Plastic Surgery Research Council

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In Vivo Characterization of an Injectable, In Situ Polymerizing Cellulosic Hydrogel Filler for Long-Term Soft Tissue Augmentation
Peter J. Taub1, Gittel T. Gold, PhD2, Luis Cardoso2, Robert Phelps, MD1, Steven B. Nicoll, PhD2.
1Mount Sinai Medical Center, New York, NY, USA, 2City College of New York, New York, NY, USA.

Purpose: Numerous processes lead to a deficiency of soft tissue, including aging, trauma or disease. At present, there is no ideal replacement material. All current permanent or semi-permanent soft tissue fillers have disadvantages. Methylcellulose (MC) is a derivative of the plant polysaccharide, cellulose, which has found several biomedical applications due to its inherent thermal gelation properties, biocompatibility and low-cost. Furthermore, the absence of the cellulose-digesting enzyme, cellulase, in humans affords improved stability of MC in vivo. The present study evaluated a novel MC formulation engineered to undergo in situ gelation via dual thermogelling and redox-initiated covalent crosslinking mechanisms and exhibit long-term stability and biocompatibility in vivo.
Methods: MC (1:1 mix of 14 and 41 kDa) was modified with functional methacrylate groups (10% modification) to allow for free radical polymerization as we previously described [1,2]. MC at 3% (w/v) macromer concentration was combined with ammonium persulfate and ascorbic acid redox initiators (10 mM each) and injected subcutaneously via a dual-barrel syringe equipped with a mixing tip and 20G needle into the dorsa of male Sprague Dawley rats (~0.75 ml/injection over the left and right flanks) as per an approved IACUC protocol. At regular intervals over 6 months, the soft tissue was subjected to ultrasound analysis to assess gel depth and migration. In addition, mechanical testing of cylindrical cores was performed via unconfined compression and biocompatibility (histologic analysis and immunohistochemistry) was assessed for capsule thickness and organization, collagen deposition, and CD68+ macrophage presence.
Results: Upon injection, gelation was complete within 10 minutes and the bulking effect was immediate (Fig. 1A). Ultrasound imaging indicated that there was no significant difference in gel depth over time, suggesting that the implants maintained their position and did not contract (Fig. 1B). The hydrogels showed no significant change in mechanical properties over the duration of the study, exhibiting a equilibrium compressive modulus (3.52 0.86 kPa) in the range of human adipose tissue (2.5-4.5 kPa). Biocompatibility studies revealed a mild foreign body reaction, as evidenced by resolution of an early CD68+ macrophage-mediated histiocytic response at the implant surface, and the complete absence of a measurable laminated fibrous capsule by the conclusion of the study. In addition, the rats displayed no discernible changes in mobility or social behavior over the course of the 6-month investigation.
Conclusion: Taken together, these findings suggest that thermoresponsive, redox-polymerized methylcellulose hydrogels may serve as safe and effective long-term filler materials for soft tissue augmentation.


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