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

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.

Internal decompression of the acutely contused spinal cord: Differential effects of irrigation only versus biodegradable scaffold implantation.

Severe spinal cord injury leads to hemorrhage, edema and elevated tissue pressures that propagate ischemia. Liquefactive necrosis of damaged tissue eventually results in chronic cavities due to a wound healing process lacking adhesive contractile cells. Biomaterials can potently influence wound healing responses. Internal decompression (ID) refers to pial opening, allowing spontaneous extrusion and irrigation of fluid necrotic debris relieving pressure and resulting in a space for biomaterial scaffold insertion. After thoracic contusions, rats were randomized to: contusion only, contusion + ID and contusion + ID + PLGA-PLL scaffold implantation, to test for neuroprotection and endogenous repair over 3 months. ID alone reduced inflammatory activity, cavity volume, and increased tissue sparing. Scaffold biodegradation produced delayed ingrowth of inflammatory and other cells resulting in endogenously derived laminin-rich tissue, marked reduction in cavitation and presence of tissue remodeling macrophages. Extensive recruitment of Schwann cells into adjacent spared white matter occurred, greatest in scaffold-implanted animals. Despite tissue preservation with myelin repair, no groups differed significantly in open field locomotion. However, across all rats, spared epicenter tissue and locomotor outcomes were correlated. Scaffold-implanted animals showed no obvious toxicity. To study the clinical feasibility, timing and indications for scaffold implantation, Göttingen minipigs underwent ID and were implanted with scaffolds 4, 6, and 24 h after T10 contusion. High intra-spinal tissue pressures fell to pre-injury levels after ID and scaffold implantation. Extrusion of necrotic debris left sufficient space for a sized scaffold. These results provided the preclinical rationale for a current clinical study of biomaterial scaffold implantation into the human injured spinal cord.

First Human Implantation of a Bioresorbable Polymer Scaffold for Acute Traumatic Spinal Cord Injury: A Clinical Pilot Study for Safety and Feasibility.

BACKGROUND AND IMPORTANCE: A porous bioresorbable polymer scaffold has previously been tested in preclinical animal models of spinal cord contusion injury to promote appositional healing, spare white matter, decrease posttraumatic cysts, and normalize intraparenchymal tissue pressure. This is the first report of its human implantation in a spinal cord injury patient during a pilot study testing the safety and feasibility of this technique (ClinicalTrials.gov Identifier: NCT02138110). CLINICAL PRESENTATION: A 25-year-old man had a T11-12 fracture dislocation sustained in a motocross accident that resulted in a T11 American Spinal Injury Association Impairment Scale (AIS) grade A traumatic spinal cord injury. He was treated with acute surgical decompression and spinal fixation with fusion, and enrolled in the spinal scaffold study. A 2 × 10 mm bioresorbable scaffold was placed in the spinal cord parenchyma at T12. The scaffold was implanted directly into the traumatic cavity within the spinal cord through a dorsal root entry zone myelotomy at the caudal extent of the contused area. By 3 months, his neurological examination improved to an L1 AIS grade C incomplete injury. At 6-month postoperative follow-up, there were no procedural complications or apparent safety issues related to the scaffold implantation. CONCLUSION: Although longer-term follow-up and investigation are required, this case demonstrates that a polymer scaffold can be safely implanted into an acutely contused spinal cord. This is the first human surgical implantation, and future outcomes of other patients in this clinical trial will better elucidate the safety and possible efficacy profile of the scaffold. ABBREVIATIONS: AIS, American Spinal Injury Association Impairment ScaleSCI, spinal cord injurytSCI, traumatic spinal cord injury.