Oral Presentation: Injectable cell encapsulated hyaluronic acid microgels for nucleus pulposus regeneration

Torabi Rahvar, Parisa; Schlagenhof, Leon; Abdekhodaie, Mohammad J.; Gantenbein, Benjamin (2024). Oral Presentation: Injectable cell encapsulated hyaluronic acid microgels for nucleus pulposus regeneration (Unpublished). In: 50th International Society for the Study of the Lumbar Spine Annual Meeting 2024. Milano, Italy. 29 May 2024.

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INTRODUCTION

Low back pain (LBP) is a widespread health problem affecting a considerable proportion of adults worldwide, with estimates suggesting that as many as 80% may experience it1 . One of the leading causes of LBP is intervertebral disc (IVD) degeneration. Mesenchymal stromal cells (MSCs) offer promising potential to regenerate IVD in the initial stages of degeneration2 . The conventional method for stem cell delivery is typically done through direct injection into the target tissue or site. Nevertheless, there is an ongoing debate regarding the survival of transplanted cells in cell suspensions within the challenging environment of degenerated IVD, which could negatively impact the effectiveness of cell therapy3 . Utilizing microgels as carriers for delivering cells shows promise in addressing this challenge. Microgels replicate the three-dimensional natural environment of cells, facilitate efficient substance transfer, and can be administered through injection4 . Due to its biocompatibility, biodegradability, non-immunogenic, non-toxic, and noninflammatory properties, hyaluronic acid has been used as a biomaterial for clinical products for over three decades5 . Herein, injectable microgels based on hyaluronic acid (HA) were developed for MSCs delivery to the IVD.

METHODS

Tyramine-grafted HA (HA-Tyr) was prepared using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and n-hydroxysulfosuccinimide (NHS) chemistry6 . HA-Tyr solutions with different concentrations (1.5, 2, and 2.5 % w/v) were extruded and microdroplets were generated using a flicking-based vibrating nozzle system. The droplets were directly collected in a H2 O 2 solution and formed microgels. The gelation time and crosslinking conditions were optimized to produce spherical microgels at a high production rate. These cell-encapsulated microgels were utilized for discogenic induction.

RESULTS

With this novel approach, uniform microgels could be fabricated with narrow distribution and spherical shape. Light microscopy images showed that the HA-Tyr microgels have spherical shape morphology within a size range of 505 ± 47µm (Figures 1A). This was also verified by scanning electron microscopy (SEM) as shown in Figure 1B. The resulting HA-Tyr microgels are injectable through needles with conventional gauges (21 G) and disperse rapidly in aqueous media after injection (Figure 1C). Live/dead staining confirmed that the concentration for the crosslinker did not damage the encapsulated cells, as there was abundant green staining, indicating live cells. Also, cell-encapsulated microgels showed an even distribution of cells within the microgels (Figure 1D).

DISCUSSION

This study demonstrates that HA-Tyr-based microgels serve as a reliable system for delivering cells to degenerated IVD by injecting cell-encapsulated microgels. In addition, the current encapsulation procedure can be adjusted to meet the needs of different applications. For instance, it can serve as a dynamic bioreactor system for cultivating MSCs and producing cell-based therapies such as growth factors. Additionally, it can create in-vitro platforms for drug screening and disease modeling or act as bioinks for bottom-up tissue engineering in bioprinting.

REFERENCES

1. McKee, Christina, et al. "Mesenchymal stem cells transplanted with self-assembling scaffolds differentiated to regenerate nucleus pulposus in an ex vivo model of degenerative disc disease." Applied Materials Today 18 (2020): 100474.

2. Friedmann, Andrea, et al. "Intervertebral disc regeneration injection of a cell-loaded collagen hydrogel in a sheep model." International Journal of Molecular Sciences 22.8 (2021): 4248.

3. Xu, Haibin, et al. "Growth differentiation factor-5–gelatin methacryloyl injectable microspheres laden with adipose-derived stem cells for repair of disc degeneration." Biofabrication 13.1 (2020): 015010.

4. Panebianco, Christopher J., et al. "Genipin-crosslinked fibrin seeded with oxidized alginate microbeads as a novel composite biomaterial strategy for intervertebral disc cell therapy." Biomaterials 287 (2022): 121641.

5. Russo, Fabrizio, et al. "A hyaluronan and platelet-rich plasma hydrogel for mesenchymal stem cell delivery in the intervertebral disc: an organ culture study." International journal of molecular sciences 22.6 (2021): 2963.

6. Jooybar, Elaheh, et al. "An injectable platelet lysate-hyaluronic acid hydrogel supports cellular activities and induces chondrogenesis of encapsulated mesenchymal stem cells." Acta biomaterialia 83 (2019): 233-244.

Acknowledgements

This research was supported by the Council for Development of Stem Cell Sciences and Technologies (#57940), Iran National Science Foundation (# 99002288) and a Swiss National Science Bridge Discovery Project # 40B2-0_211510/1

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