4.6 Article

CERVICAL SPINAL CORD THERAPEUTICS DELIVERY: PRECLINICAL SAFETY VALIDATION OF A STABILIZED MICROINJECTION PLATFORM

期刊

NEUROSURGERY
卷 65, 期 4, 页码 754-761

出版社

OXFORD UNIV PRESS INC
DOI: 10.1227/01.NEU.0000343524.45387.9E

关键词

Cell therapy; Cervical spinal cord; Microinjection; Neural progenitor cells; Pigs

资金

  1. NINDS NIH HHS [R21 NS061049, P01 NS057778-01A1, R21 NS061049-01A1, P01 NS057778, P01 NS057778-01A10002, P01 NS057778-01A19001, P01 NS057778-020002, P01 NS057778-02, P01 NS057778-029001, P01 NS057778-01A18867] Funding Source: Medline

向作者/读者索取更多资源

OBJECTIVE: The current series represents a preclinical safety validation study for direct parenchymal microinjection of cellular grafts into the ventral horn of the porcine cervical spinal cord. METHODS: Twenty-four 30- to 40-kg female Yorkshire farm pigs immunosuppressed with cyclosporine underwent a cervical laminectomy and ventral horn human neural progenitor cell injection. Cell transplantation in groups 1 to 3 (n = 6 pigs each) was undertaken with the intent of assessing the safety of varied injection volumes: 10, 25, and 50 mu L injected at 1, 2.5, and 5 mu L/min, respectively. Groups 4 and 5 (n = 3 pigs each) received prolonged immunosuppressant pretreatment in an attempt to demonstrate graft viability. The latter was undertaken in an alternate species (mini-pig versus Yorkshire pig). RESULTS: Neurological morbidity was observed in 1 animal and was attributable to the presence of a resolving epidural hematoma noted at necropsy. Although instances of ventral horn targeting were achieved in all injection groups with a coordinate-based approach, opportunities exist for improvement in accuracy and precision. A relationship between injection volume and graft site cross-sectional area suggested limited reflux. Only animals from group 5 achieved graft survival at a survival end point (t = 1 week). CONCLUSION: This series demonstrated the functional safety of targeted ventral horn microinjection despite evidence for graft site immune rejection. Improvements in graft delivery may be augmented with an adapter to improve control of the cannula entry angle, intraoperative imaging, or larger graft volumes. Finally, demonstration of long-term graft viability in future preclinical toxicity studies may require tailored immunosuppressive therapies, an allograft construct, or tailored choice of host species.

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