Safety and Function of a New Clinical Intracerebral Microinjection Instrument for Stem Cells and Therapeutics Examined in the Göttingen Minipig

Bjarkam, Carsten Reidies; Glud, Andreas Nørgaard; Margolin, Lee; Reinhart, Karl; Franklin, R T; Deding, Dorthe; Ettrup, Kåre Schmidt; Fitting, Lise Moberg; Nielsen, Mette S.; Sørensen, Jørn Nygaard; Cunningham, Miles G.

doi:10.1159/000268743

Cited by 29 publications

(28 citation statements)

References 52 publications

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“…Distinct cell types can be precisely engrafted into brain substructures (Bjarkam et al, 2010), averting the acute and long-term systemic adverse effects seen with AEDs. Further, neural grafts, with their ability to integrate within the host circuitry, would circumvent the need for daily dosing and sluggish titration required with AED administration.…”

Section: Discussionmentioning

confidence: 99%

hPSC-Derived Maturing GABAergic Interneurons Ameliorate Seizures and Abnormal Behavior in Epileptic Mice

et al. 2014

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Summary Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human PSC has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that human PSC-derived maturing GABAergic interneurons (mGIN) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness and hyperactivity. These results provide support for the potential of human PSC-derived mGIN for restorative cell therapy for epilepsy.

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Section: Discussionmentioning

confidence: 99%

hPSC-Derived Maturing GABAergic Interneurons Ameliorate Seizures and Abnormal Behavior in Epileptic Mice

et al. 2014

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“…To date, cell delivery into the human brain has been performed on hundreds of patients enrolled in clinical trials for the treatment of neurodegenerative disorders using a similar type of straight cannula and syringe. There is a growing recognition that this cell delivery strategy has substantial shortcomings [18,20,24]. RBD provides solutions for several of the limitations that exist with the tools currently being used.…”

Section: Discussionmentioning

confidence: 99%

“…Cunningham and colleagues have also explored the concept of enhancing cell transplantation by using radial trajectories [22,24]. While their Intracerebral Microinjection Instrument (IMI) is capable of placing multiple cellular deposits radial to a single proximal brain penetration, the deflection angle achieved is 25 degrees, which limits the radial distance to about 8 mm.…”

Section: Discussionmentioning

confidence: 99%

“…Such variable patient outcomes – most clearly noted in double-blind, sham-surgery controlled transplantation trials for PD [5,6] – have been partly attributed to an inability to properly distribute the cells to the target region [16,17]. There has been relatively little development of surgical tools and techniques for the delivery of cells to the human brain [18–24,44]. If unresolved, deficiencies in surgical delivery may precipitate the failure of human cell transplantation trials despite validity of the underlying biological mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Radially Branched Deployment for More Efficient Cell Transplantation at the Scale of the Human Brain

Silvestrini

Yin

Coppes

et al. 2013

Stereotact Funct Neurosurg

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Background: In preclinical studies, cell transplantation into the brain has shown great promise for the treatment of a wide range of neurological diseases. However, the use of a straight cannula and syringe for cell delivery to the human brain does not approximate cell distribution achieved in animal studies. This technical deficiency may limit the successful clinical translation of cell transplantation. Objective: To develop a stereotactic device that effectively distributes viable cells to the human brain. Our primary aims were to (1) minimize the number of transcortical penetrations required for transplantation, (2) reduce variability in cell dosing and (3) increase cell survival. Methods: We developed a modular cannula system capable of radially branched deployment (RBD) of a cell delivery catheter at variable angles from the longitudinal device axis. We also developed an integrated catheter-plunger system, eliminating the need for a separate syringe delivery mechanism. The RBD prototype was evaluated in vitro and in vivo with subcortical injections into the swine brain. Performance was compared to a 20G straight cannula with dual side ports, a device used in current clinical trials. Results: RBD enabled therapeutic delivery in a precise ‘tree-like’ pattern branched from a single initial trajectory, thereby facilitating delivery to a volumetrically large target region. RBD could transplant materials in a radial pattern up to 2.0 cm from the initial penetration tract. The novel integrated catheter-plunger system facilitated manual delivery of small and precise volumes of injection (1.36 ± 0.13 µl per cm of plunger travel). Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. While reflux of infusate along the penetration tract was problematic with the use of the 20G cannula, RBD was resistant to this source of cell dose variability in agarose. RBD enabled radial injections to the swine brain when used with a modern clinical stereotactic system. Conclusions: By increasing the total delivery volume through a single transcortical penetration in agarose models, RBD strategy may provide a new approach for cell transplantation to the human brain. Incorporation of RBD or selected aspects of its design into future clinical trials may increase the likelihood of successful translation of cell-based therapy to the human patient.

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“…3 While much recent translational research has been focused on improving the quality and quantity of human cell types for transplantation, 4 there has been very little innovation of the surgical tools and techniques used for cell delivery to the human brain. [5][6][7][8][9][10][11] If unresolved, faults with cell delivery may contribute to the failure of clinical trials despite robust preclinical evidence and a compelling biological rationale.…”

Section: Introductionmentioning

confidence: 99%

Interventional Magnetic Resonance Imaging-guided Cell Transplantation Into the Brain With Radially Branched Deployment

et al. 2015

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Intracerebral cell transplantation is being pursued as a treatment for many neurological diseases, and effective cell delivery is critical for clinical success. To facilitate intracerebral cell transplantation at the scale and complexity of the human brain, we developed a platform technology that enables radially branched deployment (RBD) of cells to multiple target locations at variable radial distances and depths along the initial brain penetration tract with real-time interventional magnetic resonance image (iMRI) guidance. iMRI-guided RBD functioned as an "add-on" to standard neurosurgical and imaging workflows, and procedures were performed in a commonly available clinical MRI scanner. Multiple deposits of super paramagnetic iron oxide beads were safely delivered to the striatum of live swine, and distribution to the entire putamen was achieved via a single cannula insertion in human cadaveric heads. Human embryonic stem cell-derived dopaminergic neurons were biocompatible with the iMRI-guided RBD platform and successfully delivered with iMRI guidance into the swine striatum. Thus, iMRI-guided RBD overcomes some of the technical limitations inherent to the use of straight cannulas and standard stereotactic targeting. This platform technology could have a major impact on the clinical translation of a wide range of cell therapeutics for the treatment of many neurological diseases.

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Safety and Function of a New Clinical Intracerebral Microinjection Instrument for Stem Cells and Therapeutics Examined in the Göttingen Minipig

Cited by 29 publications

References 52 publications

hPSC-Derived Maturing GABAergic Interneurons Ameliorate Seizures and Abnormal Behavior in Epileptic Mice

hPSC-Derived Maturing GABAergic Interneurons Ameliorate Seizures and Abnormal Behavior in Epileptic Mice

Radially Branched Deployment for More Efficient Cell Transplantation at the Scale of the Human Brain

Interventional Magnetic Resonance Imaging-guided Cell Transplantation Into the Brain With Radially Branched Deployment

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