Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails into the Spinal Cord of Small and Large Animals

Artem B. Kutikov, Simon W. Moore, Richard T. Layer, Pamela E. Podell, Nithya Sridhar, Andrea J. Santamaria, Alex A. Aimetti, Christoph P. Hofstetter, Thomas R. Ulich, James D. Guest

Research output: Contribution to journalArticle

Abstract

Background: Immature neurons can extend processes after transplantation in adult animals. Neuronal relays can form between injected neural stem cells (NSCs) and surviving neurons, possibly improving recovery after spinal cord injury (SCI). Cell delivery methods of single or multiple bolus injections of concentrated cell suspensions thus far tested in preclinical and clinical experiments are suboptimal for new tract formation. Nonuniform injectate dispersal is often seen due to gravitational cell settling and clumping. Multiple injections have additive risks of hemorrhage, parenchymal damage, and cellular reflux and require additional surgical exposure. The deposition of multiply delivered cells boluses may be uneven and discontinuous. Objective: To develop an injection apparatus and methodology to deliver continuous cellular trails bridging spinal cord lesions. Methods: We improved the uniformity of cellular trails by formulating NSCs in hyaluronic acid. The TrailmakerTM stereotaxic injection device was automatized to extend a shape memory needle from a single-entry point in the spinal cord longitudinal axis to "pioneer" a new trail space and then retract while depositing an hyaluronic acid-NSC suspension. We conducted testing in a collagen spinal models, and animal testing using human NSCs (hNSCs) in rats and minipigs. Results: Continuous surviving trails of hNSCs within rat and minipig naive spinal cords were 12 and 40 mm in length. hNSC trails were delivered across semi-acute contusion injuries in rats. Transplanted hNSCs survived and were able to differentiate into neural lineage cells and astrocytes. CONCLUSION: The TrailmakerTM creates longitudinal cellular trails spanning multiple levels from a single-entry point. This may enhance the ability of therapeutics to promote functional relays after SCI.

Original languageEnglish (US)
Pages (from-to)560-573
Number of pages14
JournalClinical Neurosurgery
Volume85
Issue number4
DOIs
StatePublished - Oct 1 2019

Fingerprint

Neural Stem Cells
Spinal Cord
Miniature Swine
Injections
Hyaluronic Acid
Spinal Cord Injuries
Suspensions
Neurons
Contusions
Astrocytes
Needles
Collagen
Animal Models
Transplantation
Hemorrhage
Equipment and Supplies
Wounds and Injuries

Keywords

  • Cell transplantation
  • Hyaluronic acid
  • Injection
  • Neural stem cells
  • Spinal cord injury
  • Stereotaxic
  • Trail

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails into the Spinal Cord of Small and Large Animals. / Kutikov, Artem B.; Moore, Simon W.; Layer, Richard T.; Podell, Pamela E.; Sridhar, Nithya; Santamaria, Andrea J.; Aimetti, Alex A.; Hofstetter, Christoph P.; Ulich, Thomas R.; Guest, James D.

In: Clinical Neurosurgery, Vol. 85, No. 4, 01.10.2019, p. 560-573.

Research output: Contribution to journalArticle

Kutikov, AB, Moore, SW, Layer, RT, Podell, PE, Sridhar, N, Santamaria, AJ, Aimetti, AA, Hofstetter, CP, Ulich, TR & Guest, JD 2019, 'Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails into the Spinal Cord of Small and Large Animals', Clinical Neurosurgery, vol. 85, no. 4, pp. 560-573. https://doi.org/10.1093/neuros/nyy379
Kutikov, Artem B. ; Moore, Simon W. ; Layer, Richard T. ; Podell, Pamela E. ; Sridhar, Nithya ; Santamaria, Andrea J. ; Aimetti, Alex A. ; Hofstetter, Christoph P. ; Ulich, Thomas R. ; Guest, James D. / Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails into the Spinal Cord of Small and Large Animals. In: Clinical Neurosurgery. 2019 ; Vol. 85, No. 4. pp. 560-573.
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AU - Layer, Richard T.

AU - Podell, Pamela E.

AU - Sridhar, Nithya

AU - Santamaria, Andrea J.

AU - Aimetti, Alex A.

AU - Hofstetter, Christoph P.

AU - Ulich, Thomas R.

AU - Guest, James D.

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N2 - Background: Immature neurons can extend processes after transplantation in adult animals. Neuronal relays can form between injected neural stem cells (NSCs) and surviving neurons, possibly improving recovery after spinal cord injury (SCI). Cell delivery methods of single or multiple bolus injections of concentrated cell suspensions thus far tested in preclinical and clinical experiments are suboptimal for new tract formation. Nonuniform injectate dispersal is often seen due to gravitational cell settling and clumping. Multiple injections have additive risks of hemorrhage, parenchymal damage, and cellular reflux and require additional surgical exposure. The deposition of multiply delivered cells boluses may be uneven and discontinuous. Objective: To develop an injection apparatus and methodology to deliver continuous cellular trails bridging spinal cord lesions. Methods: We improved the uniformity of cellular trails by formulating NSCs in hyaluronic acid. The TrailmakerTM stereotaxic injection device was automatized to extend a shape memory needle from a single-entry point in the spinal cord longitudinal axis to "pioneer" a new trail space and then retract while depositing an hyaluronic acid-NSC suspension. We conducted testing in a collagen spinal models, and animal testing using human NSCs (hNSCs) in rats and minipigs. Results: Continuous surviving trails of hNSCs within rat and minipig naive spinal cords were 12 and 40 mm in length. hNSC trails were delivered across semi-acute contusion injuries in rats. Transplanted hNSCs survived and were able to differentiate into neural lineage cells and astrocytes. CONCLUSION: The TrailmakerTM creates longitudinal cellular trails spanning multiple levels from a single-entry point. This may enhance the ability of therapeutics to promote functional relays after SCI.

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