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Bioactive Peptide Amphiphile Nanofiber Gels Enhance Burn Wound Healing

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Bioactive Peptide Amphiphile Nanofiber Gels Enhance Burn Wound Healing b u r n s 4 5 ( 2 0 1 9 ) 1 1 1 2 – 1 1 2 1 Available online at www.sciencedirect.com ScienceDirect jo urnal homepage: www.elsevier.com/locate/burns Bioactive peptide amphiphile nanofiber gels enhance burn wound healing a,b,1 a,1 c a Situo Zhou , Akishige Hokugo , Mark McClendon , Zheyu Zhang , a a,d a Reena Bakshi , Lixin Wang , Luis Andres Segovia , a c,e,f,g,h a, Kameron Rezzadeh , Samuel I. Stupp , Reza Jarrahy * a Regenerative Bioengineering and Repair (REBAR) Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA b Department of Burns and Reconstructive Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China c Simpson Querrey Institute , Northwestern University, Chicago, IL, USA d Department of Dentistry, Chengdu Women and Children’s Central Hospital, Chengdu, Sichuan, China e Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA f Department of Chemistry, Northwestern University, Evanston, IL, USA g Department of Medicine, Northwestern University, Chicago, IL, USA h Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA a r t i c l e i n f o a b s t r a c t Article history: Background: Burns are physically debilitating and potentially fatal injuries. The standard-of- Accepted 16 June 2018 care for burn wounds is the coverage with gauze dressings designed to minimize trauma to the regenerating epidermis and dermis during dressing changes. However, deep partial- and full-thickness burns always heal slowly when standard wound care alone is performed. We have previously reported that peptide amphiphile (PA) gels, pH-induced self-assembling Keywords: nanostructured fibrous scaffolds, promote cell proliferation and have great potential in Self-assembly regenerative medicine for rapid repair of tissues. In this study, we hypothesized that the PA gels are capable of accelerating wound healing in burn injury. Peptide amphiphile Nanofiber Methods: Artificially generated thermally damaged fibroblasts and human umbilical vein endothelial cells were seeded onto the various PA nanofiber gels including bioactive and Thermally damaged cells nonbioactive peptide sequences. Cell proliferation was assessed at different time points, and Wound healing thermally damaged fibroblasts and HUVECs manifested increased proliferation with time when cultured with various PA gels. To determine in vivo effects, burn wounds of rats were treated with the bioactive Arg-Gly-Asp-Ser (RGDS)-modified gel that showed greater cell proliferation in vitro. The wound closure was observed, and skin samples were harvested for histologic evaluation. Results: Cell proliferation using the RGDS-PA gel was significantly higher than that observed in other gels. The RGDS-PA gel significantly enhanced re-epithelialization during the burn wound healing process between days 7 and 28. Application of PA gels accelerates the recovery * Corresponding author at: Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Suite 465 Los Angeles, CA 90095-6960, USA. E-mail address: [email protected] (R. Jarrahy). 1 These authors contributed equally to this study. https://doi.org/10.1016/j.burns.2018.06.008 0305-4179/© 2018 Published by Elsevier Ltd. b u r n s 4 5 ( 2 0 1 9 ) 1 1 1 2 – 1 1 2 1 1113 of deep partial-thickness burn wounds by stimulation of fibroblasts and the creation of an environment conducive to epithelial cell proliferation and wound closure. Conclusions: This biomaterial represents a new therapeutic strategy to overcome current clinical challenges in the treatment of injuries resulting from burns. © 2018 Published by Elsevier Ltd. signaling [7,8]. Interestingly, these PA gels can not only 1. Introduction maintain a hydrated scaffold to support cell growth but also have the ability to display important bioactive peptide A significant number of burn injuries occur in the United States sequences that mimic native tissues such as collagen or with more than 2.5 million Americans suffering with the laminin [9,10]. The constituent PA molecules making up the sequelae of these wounds [1]. While the advances in burn nanofibers consist of four main segments: (1) a hydrophobic management and care have improved leading to increased group (2) a b-sheet-forming peptide that promotes nanofiber survival, there are a greater portion of patients remaining to formation; (3) a peptide segment that contains ionizable side combat the often-severe morbidities of long-term functional chain residues for solubility; and (4) an optional bioactive and esthetic deficits. The majority of these deficits are signaling epitope designed to interact with cellular receptors secondary to hypertrophic scarring for which there is no great and stimulate cellular activities (Fig. 1). The RGDS (Arg-Gly- preventive therapy [2]. Current wound management contin- Asp-Ser) epitope sequence is found naturally on molecules of ues to rely on various topical agents and wound dressings, fibronectin and has been shown to promote cellular motility, followed by autologous skin grafting and its associated proliferation, and differentiation in vitro [11–15]. It has been morbidities of pain, infection, and scarring, as the current used in a variety of cells types including osteoblasts [16], gold standard. Schwann cells [17], and neurons [18]. The use of the RGDS in Denatured dermis plays an essential role in wound healing, self-assembled structures and their influence on cellular and preservation of denatured dermis may be an effective behavior has been investigated for cell adhesion, cell delivery, treatment for skin burns to attenuate scar formation and differentiation, and morphology [9,19–21]. restore normal appearance [3]. It is well known that the dermis The purpose of this study is to investigate a novel bioactive predominantly comprises fibroblasts and vascular endothelial nanofiber-based hydrogel biomaterial that can accelerate burn cells [4]. These cells must be bound up in the recovery of the wound healing. To achieve this purpose, various hydrogels thermally damaged dermis. In fact, therapies designed to were applied to the thermally damaged cells to identify the support and augment the regenerative capacity of these cells appropriate bioactive nanofiber hydrogel. Moreover, in vivo have demonstrated to lessen scar contracture and, ultimately, studies were performed to investigate the use of the to improve appearance and function [5,6]. appropriate bioactive nanofibers as a wound dressing in a Peptide amphiphile (PA) nanofiber hydrogels have been rat burn model and subsequently examined in the context of shown to direct cell fate through both physical and molecular burn wound healing. Fig. 1 – A: Chemical structure of the bioactive PA molecule used in the PA5 group. B: The colored segments correspond to the 3D illustration of a nanofiber composed of 10% bioactive PA molecules. These nanofibers readily form gels through ionic crosslinks. C: The gel is viewed in SEM as an interconnected network of fibers. Scale bar: 500nm. 1114 b u r n s 4 5 ( 2 0 1 9 ) 1 1 1 2 – 1 1 2 1 NC, USA) by standard 9-fluorenyl methoxycarbonyl (Fmoc) 2. Materials and methods solid-phase peptide synthesis on rink amide MBHA resin or Glu (OtBu) Wang resin (Sigma-Aldrich, St. Louis, MO, USA). PAs were 2.1. Cell cultures and establishment of thermally damaged purified by reverse-phase HPLC (Varian ProStar 210 HPLC, cell models Varian, Inc., Palo Alto, CA, USA) using a water/acetonitrile (each containing 0.1% v/v ammonium hydroxide) gradient. Eluting Normal human fibroblasts (hFBs) (CCD-1127Sk) and human fractions containing the desired PA were confirmed by mass umbilical vein endothelial cells (HUVECs) were obtained from spectrometry (Agilent 6520 LCMS, Agilent Technologies, Santa American Type Culture Collection (ATCC) (Manassas, VA, Clara, CA, USA). Confirmed fractions were pooled, and the USA). The hFBs were maintained in Dulbecco’s Modified Eagle acetonitrile was removed by rotary evaporation before freezing Medium (DMEM) (Corning Inc., Corning, NY, USA) with 10% and lyophilization. The purity of lyophilized products was fetal bovine serum (FBS) (Life Technologies, Carlsbad, CA, USA) tested by LCMS (Agilent 6520 LCMS, Agilent Technologies, Santa and penicillin/streptomycin (Life Technologies, Carlsbad, CA, Clara, CA, USA). After lyophilization, PAs were dissolved at 1% USA). The HUVECs were cultured in EGM-2 medium with w/v in mQ water, and the pH was adjusted to 7 with NaOH, endothelial cell growth supplement (SingleQuots, LONZA, making PAs completely soluble. These solutions were then Basel, Switzerland). The medium was changed every 72h. All dialyzed against mQ water and lyophilized again. These cell cultures were maintained at 37 C and 5% CO2. When hFBs lyophilized PA powders were soluble when resuspended in and HUVECs reached to 80% confluence, cells were harvested water buffers (Fig. 1). with 0.25% trypsin-EDTA (Life Technologies, Carlsbad, CA, USA) and resuspended in phosphate-buffered saline (PBS) with 2.4. PA-cell gel fabrication 5 cell density of 1Â10 cells/ml into sterile microcentrifuge tubes (Thermo Fisher Scientific, Waltham, MA, USA). Each tube To prepare the PA gels, PAs were dissolved in aqueous 150mM contained 2ml of cell suspension. Microcentrifuge tubes NaCl, 3mM KCl, and NaOH solution to obtain a final 1wt% containing the cells were immersed in the water bath at solution at a pH between 7.2 and 7.4. To fabricate mixtures various temperatures: 37 C, 52 C, and 100 C for 90s. After containing epitope-bearing PAs, the backbone-PA (PA1 or PA4) immersion, cells were resuspended in fresh medium and was dissolved in aqueous 150mM NaCl, 3mM KCl, and NaOH 4 seeded in 96-well plates with 1Â10 cells per well for 6h. solution to obtain a 1.33wt% solution at a pH between 7.2 and 7.4. The epitope-containing PA (PA3 or PA5) was then dissolved 2.2.
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