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Adipose derived stromal cells encapsulation in hydrogel particles: potential application to osteoarthritis

Fahd Hached1, 2, Claire Vinatier1, 2, 3, Pierre-Gabriel Pinta1, 2, 3, Pierre Weiss1, 2, 3, Catherine Le Visage1, 2, Philippe Hulin4, Aurélie Billon-Chabaud1, 2, 5, Jérôme Guicheux1, 2, 3 and Gaël Grimandi1, 2, 3, 5
  • 1 INSERM U791, LIOAD, France
  • 2 University of Nantes, Faculty of Dentistry, France
  • 3 Ministry of Health, Nantes University Hospital, France
  • 4 INSERM UMS 016, SFR François Bonamy / MicroPicell platform, France
  • 5 University of Nantes, Faculty of pharmacy, France

Introduction

Osteoarthritis (OA) is a degenerative and inflammatory joint disease that affects cartilage, subchondral bone and joint tissues[1]. Mesenchymal Stromal Cells (MSCs) have generated interest since they secrete immuno-modulatory and anti-inflammatory factors[2]. Intra-articular injection of MSCs suffers major limitations including a cell death upon injection[3] and a massive leakeage outside the articular space[4]. In this study, we proposed to entrap MSCs within particles derived from alginate or silylated hydroxypropyl methylcellulose (Si-HPMC) hydrogels.

Materials and Methods

MSCs were isolated from human adipose tissue. We used a dropwise method in CaCl2 solution and developed a water/oil emulsion protocol to obtain alginate and Si-HPMC particles, respectively. To assess the hydrogel network, particles were incubated in FITC-dextran (Mw 20 to 2000kDa) solutions for 2 hours. Diffusion profiles were assessed by confocal microscopy. Ratio of internal to external fluorescence was calculated (a ratio of 1 indicates that equilibrium is reached). Mechanical properties of the particles were investigated by subjecting them to a 30% compressive displacement for 30s (MicroSquisher). A suspension of 2.106 MSCs/ml was added either to the alginate or Si-HPMC solution, the particles were collected and cultured for up to 2 months. Cell viability was followed using a Live/Dead assay. To assess their anti-inflammatory properties, MSCs were treated for 72 hours with pro-inflammatory molecules (TNF-α, IFN-y) in the culture medium. Release of prostaglandin E2 (PGE2) was measured using a EIA Kit (Cayman) and indoleamine 2,3-dioxygenase (IDO) activity was measured by tryptophan-to-kynurenine conversion. 

Results and Discussion

We obtained alginate and Si-HPMC particles with an average size of 1.5 ± 0.2 mm and 75 ± 28 µm, respectively. We evidenced a faster diffusion in Si-HPMC particles than in alginate ones

. Equilibrium was reached after 2 hours for 20 kDa dextran in Si-HPMC, with less than 30% for alginate. This data suggests that Si-HPMC could not only favor cell stimulation by the inflammatory signals but also support the release of secreted molecules. Under compression, alginate particles exhibited a Young's modulus that was 70 times greater than Si-HPMC ones 

, thereby suggesting that viscoelastic Si-HPMC particles could be more effective at protecting cells from shear stress during injection and in the articular cavity. Both Si-HPMC and alginate particles supported cell survival (viability at 2 months of 93% and 90%, respectively;

). The stimulation of encapsulated MSCs resulted in a 3-fold increase in PGE2 production in the supernatant after stimulation with pro-inflammatory cytokines, while IDO activity increased 33 times as compared to non-stimulated cells.

Conclusion

We demonstrated that Si-HPMC and alginate particles support MSCs viability and the maintenance of their anti-inflammatory properties. Diffusion assays and mechanical properties experiments indicate that Si-HPMC is a better candidate for MSCs encapsulation than alginate. Future experiments will investigate whether encapsulated MSCs in Si-HPMC may be a revelant strategy to prevent cartilage degradation and inflammation in OA.

Clinique Brétéché; French Society of Rheumatology; ROAD project: Research on OsteoArthritis Diseases; LMA project: Longévité Mobilité Autonomie

References:
[1] Hunter DJ (2011) Pharmacologie therapy for osteoarthritis the era of disease modification. Nature reviews Rheumatology 7: 13-22.
[2] Caplan Al, Correa D (2011) The MSC: an injury drugstore. Cell stem cell 9: 11-15.
[3] ter Huurne M, Schelbergen R, Blattes R, Blom A, de Munter W, et al. (2012) Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in expérimental osteoarthritis. Arthritis and rheumatism 64: 3604-3613.
[4] Hunt NC, Grover LM (2010) Cell encapsulation using biopolymer gels for regenerative medicine. Biotechnology letters 32: 733-742.

Keywords: stem cell, cytokine, Drug delivery, Capsule

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: Poster

Topic: Biomaterials for therapeutic delivery

Citation: Hached F, Vinatier C, Pinta P, Weiss P, Le Visage C, Hulin P, Billon-Chabaud A, Guicheux J and Grimandi G (2016). Adipose derived stromal cells encapsulation in hydrogel particles: potential application to osteoarthritis. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.00418

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.