Method for increasing the safety of tissue engineered products for clinical use

Regenerative medicine is the replacement of diseased tissues or organs with laboratory-made cellular products (tissue engineered products = TEPs). In recent years stem cells have emerged as the most important source for TEPs. However, stem cell therapies (e.g. TEPs) carry the risk of uncontrolled cell growth (teratoma formation). In order to solve this problem, the present invention uses radiation as a non-genetic and easily practicable approach of mitotic inactivation without loss of function. Upon irradiation, there are no chemical or genetic residues or traces as with other processes that are highly problematic for a cell product from a regulatory point of view.

Challenge

The goal of regenerative medicine is the replacement of diseased tissues or organs with laboratory-made cellular products (tissue engineered products = TEPs). In recent years stem cells have emerged as the most important source of "replacement cells". However, uncontrolled differentiation can lead to tumors (teratomas). This is a critical safety issue in using any cellular product of pluripotent stem cells. Potential solutions to this problem include positive or negative selection of therapeutical cells (e.g. via antibiotic resistance, suicide genes, fluorescent reporter genes, surface marker-based selection). However, these procedures are costly and it is unclear whether they would be applicable from a regulatory point of view. Thus, there is a need for a reliable, easy-to-perform method for mitotic inactivation of cellular products from pluripotent stem cells.

Our Solution

The present invention uses radiation as a non-genetic and easily practicable approach of mitotic inactivation. Irradiation is a suitable method for mitotic inactivation in TEPs, especially muscular TEPs, without loss of function. Two alternative approaches are chosen for this:
(i) irradiation can be carried out with precisely defined radiation doses, so that proliferative cells are switched off and, at the same time, the loss of function is prevented or minimized right from the start.
(ii) irradiation can be carried out with radiation doses that switch off proliferative cells, but also at least temporarily impair the biological function of the TEP. This impairment can be compensated for by subsequent regeneration of the TEP so that after irradiation and regeneration a TEP without proliferative cells but with biological function is obtained.
The invention thus guarantees high safety (no tumor growth) of a TEP with preserved biological activity (e.g., contraction, muscular TEP force generation).

Advantages

Use of radiation to inhibit cell proliferation in TEPs while preserving biological function (e.g. contraction force of muscle tissue).
Integrity of the engineered tissue is maintained even after weeks of irradiation.
Irradiation as a non-genetic and easily practicable approach of mitotic inactivation.
Precise metering and uniform availability, thus independence of diffusion barriers in thick tissues.
No chemical or genetic residues or traces as with other processes that are highly problematic for a stem cell product from a regulatory point of view.

Fig 1.: Irradiation inhibits cell cycle activity in human heart muscle tissue. Staining and measurement (flow cytometry) of cell cycle marker Ki67 in human engineered heart muscle (EHM) 14 days after irradiation. Source: DE102018202268.2Fig 2.:Irradiation does not affect the biological activity of human heart muscle tissue(EHM). Force of contraction (FoC) of EHM with increasing extracellular calcium concentration. EHM were irradiated and then cultured for further four weeks. Source: DE102018202268.2

Applications

Regenerative medicine (replacement of diseased tissues).

Developmental Status

Proof of concept in laboratory setting.

Patent Status

We have filed a German priority patent application (Applicant: Georg-August-Universität Göttingen public law foundation).

Contact

Dr. Stefan Uhle
Patent Manager Life Science
E-Mail: suhle(at)sciencebridge.de
Tel: +49 551 30724 154
Reference: BioC-2016-UMG

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