Development of non-degradable, permeable, cell vehicle that can be implanted and subsequently removed from a solid organ can be approached using many attractive strategies. The system should enable cell viability and secretion of therapeutic agents.

Below some of these strategies are being discussed.

1.    Alginate is an obvious and elegant solution. It was already demonstrated that it may work as a non-immunogenic envelope for cells, growing in the extra cellular matrix (1). It was used with islet cells to increase the insulin level in solid organ see Figure 1 and s video (2). The alginate was implanted in the form of a “living thread”. In that form, the alginate may be removed from the organ, if needed. The only challenge is that alginate, in its basic form, is a soft hydrogel and may rupture when pulled during removal. (1)

Figure 1. Impanation of alginate living thread consisting viable islet cells to the kidney and its effect of on glucose concentration in blood.

To be able to remove cells quickly and efficiently, it would be good to enforce the alginate with PET, PP or PCL multifilament threads.(3) Those are well tolerated non-immunogenic polymers. The end of the thread may stick out of the skin. The construct will be implemented by injection or catheter and removed by pulling the thread. The cells must be seeded within the yarn while alginate is used as a external layer that isolates the yarns from surrounding environment. (See Figure 2A). Optionally alginate itself can be enforced (4,5) to constitute a strong thread.

Advantageously, alginate based medical devices are in advanced clinical trials and were injected to human heart to mechanically stabilize the scare during the healing (5,6).

Another system that may be investigated is forming the strong permanent alginate “pocked” that will be filled or emptied by cells injection / aspiration.

2.    Other strategies can be based on nanofibers mats formed in a shape of tubes (7). The tube made out of nanofiber is permeable for cell’s metabolites but not for cells themselve. In this solution, the tube may be filled with hydrogels that host the cells. The membrane would be permeable and cells can stay viable while secreting the therapeutic agents. Nanofibers are currently used as a surgical suture, so they are strong enough to be pulled after implantation. The suitable polymers include non-degradable PP or PET alternatively polyurethanes.  The same benefits can be achieved by applying densely woven or braided porous textiles, based on microfibers of the polymer.

3.    Other solution can be based on cross linked polyethylene glycol (PEG) or polyacrylates (PA) that will work similarly to alginate hydrogels, but will be stronger, so easier to remove.(8)

The concerns are: complete removal of the cells and disabling cell migration out of the vehicle. If  adherent cell will be used, there should be no problem to remove the cells; also continuous membrane of alginate is an efficient barrier for cell migration since it cannot be colonized by the cells.
In the case of suspension cells, which may flow out of ruptured alginate envelope; one solution could be placing the optical fiber in the cavity after thread removal and subsequent UV irradiation.
The device can have the shape of the loop for cell delivery; the solid organ is used as a pulley.  This way the access into exact location of the organ would be preserved. It can be used to optimize therapy see Figure 2 B

Figure 2. Alginate enforced with polymer thread, seeded with cells and removable by pulling upon request (A), The loop made out of enforced alginate thread can be used to switch on/off cellar activity.

Conclusion

Collectively all solutions discussed above are in fact medical devices, to be used in the clinic, min 3 years (11), is required, excluding the development phase.

References:

  1. Onoe H, Okitsu T, Itou A, Kato-Negishi M, Gojo R, Kiriya D, et al. Metre-long cell-laden microfibres exhibit tissue morphologies and functions. Nat Mater. 2013 Jun;12(6):584–90.
  2. nmat3606-s7.mov [Internet]. [cited 2016 May 27]. Available from: http://www.nature.com/nmat/journal/v12/n6/extref/nmat3606-s7.mov
  3. Liberski AR, Delaney JT, Schäfer H, Perelaer J, Schubert US. Organ weaving: woven threads and sheets as a step towards a new strategy for artificial organ development. Macromol Biosci. 2011 Nov 10;11(11):1491–8.
  4. Liberski AR. Three-dimensional printing of alginate: From seaweeds to heart valve scaffolds. QScience Connect. 2016 Apr 1;2016(2):3.
  5. Hong S, Sycks D, Chan HF, Lin S, Lopez GP, Guilak F, et al. 3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures. Adv Mater. 2015 Jul 1;27(27):4035–40.
  6. Alginate-for-cardiac-regeneration-from-seaweed-to-clinical-trials.pdf [Internet]. [cited 2016 May 27]. Available from: http://albert-liberski.eu/wp-content/uploads/2016/04/Alginate-for-cardiac-regeneration-from-seaweed-to-clinical-trials.pdf
  7. Sun B, Jiang X-J, Zhang S, Zhang J-C, Li Y-F, You Q-Z, et al. Electrospun anisotropic architectures and porous structures for tissue engineering. J Mater Chem B. 2015 Jul 1;3(27):5389–410.
  8. Bartolo LD, Bader A. Biomaterials for Stem Cell Therapy: State of Art and Vision for the Future. CRC Press; 2013. 664 p.
  9. O’Cearbhaill ED, Ng KS, Karp JM. Emerging medical devices for minimally invasive cell therapy. Mayo Clin Proc. 2014 Feb;89(2):259–73.
  10. Caplan AI. Adult Mesenchymal Stem Cells: When, Where, and How. Stem Cells Int. 2015;2015:628767.
  11. Kaplan AV, Baim DS, Smith JJ, Feigal DA, Simons M, Jefferys D, et al. Medical Device Development From Prototype to Regulatory Approval. Circulation. 2004 Jun 29;109(25):3068–72.

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