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Novel Implantation Technique May Enhance Outcomes of Intracerebral Cell Therapy

Key findings

  • In a novel approach to intracerebral cell therapy for Parkinson's disease, called "columnar injection," graft material is intentionally extruded into the surgical cannula track as the cannula is withdrawn, with precise control of volume, distance and rate
  • In animal models, the technique produced a column of cells centered on the intended target, more evenly distributed than in grafts implanted with bolus injection, and with a greater number of viable dopaminergic neurons
  • Columnar injection may minimize unwanted additional host tissue damage and promote better interaction between graft surface and host tissue, resulting in improved survival of engrafted cells

Numerous forthcoming clinical trials will evaluate whether the transplantation of stem cell-derived neurons can treat Parkinson's disease. A variety of surgical approaches have been described for implanting cells or fetal tissue into the brain, but all involve injecting graft material at one or more points with the cannula fixed in position, depositing a bolus of material. This disrupts tissue beyond the damage incurred as the cannula passes to the target site.

Jeffrey S. Schweitzer, MD, PhD, neurosurgeon, Bob S. Carter, MD, PhD, chief of the Department of Neurosurgery at Massachusetts General Hospital, and Kwang-Soo Kim, PhD, director of the Molecular Neurobiology Laboratory at McLean Hospital, and colleagues have devised an alternative approach to intracerebral cell therapy. They use the cannula track itself as the graft site, extruding graft material into the track as the cannula is withdrawn from the target, with precise control of volume, distance and rate.

That method, called "columnar injection," produces a column of cells centered on the intended target, which is more evenly distributed than in grafts implanted with bolus injection. In Operative Neurosurgery, the researchers report that in a rat model of intracerebral cell therapy, columnar injection also resulted in a significantly greater number of mature dopaminergic neurons.

Technique Details

Columnar injection can be implemented with any syringe device that provides single-point or multiple-point injections. The researchers modified an FHC MicroTargeting and Stardrive system for their experiments.

The technique is dynamic—cell deposition and removal of the cannula (syringe barrel) take place simultaneously. Extruded cells are continuously deposited into the area the cannula just vacated as it was withdrawn at a fixed rate. The key is to separate control of the cannula and plunger.

Both the cannula and the plunger are withdrawn from the target, but the plunger is withdrawn more slowly. This difference results in a net downward movement of the plunger within the cannula, resulting in the ejection of material into the track created during cannula insertion. The pressure of ejection fills or expands the existing cavity in the host tissue.

The volume injected per distance traveled is set by adjusting the length of an adjustable lever arm, and the distance traveled per unit time is independently set using a digital motorized drive. The system can be calibrated to use different sizes of syringes and different gear ratios of plunger-to-barrel movement to achieve the desired rate and volume of injection.

Short-term Study

In athymic (immunocompromised) rats, the researchers tested columnar injection against bolus injection, using each animal as its own control. They differentiated human embryonic stem cells into midbrain dopamine progenitors and labeled them with green fluorescent protein. The rats received a bolus injection of cells into the left striatum and a columnar injection into the right, then were evaluated one day later.

The expectation with bolus injection is that the ultimate graft will surround the point of injection. However, bolus injection in this study produced central acellular areas. These were interpreted as areas of cell death or displacement by the carrier solution and cannula.

In contrast, columnar injection produced an even cylinder of cell deposition, centered along the track created by the injection cannula.

Longer-term Study

The researchers repeated the experiment with rats that they evaluated after eight weeks. The grafts were examined with immunofluorescent staining for human nuclear antigen (hNuc) and tyrosine hydroxylase (TH).

Bolus injections yielded grafts that had a teardrop shape. TH+ cells were located primarily at the periphery, and most of the grafts contained prominent acellular areas.

Grafts from columnar injection retained a cylindrical form. Distribution of TH+ cells was more uniform than in the bolus grafts, and hNuc staining did not show appreciable acellular regions.

There was substantial variability from animal to animal, but stereological counting showed significantly longer survival of TH+ cells in columnar grafts than in bolus grafts. TH+ neurites were also larger in the columnar grafts.

Mechanisms of Columnar Injection

The researchers explain that two mechanisms underlie their findings:

  • In both bolus and columnar grafts, the graft and host exert pressure on each other, but in columnar grafts, the pressure is more evenly distributed over a larger surface area. Thus, there is less pressure per unit volume of the graft
  • Cylindrical columns have a greater ratio of surface area to volume than the more spheroid bolus grafts, which facilitates diffusion into and out of the graft. This difference presumably helped produce the longer-surviving dopaminergic neurons and allowed for their more even distribution and improved neurite outgrowth

Furthermore, the researchers believe the more uniform distribution of columnar grafts will prevent hot spots of greater engrafted cell density, one of the proposed causes of graft-induced dyskinesia. They're currently using rat models of Parkinson's disease to study the long-term functional outcomes of columnar injection.

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In this video, Jeffrey Schweitzer, MD, PhD, discusses his research using stem cell technology to restore normal function in patients with movement disorders. He believes this technology may be able to improve outcomes for patients with tremor, Parkinson's disease and dystonia.