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Aerobic Exercise And IGF-Releasing Porous Scaffolds Synergistically Promote Functional Recovery Post Volumetric Muscle Loss
Yori Endo1, Mohamadmahdi Samandari2, Mehran Karvar1, Azadeh Mostafavi3, Jacob Quint2, Chiara Rinoldi4, Iman K. Yazdi5, Wojciech Swieszkowski4, Joshua Mauney6, Shailesh Agarwal1, Ali Tamayol2,3*, Indranil Sinha1
1Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2Department of Biomedical Engineering, University of Connecticut, Farmington, CT, USA 3Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA 4Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology. Warsaw, Poland 5Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 6Departments of Urology and Biomedical Engineering, University of California, Irvine, Irvine, CA, USA

Background: Volumetric muscle loss (VML), a composite defect of skeletal muscle, heals by scaring with minimal muscle regeneration, leading to a permanent disability. Current surgical and physical therapies are inadequate and therefore regenerative therapy is needed for effect treatment of VML. Despite some of the promising outcomes demonstrated by acellular scaffold-based therapies, their efficacy is limited to the maintenance of remnant muscles with minimal to no induction of muscle regeneration.
Methods: A colloidal scaffold with hierarchical porosity that sustains efficacious levels of recombinant IGF-1 at the local injury site was engineered. The scaffold was implanted with a handheld 3D printer onto VML defects created in the hindlimbs of a mouse model, and functional recovery of the animals were examined after 8 weeks.
Results: The present study showed that a significant loss of muscle mass and function was accompanied by a down-regulation of insulin-like growth factor 1 (IGF-1) responsible for muscle maintenance and regeneration within the injured muscle tissues. Treatment of myoblasts with 10 ng/mL IGF-1 promoted their proliferation and differentiation into mature myotubes in vitro. The foam-like scaffold can be in situ-printed using a handheld 3D printer onto remnant muscle without the need for suturing. The scaffold demonstrated a compressive modulus of 9 2 kPa and an adhesion strength of 11 3 kPa. Post 8 weeks of implantation, the foam-like scaffolds carrying IGF-1 significantly improved functional recovery as measured by muscle force production. Histological analysis confirmed regeneration of new muscle tissue within the foam-like scaffolds, only in the group carrying IGF-1. In addition, the scaffolds significantly reduced fibrosis and increased the expression of neuromuscular junctions in the newly regenerated muscle tissue. When recovery was coupled with regimented exercise comprised of 40 min of running of treadmill at no incline given three times weekly for 8 weeks, the foam-like scaffolds with IGF-1 augmented the treatment outcome in a synergistic fashion, demonstrating greater average maximum running speed and distance fun as well as force production.
Conclusion: Exercise therapy combined with regenerative therapy based on IGF-1-releasing porous foam the synergistically improve muscle regeneration and functional recovery after VML.


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