Table 1.
Acute | <48hrs |
Goal: Transplantation within the early stages post-injury (e.g. 24-48 hours) to target inflammation and promote neuroprotection, limit axonal retraction, and reduce secondary tissue damage. | |
Cells used: Growth-supportive/permissive, anti-inflammatory, and pro-vascular cells. In addition, donor cells may be able to restore metabolic homeostasis, thus enhancing neuroprotection. Usually delivered to the lesion epi-center or peri-lesional area. | |
Considerations and barriers to cell therapy: Donor cell survival may be limited as the pro-inflammatory internal milieu of the lesion epicenter is not conducive for survival at such early time post-injury. This may not be a concern, provided donor cells survive long enough acutely to exhibit the necessary effects (e.g. cells are transplanted with the intended purpose of secreting anti-inflammatory and/or neuroprotective factors). | |
References: 4,6,11,84–89 | |
Sub-acute* | 48 h–4wks |
Goal: Facilitate repair during ongoing neuroplasticity and anatomical reorganization within the injured host spinal cord. | |
Cells used: Growth-supportive/permissive (may modify the glial scar) cells, pro-vascular cells, and neurons capable of forming networks and integrating with host neurons—delivered to lesion epicenter or peri-lesion area. Also, neuromodulatory cells (e.g., serotonergic) which can be delivered distant to injury near denervated cells (e.g., lumbar spinal cord). | |
Considerations and barriers to cell therapy: With ongoing anatomical and biochemical changes during this stage, care needs to be taken to not disrupt otherwise beneficial neuroplastic mechanisms. Potential disruption and/or inhibition of adaptive plasticity is the greatest barrier to cell transplantation at this time point injury. However, treatment during this stage when plasticity is ongoing may enable better, if not most optimal, growth and integration between donor and host. | |
References: 8,9,22,43,75,88,90 | |
Chronic | >4–12 weeks |
Goal: Cells that may facilitate delayed repair and contribute to additional plasticity. Modify the existing glial scar at the lesion site, and promote vascularization. While there has been some concern that the capacity for repair may be reduced at very late chronic stages, following a longer period of wound healing/scarring, there is mounting evidence to suggest that this “window” for treatment can be reopened to facilitate repair at even very late stages. | |
Cells used: As described for the sub-acute stage. | |
Considerations and barriers to cell therapy: Perhaps one of the most important considerations here is what defines the treatment time as “chronic”. “Early” chronic stages (about 4–12 weeks) have been described as “sub-chronic” or intermediate, with “chronic” referring to even later stages (>12 weeks). Anatomical and biochemical changes become more stable at around 4–6 weeks, with less spontaneous axonal sprouting and plasticity during this stage. Immunological events may still be ongoing within the injured spinal cord at this time, but become more stable 8–12 weeks post-injury. If transplantation requires axonal growth, the donor cells need to stimulate it, or an additional treatment may be required to do so. Directing host and donor growth may require activity-based therapies or neural stimulation (e.g.,91). The greatest barrier to cell therapy at the chronic timepoint is the state of the lesion itself. It is unknown if the potential for repair is reduced, whether the chronic state of the scar is no longer receptive for growth of donor or host cells and whether the benefits and effects of transplantation will be comparable to what has been shown at more acute stages. Clinically and logistically, transplantation at the acute stage post-injury can be performed in combination with other necessary surgeries (e.g., decompression). In contrast, surgery at the chronic stage may be more difficult once more extensive scarring has occurred and the chronically injured patient may not recover from a surgery as quickly. | |
References: 7,51,90,92 |
* Despite being misleading (sub-acute would typically refer to events pre-acutely), this is a commonly used term in the field to refer to times soon after the early acute stages of injury.