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1.
Stereotact Funct Neurosurg ; 95(1): 60-68, 2017.
Article En | MEDLINE | ID: mdl-28132063

BACKGROUND: Cell-based therapies are a promising treatment option for traumatic, tumorigenic and degenerative diseases of the spinal cord. Transplantation into the spinal cord is achieved with intravascular, intrathecal, or direct intraparenchymal injection. The current standard for direct injection is limited by surgical invasiveness, difficulty in reinjection, and the inability to directly target anatomical or pathological landmarks. The objective of this study was to present the proof of principle for minimally invasive, percutaneous transplantation of stem cells into the spinal cord parenchyma of live minipigs under MR guidance. METHODS: An MR-compatible spine injection platform was developed to work with the ClearPoint SmartFrame system (MRI Interventions Inc.). The system was attached to the spine of 2 live minipigs, a percutaneous injection cannula was advanced into the spinal cord under MR guidance, and cells were delivered to the cord. RESULTS: A graft of 2.5 × 106 human (n = 1) or porcine (n = 1) neural stem cells labeled with ferumoxytol nanoparticles was transplanted into the ventral horn of the spinal cord with MR guidance in 2 animals. Graft delivery was visualized with postprocedure MRI, and characteristic iron precipitates were identified in the spinal cord by Prussian blue histochemistry. Grafted stem cells were observed in the spinal cord of the pig injected with porcine neural stem cells. No postoperative morbidity was observed in either animal. CONCLUSION: This report supports the proof of principle for transplantation and visualization of pharmacological or biological agents into the spinal cord of a large animal under the guidance of MRI.


Magnetic Resonance Imaging , Neural Stem Cells/transplantation , Spinal Cord/surgery , Stem Cell Transplantation/methods , Animals , Humans , Spinal Cord/diagnostic imaging , Swine , Swine, Miniature
2.
Neurosurgery ; 77(4): 604-12; discussion 612, 2015 Oct.
Article En | MEDLINE | ID: mdl-26134596

BACKGROUND: Although multiple clinical trials are currently testing different stem cell therapies as treatment alternatives for many neurodegenerative diseases and spinal cord injury, the optimal injection parameters have not yet been defined. OBJECTIVE: To test the spinal cord's tolerance to increasing volumes and numbers of stem cell injections in the pig. METHODS: Twenty-seven female Göttingen minipigs received human neural progenitor cell injections using a stereotactic platform device. Cell transplantation in groups 1 to 5 (5-7 pigs in each) was undertaken with the intent of assessing the safety of an injection volume escalation (10, 25, and 50 µL) and an injection number escalation (20, 30, and 40 injections). Motor function and general morbidity were assessed for 21 days. Full necropsy was performed; spinal cords were analyzed for graft survival and microscopic tissue damage. RESULTS: No mortality or permanent surgical complications were observed during the 21-day study period. All animals returned to preoperative baseline within 14 days, showing complete motor function recovery. The histological analysis showed that there was no significant decrease in neuronal density between groups, and cell engraftment ranged from 12% to 31% depending on the injection paradigm. However, tissue damage was identified when injecting large volumes into the spinal cord (50 µL). CONCLUSION: This series supports the functional safety of various injection volumes and numbers in the spinal cord and gives critical insight into important safety thresholds. These results are relevant to all translational programs delivering cell therapeutics to the spinal cord.


Neural Stem Cells/transplantation , Spinal Cord Injuries/therapy , Stem Cell Transplantation/methods , Animals , Female , Graft Survival/physiology , Humans , Injections, Spinal , Microinjections , Spinal Cord/pathology , Spinal Cord Injuries/pathology , Swine , Swine, Miniature
3.
Ther Deliv ; 4(11): 1397-410, 2013 Nov.
Article En | MEDLINE | ID: mdl-24228990

Current literature demonstrates the efficacy of cell-based therapeutics in small animal models of varied spinal cord diseases. However, logistic challenges remain towards development of an optimized delivery approach to the human spinal cord. Clinical trials utilize a variety of methods to achieve this aim. In this article, the authors review currently employed delivery methods, compare the merits of alternate delivery paradigms, introduce their implementation in completed and ongoing clinical trials, and discuss promising near-term advances in image-guided delivery and in vivo graft tracking.

4.
J Vis Exp ; (70): e4371, 2012 Dec 07.
Article En | MEDLINE | ID: mdl-23242422

This is a compact visual description of a combination of surgical technique and device for the delivery of (gene and cell) therapies into the spinal cord. While the technique is demonstrated in the animal, the procedure is FDA-approved and currently being used for stem cell transplantation into the spinal cords of patients with ALS. While the FDA has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for validating the combination of a surgical procedure, a device, and the safety of a final therapy for human use. The size, anatomy, and general vulnerability of the spine and spinal cord of the swine are recognized to better model the human. Moreover, the surgical process of exposing and manipulating the spinal cord as well as closing the wound in the pig is virtually indistinguishable from the human. We believe that the healthy pig model represents a critical first step in the study of procedural safety.


Cell- and Tissue-Based Therapy/methods , Genetic Therapy/methods , Spinal Cord/surgery , Animals , Female , Models, Animal , Swine , Swine, Miniature
5.
Per Med ; 9(6): 645-655, 2012 Aug.
Article En | MEDLINE | ID: mdl-29768799

The last decade has witnessed an increasing number of biologic (e.g., cell- or viral vector-based) therapeutics supported by preclinical efficacy data for the treatment of afflictions to the CNS. While some international investigators have undertaken preliminary clinical safety studies, published literature indicate varying degrees of rigor with respect to study design and technical approach. To our knowledge, ours is the first group to have systematically generated preclinical validation data for a delivery approach and translated this into a Phase I trial attempting to covalidate the safety of a direct, targeted delivery approach, as well as a cell-based therapeutic. This article discusses the rationale for cell-based therapy in amyotrophic lateral sclerosis and several of the unique considerations encountered during this process.

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