Formation of epithelial structures of variegated geometries and sizes is essential for organogenesis, tumor growth, and wound repair. Although epithelial cells are predisposed with potential for multicellular clustering, it remains unclear whether immune cells and mechanical cues from their microenvironment influence this process. To explore this possibility, we cocultured human mammary epithelial cells with prepolarized macrophages on soft or stiff hydrogels. In the presence of M1 (proinflammatory) macrophages on soft matrices, epithelial cells migrated faster and subsequently formed larger multicellular clusters compared to cocultures with M0 (unpolarized) or M2 (anti‐inflammatory) macrophages. By contrast, stiff matrices disabled active clustering of epithelial cells due to their enhanced migration and cell–ECM adhesion, regardless of macrophage polarization. We found that the copresence of soft matrices and M1 macrophages reduced focal adhesions, but enhanced fibronectin deposition and nonmuscle myosin‐IIA expression, which altogether optimize conditions for epithelial clustering. Upon ROCK inhibition, epithelial clustering was abrogated, indicating a requirement for optimized cellular forces. In these cocultures, TNF‐α secretion was the highest with M1 macrophages and TGF‐β secretion was exclusively detectable in case of M2 macrophages on soft gels, which indicated potential role of macrophage secreted factors in the observed epithelial clustering. Indeed, exogenous addition of TGF‐β promoted epithelial clustering with M1 coculture on soft gels. According to our findings, optimization of both mechanical and immune factors can tune epithelial clustering responses, which could have implications in tumor growth, fibrosis, and would healing.
- Award ID(s):
- 1806138
- NSF-PAR ID:
- 10093314
- Date Published:
- Journal Name:
- Journal of Materials Chemistry B
- Volume:
- 7
- Issue:
- 10
- ISSN:
- 2050-750X
- Page Range / eLocation ID:
- 1697 to 1707
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Abstract -
Abstract Wound debridement is crucial for proper wound care as it promotes fast and efficient wound healing through removal of necrotic tissue. The latter not only impairs new healthy tissue formation but also increases the odour and the wound exudate, allowing bacteria and other harmful foreign invaders to spread and infect the wound. Hydrogel wound dressings are usually applied for promoting autolytic wound debridement but this is slow and not a very efficient process. On the other hand, enzymatic products for wound debridement are either ointments or gels and they are easily washed out when used for treating highly exuding wounds. This study is an attempt to combine enzymatic debridement functionality with the high swelling ability of polyzwitterionic networks and to produce an innovative dressing with debridement functionality for the healing of highly exuding wounds. For this purpose, two polyzwitterionic hydrogels were synthesized, poly(sulfobetaine methacrylate) and poly(carboxybetaine methacrylate) hydrogels, which were loaded with the protease subtilisin DY for imparting debridement functionality. The swelling ability and mechanical properties of zwitterionic polymer (ZP) hydrogels were shown to depend on their different propensities to physical network formation. Poly(carboxybetaine methacrylate) hydrogels demonstrated better capacity for wound exudate absorption as well as for exerting higher enzymatic debridement activity. Both ZP hydrogels were shown to be non‐cytotoxic which confirms their appropriateness for direct contact with injured tissues. Thus, the newly developed ZP hydrogels demonstrate the potential to be used as new dressing materials with enzymatic debridement functionality for highly exuding wounds. © 2019 The Authors.
Polymer International published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. -
Abstract PCL (poly‐caprolactone) nanofibers have good biocompatibility and high porosity, which are usually utilized for application in wound dressings. However, wound healing could be hindered by the overproduction of reactive oxygen species (ROS) and different factors. Pure nanofibers cannot satisfy these requirements of wound healing.
N ‐acetylcysteine (NAC), as an antioxidant, meets the requirements for wound healing by resisting the overproduction of ROS and by promoting angiogenesis and maturation of the epidermis. In this study, we prepared a sandwich structured PCL‐Col/NAC scaffold using the molding method, which consisted of PCL nanofibers at the core and NAC‐loaded collagen on both sides. The hydroscopicity and tensile modulus of PCL‐Col/NAC scaffolds showed best performance of these properties among groups. Meanwhile, the drug release profiles of PCL‐Col/NAC scaffolds were investigated using the HPLC method and the results suggested a sustained drug release of NAC for PCL‐Col/NAC scaffolds. In addition, PCL‐Col/NAC scaffolds presented better properties than the control groups in cell migration and proliferation. The in vivo wound healing therapy effect was studied using an oval (2 × 1 cm) full‐thickness skin defect wound model for SD rats. After 21 days, gross view and histological analysis showed a favorable beneficial therapeutic effect as well as better epidermal maturation compared with the control groups. CD31 immunohistology results revealed relatively more new vessels in the PCL‐Col/NAC group than the control groups. This study developed novel PCL‐Col/NAC scaffolds with an excellent hydroscopicity, tensile modulus and the ability to promote epidermal maturation and angiogenesis, demonstrating its promising potential in wound healing treatment. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019. -
Abstract In vitro evaluations provide vital information on the ability of tissue engineered scaffolds to support cell life and promote natural physiological behaviors in culture. Such assessments are necessary to conduct before implementation of the scaffolds for tissue healingin vivo . The scaffold extracellular matrix must provide the biochemical and mechanical cues necessary to promote cellular attachment, migration and proliferation before differentiation and new tissue deposition can occur. In this study, anin vitro evaluation was conducted to assess the ability of scaffolds three‐dimensional (3D) printed with a previously developed alginate‐polyvinyl alcohol‐hydroxyapatite formulation to promote proliferation of encapsulated MC3T3 cells. A systematic investigation was conducted to increase cell proliferation, and it was determined that the concentration and duration of the calcium bath have a less effect on proliferation than the composition of the formulation itself. Collagen gel was incorporated into the formulation to provide cells with adhesion sites necessary to sufficiently attach to the matrix. Enhanced proliferation was achieved within scaffolds of increased collagen content and sufficient crosslinking. This highlighted the importance of the synergistic effect created as a result of sufficient ligand density coupled with appropriate scaffold mechanical rigidity to provide a suitable environment for proliferation. Thus, these 3D printed tri‐polymer scaffolds have the ability to support cell proliferation and have potential to promote cell differentiation and new bone tissue deposition. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3262–3272, 2017. -
Abstract Impaired wound healing is a common complication for diabetic patients and effective diabetic wound management remains a clinical challenge. Furthermore, a significant problem that contributes to patient morbidity is the suboptimal quality of healed skin, which often leads to reoccurring chronic skin wounds. Herein, a novel compound and biomaterial building block, panthenol citrate (PC), is developed. It has interesting fluorescence and absorbance properties, and it is shown that PC can be used in soluble form as a wash solution and as a hydrogel dressing to address impaired wound healing in diabetes. PC exhibits antioxidant, antibacterial, anti‐inflammatory, and pro‐angiogenic properties, and promotes keratinocyte and dermal fibroblast migration and proliferation. When applied in a splinted excisional wound diabetic rodent model, PC improves re‐epithelialization, granulation tissue formation, and neovascularization. It also reduces inflammation and oxidative stress in the wound environment. Most importantly, it improves the regenerated tissue quality with enhanced mechanical strength and electrical properties. Therefore, PC could potentially improve wound care management for diabetic patients and play a beneficial role in other tissue regeneration applications.