- Surgery
- Grafts
- Nerve conduits
Surgical reconstruction of nerves – what makes it possible ? Overall process?
- Suture individual fascicles of the nerve back together
- Only possible if the nerve severs are close together. If the gap is too large, there is a decrease in blood flow and overstretching of the nerve is seen.
Stretch-repair relationship?
8% nerve stretch = 50% decrease in blood flow.
Complete ischaemia at 15% of nerve stretching
GRAFTS - autologous - advs and disadvs
Autologous grafts are taken from other nerves within the body of the same person.
ADVS - low risk of immune rejection
DISADVS - loss of function at donor site, 2 surgeries required, limited nerve size and type available
GRAFTS - allogeneic - advs and disadvs
Graft taken from different person.
ADVS - no second surgery required. No loss of function at donor site due to taking from same person
DISADVS - limited availability and higher risk of immune rejection
NERVE CONDUITS - how do they work?
Guide regenerating axons and prevent infiltration of scar tissue.
Increase the concentration of intraluminal proteins and important in guiding regeneration.
Properties of an ideal nerve conduit?
- Permeable to proteins and plasma
- Porous
- Mechanically malleable (if too stiff the surrounding tissue may become injured)
- Degradable in the long term but lasts long enough for regeneration to take place
- Biocompatible
- Suturable
- Sterile / sterylisable
Classes of biomaterials that may be appropriate for designing a nerve conduit?
Collagen
Fibronectin
Gelatin
Top-down approach to designing nerve conduits - DECELLULARISED NERVE CONDUIT ?
Retain ECM architecture and remove antigens
Nerve chemically and biologically decellularised –> creates a scaffold for nerve regeneration, clears pathways to allow cell migration/axonal regeneration
The axon will distribute evenly throughout the nerve thickness allowing functional incorporation of the neve conduit
Bottom - up approach of nerve conduit –> what does this involve?
Design own nerve conduit from scratch!
Make own design for what is needed / going to work best for that particular situation
Several materials and a mixture of natural and synthetic could be used. Can also be biodegradable!
Synthetic materials used to produce nerve conduits?
- PLA (polylactic acid)
- Poly (lacto-go-glycolic) acid
- Poly caprolactone
- Polyethylene glycol
Commerically available nerve conduits?
- Neurotube - PGA
- Neuragen - Type 1 collagen
- Neurolac
A range of fabrication methods are employed for these
Synthetic, non-biodegradable materials used for nerve conduits?
Silicone
Gore-Tex
Length limitations - what is the relevance?
Chance of survival of nerve regeneration decreases once the gap reaches a certain size
A short gap means a fibrin cable is robust enough to provide a regeneration platform
At longer lengths thinning of the nerve restricts regeneration –> no fibrin cables are seen at long length
Critical gap length - what is meant by this?
Length at which regeneration of the nerve occurs 50% of the time
Current strategies are aiming to increase the critical gap length
What approaches are involved in increasing the critical gap length
- Use of ECM componants
- Cell grafts
- Intralumenal support
- Neurotrophic factors
OR A COMBINATION OF THE ABOVE
Use of ECM in increasing critical gap length
- Hydrogels (high concs h20 prevent axonal penetration)
- Laminin, fibronectin and collagen – > problem is that batches of each greatly vary, meaning that they are not massively robust therefore always suitable for clinic
Intralumenal proteins in increasing critical gap length
Engineered constructs to contain different proteins inside to recreate an accurate nerve scaffold - CASE STUDY EXAMPLE
Neurotrophic factors in nerve regeneration –> how used / why important?
- Support axonal growth, migration and proliferaton of schwann cells and modulation of intrinsic signalling pathways
- Improves functionalisation
- Need controlled release (like BMPS) into scaffold - encapsulation methods used often
Schwann cells in nerve regeneration - why important? How are they recapitulated?
- Schwann cells secrete factors critical for regeneration. Stem cells used where schwann cells unavailable
CELL GRAFTS –> genetically modified cells –> can produce appropriate stimuli for regeneration. Grafts must contain NT factors, schwann cells, stem cells and GM cells
