Targeting stem cells following i.v. injection using magnetic particle based approaches

A problem presented at the UK MMSG Keele 2012.

Presented by:
Prof Alicia El Haj (Institute for Science & Technology in Medicine, Keele University)
Mr Thomas Kwan (ISTM, Keele University)
Participants:
M Albert-Gimeno, EJ El Haj, LS Gallimore, I Hadji, TV Joshi, TD Kwan, GE Lang, S Moise, S Naire, FZ Nouri, GW Richardson, RJ Whittaker

Problem Description

The success of using stem cell-based therapies for tissue repair and regeneration requires a suitable type and source of stem cells, the ability to deliver and track the cells in vivo, and effective mechanisms for targeting the cells to the site of tissue injury. The efficacy of using stem-cell based therapies first relies on the ability to specifically track and target these cells to sites of tissue injury.

The specific targeting of cells to sites of tissue damage in vivo is a major challenge precluding the success of stem cell-based therapies. Magnetic particles, widely used in a variety of biomedical applications, may provide a solution.They are characteristically of low or non-toxicity, are biocompatible and magnetic (superparamagnetic in the case of iron oxide particles), and can be fabricated in a highly controlled manner, allowing for diverse functionalities according to the application. These properties provide a foundation upon which magnetic particle labelling of cells may be used to specifically target cells in vivo using magnetic fields following injection.

We have been using in vitro and in vivo experimental approaches to determine the potential for using magnetic particles to label human MSCs and targeting of these during fluid flow using a magnetic field. To examine cell trapping using magnetic particles, we designed a simple in vitro fluid flow system incorporating a magnetic trapping chamber. Experiments using this system demonstrated that MSCs labelled with 250 nm diameter magnetic particles could be specifically trapped during fluid flow, with a calculated trapping efficiency of 33%. Whilst the majority of cells in flow were not trapped as they passed the magnet, continuous flow would lead to increased trapping and accumulation of cells. Indeed, this was evident in our in vitro experiments where cell trapping occurred quickly after initiation of flow (within 30 seconds) and increased substantially with continuous flow. We next assessed the effect of particle concentration and fluid flow rate on the extent of cell trapping. We were then able to study the effects of other parameters such as presence of protein, blood cells and viscosities on the ability to target and trap stem cells within our experimental chamber.

Our results provide a model for testing MSCs labelled with magnetic particles to define successful trapping of MSCs during fluid flow which ultimately can be translated to in vivo targeted delivery of cells via the circulation in a variety of tissue repair models.

The study group is asked to help us to better understand

  1. the mechanics of the fluid flow and magnetic field, and how they influence the trajectories and trapping of the injected cells and particles. Ideally, we hope to have a mathematical model of our in vitro system which would help us validate our experimental results.
  2. the sensitivity of multiple parameters in the vascular system of a patient (e.g., blood flow rates, viscosity, etc.) in relation to the delivery to a specific tissue.
  3. the limitations of using magnetic fields for directed targeting to specific organs in terms of location, depth of body and size of repair site.
  4. the degree of dosing of magnetic particles and strength of magnetic field for different applications within a patient

Experimental data will be provided at the study group.

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Study Group Report

The previous work on directing paramagnetic particles in the bloodstream with magnets discussed above proves that in two-dimensions the magnetic force felt by the particles cannot attain a maximum away from the surface of the magnet. We attempted, but were unable to extend this result to three dimensions during the study group. However, it seems safe to conclude that any static arrangement of magnets on a patient's skin, capable of focussing magnet force at a target site deep in the tissue would have to be truly three-dimensional, if it exists at all.

We demonstrated through example calculations that the force felt by magnetic particles decays rapidly, like r-7, away from the magnet. This result will enable the experimentalists to approximate how strong a force their magnet will generate at a given distance into tissue. Whilst the forces due to the magnet and the blood di er in magnitude making it unlikely that the magnet will be strong enough to fix the position of an SPIO loaded cell in the bloodstream, they could slow cells down or cause their paths through the vessel to deviate sufficiently to substantially increase the likelihood of the cell coming into contact with the cell wall.

Numerical results demonstrate a possible framework for simulations of cell motion through the bloodstream in the presence of a magnet. The interface between cell and blood is seen to di use at some of the later time points and there is some pinching of the cell under the influence of strong magnets. Both these problems could be addressed in future work by incorporating a model of the cell membrane.

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