title: Cervical spinal cord therapeutics delivery: preclinical safety validation of a stabilized microinjection platform.
abstract: 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 microL injected at 1, 2.5, and 5 microL/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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cleveland Clinic Foundation, The Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Riley
authors.forename: Thais
authors.initials: T
authors.lastname: Federici
authors.forename: John
authors.initials: J
authors.lastname: Park
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Colin K
authors.initials: CK
authors.lastname: Franz
authors.forename: Craig
authors.initials: C
authors.lastname: Tork
authors.forename: Jacalyn
authors.initials: J
authors.lastname: McHugh
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Teng
authors.forename: Clive
authors.initials: C
authors.lastname: Svendsen
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Boulis
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000166:cytology / Q000502:physiology / Q000637:transplantation; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002574:Cervical Vertebrae / Q000033:anatomy & histology / Q000601:surgery; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology; D046748:Hematoma, Epidural, Spinal / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007260:Infusion Pumps; D007796:Laminectomy; D008845:Microinjections / Q000009:adverse effects / Q000295:instrumentation* / Q000379:methods; D055495:Neurogenesis / Q000502:physiology; D011183:Postoperative Complications / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D013116:Spinal Cord / Q000166:cytology* / Q000502:physiology / Q000601:surgery*; D013118:Spinal Cord Diseases / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000295:instrumentation* / Q000379:methods; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D013238:Stereotaxic Techniques; D034421:Sus scrofa; D013594:Syringes / Q000009:adverse effects / Q000592:standards*; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000295:instrumentation / Q000379:methods; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents