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Electrospun Synthetic Scaffolds: A Biomimetic Approach to Prevent Hypertrophic Scar Contraction
Kyle J. Miller, BA1, Elizabeth R. Lorden, BS2, Ellen Hammett, ,2, Mohamed M. Ibrahim, MD1, Carlos Quiles, MD1, Angelica Selim, MD3, Kam W. Leong, Ph. D2, Howard Levinson, MD1.
1Division of Plastic Surgery, Department of Surgery, Duke University School of Medicine, Durham, NC, USA, 2Department of Biomedical Engineering, Duke University, Durham, NC, USA, 3Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
Over 2.4 million Americans and tens of millions of patients worldwide suffer from hypertrophic scar contraction (HSc) following serious thermal injury. HSc is a debilitating condition that results in disfigurement and decreased range of motion in affected joints. In unwounded skin, native collagen is arranged randomly, myofibroblasts are absent, and matrix stiffness is low. Conversely, in HSc, collagen is arranged in linear arrays while myofibroblast density and matrix stiffness are high. The current standard of care for HSc involves skin grafting with or without the placement of a collagen based bioengineered skin equivalent (BSE). Present BSEs assist in tissue regeneration but do not target Hsc because they are brittle and rapidly degrade prior to completion of the remodeling phase of repair. To overcome this significant unmet medical need, we have created an elastomeric biomimetic BSE which will persist through the remodeling phase of repair.
Electrospun scaffolds were created with randomly-oriented fibers akin to collagen fiber alignment in unwounded human skin. Mechanical properties were characterized via microstrain analysis. Human dermal fibroblast ingrowth and matrix contraction were compared in vitro between scaffolds and fibroblast populated collagen lattices (FPCL, a 3-dimensional in vitro model of wound healing that is the progenitor for present-day BSEs). To test HSc reduction in vivo, scaffolds were surgically placed beneath skin grafts in an immune competent murine HSc model. In vivo statistics utilized student’s t-test and ANOVA. In vitro statistics utilized Tukey’s HSD. All pairings tested, significance judged as p<0.05.
Scaffolds demonstrated a lower (but not statistically significant) elastic modulus than human skin and a collagen-based clinical BSE (Integra™), suggesting scaffolds will not prohibit movement in vivo. Ultimate tensile strength of scaffolds was greater than human skin, while Integra™ was significantly weaker, making the scaffolds tougher than their surrounding environment and giving them the ability to withstand forces experienced by skin in vivo. Scaffolds supported fibroblast ingrowth and proliferation analogous to the FPCL, but prevented nuclear alignment observed in FPCL. After seven days of culture, the scaffold contracted only 8 +/- 1.5% whereas the FPCL contracted 66 +/- 9%, with significantly fewer activated myofibroblasts in the scaffold. To confirm that the scaffolds reduce HSc in vivo, scaffolds were surgically inserted beneath skin grafts in a validated immune competent murine HSc model. The scaffolds limited HSc contraction to 6 +/- 0.2%, whereas wounds treated with Integra™ contracted 65 +/- 5% and control scars contracted 68 +/- 4%. Skin grafts were healthy and scaffolds were found to promote fibroblast invasion, angiogenesis, and macrophage recruitment.
The data demonstrate that biomimetic electrospun scaffolds provide mechanical support to prevent wound bed contraction during healing and prevent fibroblast alignment and myofibroblast activation associated with HSc. These findings suggest the importance of mechanical properties in the prevention of HSc contraction, and will help guide the rational design of future generations of BSEs in treating the millions of patients who suffer from burns each year.
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