Healing of nerves, blood vessel, muscles, tendon, cartilage and bone Peripheral nerves History



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Healing of nerves, blood vessel, muscles, tendon, cartilage and bone

Peripheral nerves
History

Galen 200AD - not possible

Guy deChauliac (1300s) - repaired ends with restoration

Muller/Schwann 1842 - regeneration confirmed

Waller - distal parts degerated

Tinel (1918) - tingling = nerve regeneration vs pain = nerve irritation

Seddon/Woodhall - bridge/cable grafts/primary/secondary repair

Sidney Sunderland(1978) - anatomy of nerves


Anatomy

 Cell bodies

 motor nerves - anterior horn of the spinal cord

 sensory nerve - dorsal root ganglia

 Motor nerves terminate at motor end plates in muscle and sensory nerves terminate in sensory receptors in skin.

 When neuronal cell body is injured the entire cell dies

 Axonal injury do not result in cell death rather the damaged neurons respond by regenerating new distal axonal segments

 Axonal coverings:

 +/-myelin sheath

 Schwann cells.

 Endoneurium. Resists longitudinal forces

 perineurium = nerve fascicles. Ala blood brain barrier. Removal leads to cessation of nerve function.

 epineurium surround groups of perineural bound bundles. The vessels run in the epineurium. The epineurium is rich in fibroblasts. Thicker around joints

 An inner epineurium surrounds one or more fascicular bundles within larger peripheral nerves with the outer epineurium surrounding the entire peripheral nerve

 Proteins and other substances required for maintenance of cellular homeostasis and for signal transmission are synthesized primarily within the cell body. These substances are then transmitted down the axon through a micro tubular system to the site where they are required

 Blood supply

• Vasa nervorum enter the nerve segmentally.

• Longitudinal vessels run both superficially in the outer epineurium and deep between the fascicles.


Physiology

Action Potentials

• Localised potentials: Occur over short distances, decrease over distance, important at sensory nerve endings and inter-cellular junctions.

• Action potentials: Conducted impulses that do not diminish over time.

• Action potentials in unmyelinated fibres progress at a rate directly proportional to the size of the fibre.

• In myelinated fibres, AP’s jump from one node of Ranvier the next, a process called saltatory conduction, that speeds up conduction tremendously.

Axoplasmic flow

• Bidirectional: Antegrade may be either fast or slow.

• Fast antegrade flow plays a functional role for transport of neurotransmitter vesicles and plasma membrane constituents.

• Slow antegrade flow is important for structural elements of the cytoskeleton: micro tubules and filaments and neuro-filaments.

• Retrograde flow is for evacuation of waste products, recycling of cell products and the relay of information to the cell body.
Nerve injury
4 PHASES OF REGENERATION

Degeneration: The phase of delay: About 1 month

Axon penetration of nerve interface: Crossing the gap

Distal axon regeneration down the endoneurial tube: ~1mm/d

Functional recovery

Degeneration

Distal

Wallerian degeneration - process of fragmentation of the axon distal to the injury as well as its myelin sheet

 Injury causes release of ca2+ ions which mediate activation of proteases that results in the formation of free radicals which both contribute to tissue breakdown

 As tissue degenerates the Schwann cells proliferate and become phagocytic

 They phagocytize degenerating axonal elements and myelin -> clearing of distal axonal segments and contribute to the phagocytic process

 End result = hollow endoneural sheath with adjacent Schwann cells which then collapses. By the end of 2-6 weeks, no histological trace of the distal axon can be found.

Proximal

 limited degeneration occurs in a similar fashion (called axonal degeneration).

 Distance of proximal degeneration depends on the severity of the injury and degrades to the next node of Ranvier

 Schwann cells secrete cytokines nerve growth factor(promotes axonal extension)

 Macrophages contribute


  1. NGF

  2. nsulin like GF (IGF promotes axonal elongation)

  3. PDGF apolipoprotein E (axonal elongation and myelination)

Changes in cell body after injury

 Microscopy

 Nucleus swells and cell becomes rounder

 Ribosomes increase in number

 RER breaks up and moves to the periphery

 Marginated ER fragments (Nissle bodies)

 These changes are termed Chromatolysis

 As changes occur there is a decreased synthesis of neuro transmitter and increased synth of lipids and protein which are transported to site of injury

 At site of injury axons sprout from proximal nerve segment within 24 hrs

 They derive from both the cut axonal end and from nodes of Ranvier

 Initially unmyelinated and individual axons may produce more than one sprout

 A region of axo-plasmic enlargement known as the growth cone develop at the tip of the sprouts.

 The growth cone includes many intracellular structures including endoplasmic reticulum, microtubules, microfilaments, large mitochondria and lysosomes

 They include Schwann cells at their periphery

 Actin rich filopodia extend out and then contract from the most distal part of the growth cones in ameboid fashion and out in different directions until they come into contact with a favourable physical substrate.

Substrates include

Schwann cells

 Attachment factors such as fibronectin and laminin

 Substances found within endoneural sheaths


Neurotrophic factors released by the denervated structures contribute to the growth of the axon towards it and applies to both motor and sensory nerves

 NGF is one of the factors which contributes to the accelerated and directed growth of axons

 IGF may also have similar role

 FGF and IL -1 stimulate Schwann cells proliferation and may be involved along with ciliary neurotrophic factors

 The ultimate amount of axons reaching the end organ is generally less than the pre injury number and central compensation and re-education must occur to maximize the final result.
Cell body and proximal nerve hypertrophy

Following injury, the cell body and the proximal axon hypertrophy d/t the accumulation of gel like amorphous substance containing mucopolysaccaride.

RNA and protein content in the cell body ­increases

Axoplasmic flow continues for a short while.


Schwannoma formation

Schwann cells and fibroblasts proliferate to form a Schwannoma- a mass of scar tissue.


Axonal sprouting

  • After a delay of 24 hours to 4 days, the proximal axon forms a growth cone from which several axons (filopodia) start to sprout.

  • This quiescent phase is a period of protein synthesis by the cell bodies.

  • Sprouting occurs both from the growth cone and proximally from several nodes of Ranvier proximal to the injury.

  • The aim of sprouting is for axons to bridge the gap.

  • The regenerating unit is guided distally by a combination of forces.

    • Contact guidance

    • neurotropism are both operative

    • chemical and electrical mediators facilitate the filopodia’s search for a distal remnant. Schwann-cell-insulin-like GF may play a role.

  • A large gap or the presence of abundant scarring or FB, will diminish the number of axons that successfully bridge the gap and enter distal endoneurial tubules.

  • Smaller fibres (eg, pain and temperature) seem to be more successful in penetrating endoneurial tubules.

  • When one axonal sprout makes contact with the distal neural elements, it attaches by fusion of cell membrane. Some degree of contraction occurs pulling the proximal and distal ends together.

  • The new axons are rapidly enveloped by Schwann cells from the proximal nerve end.

  • Myelination is determined by the proximal parent nerve.


Regeneration down the distal endoneurial tube

Distal axon regeneration down the neural tube occurs at a variable rate dependent on a number of factors:

Site: Regeneration is faster proximally than distally. 8 mm/d in the upper arm; 1 mm/d in the hand.

Scar tissue: Retards the rate of progress to about 0.25 mm per day.

Grafts: In non vascularised nerve grafts, 3-4 mm/day.

Trophic factors:

Steroids slow the rate of regeneration;

T3 and nerve growth factor increase it.

When the axon encounters the target organ, other sprouts are triggered to degenerate.

Tinel sign is most useful to determine the rate of axonal regeneration.

Usually there is a delay period of about a month before the Tinel becomes positive.

As axons advance, myelination proceeds in a centrifugal manner.

By 3 weeks after injury, axon regeneration is the predominant feature. If these axons become trapped in proliferating fibroblastic tissue, neuroma results.
Changes in the motor end plates and muscle

After about 3 months, the motor end plates start to become increasingly distorted due to connective tissue in-growth. Muscle fibres start to undergo progressive shrinkage. Re-innervation, however, is possible for up to 3 years following injury.

Atrophy and degeneration of end plates and muscle can be retarded by external stimulation.

Sensory recovery is dependent on the re-innervation of existing sensory corpuscles rather than on the development of new ones.

There is a variable return of function after end organ re-innervation.

Re-education and rehabilitation improve the degree of functional recovery.



Injury Classification

Severity of injury to the axon can vary and affect the healing response. Two classifications by seddon(1948) and sunderland(1968)


Seddon:

 neuropraxia - conduction block with no actual structural damage to cell, and axonal regeneration is not required after this injury which is usually a transient compression of the nerve

 axonotmesis - involves damage to internal nerve structures whereas outer most epineurium remains intact (Sunderland classifies this group according to the nerve structure that is actually damaged)

 neurotmesis - involves all peripheral structures such as laceration of the nerve and is the most common type leading to surgical intervention





Testing

Sensory


Slow adapting fibers (pulse thruout duration)

static 2PD

Semmes-Weinstein monofilament

Quick adapting fibers (on-off)

vibration

moving 2PD


Threshold test (a single nerve fibre to a group of receptors)

- Semmes-Weinstein monofilament and vibration

- best test for nerve compressions

Innervation density test (density of innervation to an area)

- static and moving 2pd

- best test for acute nerve trauma but not gradual compression

Nerve conduction velocities and latencies
Repair
Number of factors influence the results of nerve repair:

Local factors


  1. Injury at Multiple levels: and more severe injuries create defects with significant scarring between ends esp true in severe ischaemic insult. The regenerating axons have limited ability to generate the proteases required for scar penetration and thus branch inresponse to this. GROWTH THRU NERVE GRAFT IS 2-3 MM/D WHEREAS GROWTH through scar is 0.25mm/d> as severity of injury increases the chance of injured nerve not finding distal sheath increases.

  2. Injury to proximal Nerve - injuries more proximal to involved muscles and sensory end organs achieve much better results than when structures must regenerate over long distances. This is partly due to target organ degeneration and increased homogeneity of distal nerves which lead to less cross innervation .More proximal muscles tends to require less precise function than distal muscle.

  3. Devascularization

  4. Poor wound bed - massive crush injury, scarring, hematoma, infection

Patient factors

  1. Delayed Repair - if long time passes between injury and repair the sheath diminishes in size limiting myelin thickness, axonal size and functional result. Esp true in motor nerves as the motor end plates atrophy and become less functional with time

  2. Increased age - age significant variable affecting results with individuals over 40 achieving much poorer results than those under 40. May involve cortical plasticity rather than axonal regeneration

Surgical factors

  1. surgical skill (alignment, gap, handling), rehabilitation.


Basic principle of repair

1) Careful handling of tissue

2) Limited devascularization of proximal and distal nerve

3) Tension free closure

4) Careful coaptation of nerve ends
Primary vs Secondary Repairs (>1 week)

 Primary repair shown to be superior in animals and human studies

 Indications for secondary repair

1. crush injury

2. contaminated bed

3. other injuries



Techniques

1. Epineural

2. Group fascicular

3. Individual fascicular

Fascicular repair has not shown to give better results than epineural repair probably as there is increases scarring generated by intraneural repair.
Fascicular matching - mainly to separate sensory from motor nerves

1. Intraop nerve stimulation

awake patient

proximal stump - map sensory

distal stump - map motor (only work first 1-3 days)

2. Histochemical analysis

Anticholinesterase - myelinated motor and small unmyelinated axons but not myelinated sensory nerves

Carbonic anhydrase - myelin and axons of myelinated sensory nerves

Proximal end - indefinite period, Distal end - first 9 days

Need to resect nerve ends to histochemistry, 1-2 hrs processing time.

? more useful in late reconstruction
Aftercare

Immobilise for 3 weeks

Splinting positions

Sensory reeducation




Blood vessels
Anatomy

Anatomy varies depending on size of vessel

Blood vessels are composed of following layers or tunics

1) Tunica Intima - consists of a layer of endothelial cells lining the inner surface that rest on basal lamina and have turnover of 1%/ day beneath endothelium is the subendothelium consisting of loose areolar tissue that may contain occasional smooth muscle cells that are both arranged longitudinally

2) Tunica Media - consists chiefly of concentric layers of helically arranged smooth muscle cells interposed with variable amounts of elastic and reticular fibres

In ateries the intima and media are separated by the internal elastic lamina composed of elastin and is fenestrated to allow diffusion to nourish vessel wall

A thinner external elastic lamina is often found separating the media from the outer adventitia

3) Tunica Adventitia -consists principally of longitudinally orientated collagen fibres collage in the adventitia is type I and in the media is mainly type III


Vaso Vasorum (vessels of Vessels in larger vessels)branch in the adventitia and the outer part of the media; and provide metabolites to the adventitia and media and the inner layers are diffused from the lumen





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