Design and fabrication of a biodegradable, covalently crosslinked shape-memory alginate scaffold for cell and growth factor delivery.

The successful use of transplanted cells and/or growth factors for tissue repair is limited by a significant cell loss and/or rapid growth factor diffusion soon after implantation. Highly porous alginate scaffolds formed with covalent crosslinking have been used to improve cell survival and growth factor release kinetics, but require open-wound surgical procedures for insertion and have not previously been designed to readily degrade in vivo. In this study, a biodegradable, partially crosslinked alginate scaffold with shape-memory properties was fabricated for minimally invasive surgical applications. A mixture of high and low molecular weight partially oxidized alginate modified with RGD peptides was covalently crosslinked using carbodiimide chemistry. The scaffold was compressible 11-fold and returned to its original shape when rehydrated. Scaffold degradation properties in vitro indicated ~85% mass loss by 28 days. The greater than 90% porous scaffolds released the recombinant growth factor insulin-like growth factor-1 over several days in vitro and allowed skeletal muscle cell survival, proliferation, and migration from the scaffold over a 28-day period. The compressible scaffold thus has the potential to be delivered by a minimally invasive technique, and when rehydrated in vivo with cells and/or growth factors, could serve as a temporary delivery vehicle for tissue repair.

[1]  H. Vandenburgh,et al.  Growth, differentiation, transplantation and survival of human skeletal myofibers on biodegradable scaffolds. , 2008, Biomaterials.

[2]  L. Shapiro,et al.  Novel alginate sponges for cell culture and transplantation. , 1997, Biomaterials.

[3]  S. Rosenthal,et al.  Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Eben Alsberg,et al.  Shape retaining injectable hydrogels for minimally invasive bulking. , 2004, The Journal of urology.

[5]  R. Langer,et al.  Biodegradable, Elastic Shape-Memory Polymers for Potential Biomedical Applications , 2002, Science.

[6]  Yoshito Ikada,et al.  Challenges in tissue engineering , 2006, Journal of The Royal Society Interface.

[7]  G. Adams.  Invited Review: Autocrine/paracrine IGF-I and skeletal muscle adaptation. , 2002, Journal of applied physiology.

[8]  Ruth Duncan,et al.  Radioiodination of Alginate via Covalently-Bound Tyrosinamide Allows Monitoring of its Fate In Vivo , 1995 .

[9]  M. Rudnicki,et al.  Cellular and molecular regulation of muscle regeneration. , 2004, Physiological reviews.

[10]  G. Goldspink,et al.  Different roles of the IGF‐I Ec peptide (MGF) and mature IGF‐I in myoblast proliferation and differentiation , 2002, FEBS letters.

[11]  D J Mooney,et al.  Alginate hydrogels as synthetic extracellular matrix materials. , 1999, Biomaterials.

[12]  Jon A. Rowley,et al.  Controlling Mechanical and Swelling Properties of Alginate Hydrogels Independently by Cross-Linker Type and Cross-Linking Density , 2000 .

[13]  G. Cooney,et al.  Effect of human insulin-like growth factor-binding protein-1 on the half-life and action of administered insulin-like growth factor-I in rats. , 1993, The Journal of endocrinology.

[14]  E. Froesch,et al.  Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. , 1989, Acta endocrinologica.

[15]  David J Mooney,et al.  Regulating myoblast phenotype through controlled gel stiffness and degradation. , 2007, Tissue engineering.

[16]  D. Mooney,et al.  Regulating activation of transplanted cells controls tissue regeneration. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Jeff W Lichtman,et al.  Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors , 2009, Proceedings of the National Academy of Sciences.

[18]  Johnny Huard,et al.  Development of Approaches to Improve Cell Survival in Myoblast Transfer Therapy , 1998, The Journal of cell biology.

[19]  H. Vandenburgh,et al.  The role of multifunctional delivery scaffold in the ability of cultured myoblasts to promote muscle regeneration. , 2011, Biomaterials.

[20]  D. Mooney,et al.  Decoupling the dependence of rheological/mechanical properties of hydrogels from solids concentration , 2002 .

[21]  Mark R. Soboleski,et al.  Green fluorescent protein is a quantitative reporter of gene expression in individual eukaryotic cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  David J. Mooney,et al.  Synthesis of cross-linked poly(aldehyde guluronate) hydrogels , 1999 .

[23]  G. Cossu,et al.  Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. , 2010, The Journal of clinical investigation.

[24]  W. Pan,et al.  Interactions of IGF-1 with the Blood-Brain Barrier in vivo and in situ , 2000, Neuroendocrinology.

[25]  N. Rosenthal,et al.  Proliferation precedes differentiation in IGF-I-stimulated myogenesis , 1996, The Journal of cell biology.

[26]  J. Huard,et al.  Management of Skeletal Muscle Injuries in Military Personnel , 2005 .

[27]  H. Richards,et al.  Quantitative GFP fluorescence as an indicator of recombinant protein synthesis in transgenic plants , 2003, Plant Cell Reports.

[28]  D. Mooney,et al.  Hydrogels for tissue engineering: scaffold design variables and applications. , 2003, Biomaterials.

[29]  P Eiselt,et al.  Porous carriers for biomedical applications based on alginate hydrogels. , 2000, Biomaterials.

[30]  A Lendlein,et al.  Shape-memory polymers as stimuli-sensitive implant materials. , 2005, Clinical hemorheology and microcirculation.

[31]  David J Mooney,et al.  Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. , 2005, Biomaterials.

[32]  T. Partridge,et al.  Dynamics of Myoblast Transplantation Reveal a Discrete Minority of Precursors with Stem Cell–like Properties as the Myogenic Source , 1999, The Journal of cell biology.

[33]  Eben Alsberg,et al.  SHAPE-DEFINING SCAFFOLDS FOR MINIMALLY INVASIVE TISSUE ENGINEERING , 2004, Transplantation.

[34]  M. Koutsilieris,et al.  Type I insulin-like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. , 2007, Journal of musculoskeletal & neuronal interactions.