Personally i feel that there is not much to discuss here, but still something (which is called as the GEMINI spinal cord fusion (SCF) protocol) that Dr.Canavero has to present in his defense, is as follows.
I'll like to summarize it here.
A reference :
Surg Neurol Int 2015,
6:18
GEMINI SCF:
- A sharp severance of the cords is not as damaging as clinical spinal cord injury
- The gray matter "motor highway" is more important than the pyramidal tract in human motor processing.
Principle 1: Sharp Severance
The key to SCF is a sharp severance of the cords themselves, with its attendant minimal damage to both the axons in the white matter
and the neurons in the gray laminae. This is a key point: A typical force generated by creating a sharp transection is
less than 10 N versus approximately
26000 N experienced during spinal cord injury, a 2600× difference.
A specially fashioned diamond microtomic snare-blade is one option (unpublished); a nanoknife made of a thin layer of silicon nitride with a nanometer sharp cutting edge is another alternative. Notably, the mechanical strength of silicon is superior to that of steel.
Principle 2: Gray Matter 'Motor Highway' Vs Pyramidal Tract
In man, motricity is only modestly subserved by long axonal systems coursing through the spinal white matter as taught in contemporary anatomical and neurology textbooks (parenthetically, "
Subdivision of the (human) white matter…into tracts is…not feasible, because most of the tracts mix with one another and overlap"). Skilled voluntary movements of the hand in man are often considered to be dependent on the direct access of motor neurons (MN) from the primary motor cortex to the cord (monosynaptic Pyramidal Tract). However, indirect pathways from the motor cortex (e.g. corticobulbospinal pathways via, e.g., the reticulospinal tracts) and
spinal interneuronal systems by far contribute the majority of inputs to the MNs: In man, the corticospinal tract predominantly terminates in the intermediate layers of the spinal cord where many interneurons are located. Laruelle wrote:
The plurisegmentary association is brought about not only via the known cordonal pathways, but via a gray-matter-based system of intrinsic fibers, which cover up to several cord segments: These confer conductive properties to the cord gray matter ". This association is further enacted via short fibers lying closest to the spinal gray matter that connect nearby spinal segments over short or very short distances (e.g., the lateral limiting layer of the Ground Bundles). This explains why «
in man, recovery of motor function including the distal movement is compatible with …degeneration of 83% of the pyramidal tract fibers», as occurs for lesions restricted to the human lateral corticospinal tracts. In the words of Bucy et al., "The pyramidal tract…is not essential to useful control of the skeletal musculature…In the absence of the corticospinal fibers other fiber systems, particularly some…multineuronal mechanism passing through the mesencephalic tegmentum, are capable of producing useful, well-coordinated, strong and delicate movements of the extremities."
In a recent case report, a subject with tetraplegia (ASIA A) recovered 15 months later to ASIA D, despite a 62% atrophy of the white matter tissue at the injury epicenter, including the pyramidal tracts. Even in multiple sclerosis, long regarded as the prototypical white matter (long axons) disease,
it is the damage to the gray matter that accounts for most of the related motor disability - even in cases without white matter loss. Similar anatomical arguments - propriospinal transmission versus spinothalamic tract in the case of nociception - could be made for the sensory return.
In GEMINI, the gray matter neuropil will be restored by spontaneous regrowth of the severed axons/dendrites over very short distances at the point of contact between the apposed cords.
Fusogen-Assisted Neural Reconstitution
GEMINI exploits special substances (fusogens/sealants: Poly-ethylene glycol [PEG], Chitosan) that have the power to literally fuse together severed axons or seal injured leaky neurons.It is based on the concept of
biological fusion, which occurs both naturally (e.g., in myoblasts) and artificially (e.g. hybridoma cells):
Up to 10% of severed axons in some invertebrates can undergo spontaneous fusion with their separate distal segments. Different technologies can induce axonal fusion: Chemical, laser, and electrofusion. Chemical fusion is likely mediated by a dehydration effect and volume-exclusion aggregation of membrane lipids bringing adjacent lipids into physical contact. Two scenarios are particularly attractive:
(i) A PEG containing solution is flowed for 2 min (more than 3' is actually deleterious) over the lesion site, and then flushed out, as outlined by Bittner
et al.; or
(ii) a semi-interpenetrating network of PEG and photo-cross-linkable chitosan can be employed as an
in situ-forming nerve adhesive/fusogen.
Chitosan nanoparticles or PEG can also be injected IV for several hours to enhance the effect. Interestingly, there may be a body temperature effect on PEG's viscosity and efficacy (Kouhzaei
et al.). In contrast, chitosan in an injectable solution that moves throughout the systemic circulation - apparently regardless of viscosity: Thus the route of administration does not appear to matter in a manner similar to PEG. Animal experiments on transected cords have already given proof-of-principle of the feasibility of fusogen-assisted SCF. Anyway, PEG-mediated functional reconnection between closely apposed proximal and distal segments of severed axons takes many minutes of absolute immobility of the axon segments and an untested period of immobilization of the tissue for the repair to become permanent. The question is whether this is actually required for successful reconstitution of motor (and sensory) transmission, also considering how perfect one-on-one axonal alignment is impossible. As proven by Bittner et al, in peripheral nerves in vivo, behavioral recovery is excellent and improves over time after PEG fusion. This means that
a sufficient number of axonal proximal stumps get fused with the distal counterparts in such a way to ensure appropriate electrophysio-logical conduction, likely the result of tight axonal packing. This number is likely low (10-15%), and yet enough for recovery, reflecting the potential for substantial plasticity in the injured CNS. A similar figure applies to the damaged spinal cord in man, where the number of axons in the spinal white matter is estimated at over 20 million, with about 1 million pyramidal fibers. Also, reconnection with an adjacent axon, as long as it is not an extreme mismatch, may restore acceptable function. Dense axonal packing would ensure that a number of fibers would get fused.
Tangentially, collagen conduits containing autologous platelet-rich plasma have allowed successful axonal regeneration and neurological recovery in clinical peripheral nerve injury with gaps up to 12 cm (16 cm along with an added sensory nerve graft).
Electricity-Accelerated Recovery
In GEMINI, local sprouting between neurons in the gray matter (see above) will reestablish a functional bridge over days to weeks. This process is accelerated by electrical stimulation via application of a spinal cord stimulator (SCS) straddling the fusion point. For instance,
1 h of continuous electrical stimulation at 20 Hz applied right after suturing together the stumps of a transected peripheral nerve cut the regeneration time from 8-10 to 3 weeks; similar accelerations are seen in man.
The role of electrical stimulation goes well beyond acceleration of axonal and dendritic regrowth. The spinal cord has the capacity to execute complex stereotyped motor tasks in response to rather unspecific stimuli even after chronic separation from supraspinal structures. However, being deprived of sufficient supraspinal drive, neural processing, and pattern generating networks caudal to a spinal cord lesion lose an adequate, sustainable state of excitability to be fully operational: SCS (15-60 Hz, 5-9 V) provides a multi-segmental tonic neural drive to these circuitries and "tune" their physiological state to a more functional level. Thus,
"loss of voluntary control of movement may be attributed to not only a physical disruption of descending connections, but also to a physiological alteration of the central state of excitability of the spinal circuitry…(spinal cord) stimulation may facilitate excitation of propriospinal neurons which support propagation of the voluntary command to the lumbosacral spinal cord…after repetitive epidural stimulation and training…multiple, novel neuronal pathways and synapses (are established)." The result is recovery of intentional movement in the setting of complete paralysis of the legs. Similar arguments and results apply to the cervical spinal cord. Of course, useful plasticity will not only occur in the cord, but also at higher levels, including the motor cortex.
STEPS:
- The sharp severance of the cervical cords (donor's and recipient's), with its attendant minimal tissue damage
- The exploitation of the gray matter internuncial sensori-motor "highway" rebridged by sprouting connections between the two reapposed cord stumps. This could also explain the partial motor recovery in a paraplegic patient submitted to implantation of olfactory ensheathing glia and peripheral nerve bridges: A 2-mm bridge of remaining cord matter might have allowed gray matter axons to reconnect the two ends [38]
- The bridging as per point 2 above is accelerated by electrical SCS straddling the fusion point
- The application of "fusogens/sealants": Sealants "seal" the thin layer of injured cells in the gray matter, both neuronal, glial and vascular, with little expected scarring; simultaneously they fuse a certain number of axons in the white matter.
During CSA, microsutures (mini-myelorrhaphy) will be applied along the outer rim of the apposed stumps.
Post Op:
A cephalosomatic anastomosee will thus be kept in induced coma for 3-4 weeks following CSA to give time to the stumps to refuse (and avoid movements of the neck) and will then undergo appropriate rehabilitation in the months following the procedure.
In addition, the immunosuppressant regime that will be instituted after CSA is expected to be pro-regenerative.
