Lung Surfactant Accelerates Skin Wound Healing: A Translational Study with a Randomized Clinical Phase I Study.

Lung surfactants are used for reducing alveolar surface tension in preterm infants to ease breathing. Phospholipid films with surfactant proteins regulate the activity of alveolar macrophages and reduce inflammation. Aberrant skin wound healing is characterized by persistent inflammation. The aim of the study was to investigate if lung surfactant can promote wound healing. Preclinical wound models, e.g. cell scratch assays and full-thickness excisional wounds in mice, and a randomized, phase I clinical trial in healthy human volunteers using a suction blister model were used to study the effect of the commercially available bovine lung surfactant on skin wound repair. Lung surfactant increased migration of keratinocytes in a concentration-dependent manner with no effect on fibroblasts. Significantly reduced expression levels were found for pro-inflammatory and pro-fibrotic genes in murine wounds. Because of these beneficial effects in preclinical experiments, a clinical phase I study was initiated to monitor safety and tolerability of surfactant when applied topically onto human wounds and normal skin. No adverse effects were observed. Subepidermal wounds healed significantly faster with surfactant compared to control. Our study provides lung surfactant as a strong candidate for innovative treatment of chronic skin wounds and as additive for treatment of burn wounds to reduce inflammation and prevent excessive scarring.

Tissue Concentrations of Zinc, Iron, Copper, and Magnesium During the Phases of Full Thickness Wound Healing in a Rodent Model.

Wound healing is a complex orchestration of processes involving cell proliferation, migration, differentiation, anabolism, and catabolism in order to restore skin continuity. Within these processes, elements such as metallic ions are involved due to their implications in cell behavior and enzymatic activity regulation. This study analyzed the kinetics of zinc, iron, copper and magnesium concentrations in a full thickness open wound rat model over 14 days. We made wounds with a diameter of 6 mm on the back of Lewis rats and let them heal naturally prior to analysis by histology and inductively coupled plasma mass spectrometry analysis. Histological and immunofluorescence analysis confirmed an inflammation phase until 7 days, epithelial proliferation phase from 16 h to 10 days, and remodeling phase from 7 days onward. These defined phases were correlated with the measured metal element kinetics. Zinc concentrations showed an inverted parabolic progression between 30.4 and a maximum of 39.9 µg/g dry weight. Magnesium values had a similar pattern between 283 and 499 µg/g dry weight. Copper concentrations, on the other hand, followed an inverted sigmoid trend with a decrease from 9.8 to 1.5 µg/g dry weight. Iron had a slight decrease in concentration for 24 h followed by an increase to a maximum of 466 µg/g dry weight. In conclusion, zinc, iron, and copper, even though differing in their total mass within the wound, exhibited concentration curve transitions at day 3. Interestingly, this time point correlates with the maximum proliferating keratinocyte rate during the proliferation phase.

What is the effect of nicotinic acetylcholine receptor stimulation on osteoarthritis in a rodent animal model?

OBJECTIVES: Despite the rising number of patients with osteoarthritis, no sufficient chondroprotective and prophylactic therapy for osteoarthritis has been established yet. The purpose of this study was to verify whether stimulation of the nicotinic acetylcholine receptor via nicotine has a beneficial effect on cartilage degeneration in the development of osteoarthritis and is capable of reducing the expression of proinflammatory cytokines and cartilage degrading enzymes in synovial membranes after osteoarthritis induction. METHODS: Experimental osteoarthritis was induced in Lewis rats using a standardized osteoarthritis model with monoiodoacetate. A total of 16 Lewis rats were randomized into four groups: control, sham + nicotine application, osteoarthritis, and osteoarthritis + nicotine application. Nicotine (0.625 mg/kg twice daily) was administered intraperitoneally for 42 days. We analyzed histological sections, radiological images and the expression of the proinflammatory cytokines, such as interleukin-1ß, tumor necrosis factor-α and interleukin-6, and of matrix metalloproteases 3, 9 and 13 and tissue inhibitors of metalloprotease-1 in synovial membranes via quantitative polymerase chain reaction. RESULTS: Histological and x-ray examination revealed cartilage degeneration in the osteoarthritis group compared to control or sham + nicotine groups (histological control vs osteoarthritis: p = 0.002 and x-ray control vs osteoarthritis: p = 0.004). Nicotine treatment reduced the cartilage degeneration without significant differences. Osteoarthritis induction led to a higher expression of proinflammatory cytokines and matrix metalloproteases as compared to control groups. This effect was attenuated after nicotine administration. The differences of proinflammatory cytokines and matrix metalloproteases did not reach statistical significance. CONCLUSION: With the present small-scale study, we could not prove a positive effect of nicotinic acetylcholine receptor stimulation on osteoarthritis due to a conservative statistical analysis and the consecutive lack of significant differences. Nevertheless, we found promising tendencies of relevant parameters that might prompt further experiments designed to evaluate the potency of stimulation of this receptor system as an additional treatment approach for osteoarthritis.

Skin tissue generation by laser cell printing.

For the aim of ex vivo engineering of functional tissue substitutes, Laser-assisted BioPrinting (LaBP) is under investigation for the arrangement of living cells in predefined patterns. So far three-dimensional (3D) arrangements of single or two-dimensional (2D) patterning of different cell types have been presented. It has been shown that cells are not harmed by the printing procedure. We now demonstrate for the first time the 3D arrangement of vital cells by LaBP as multicellular grafts analogous to native archetype and the formation of tissue by these cells. For this purpose, fibroblasts and keratinocytes embedded in collagen were printed in 3D as a simple example for skin tissue. To study cell functions and tissue formation process in 3D, different characteristics, such as cell localisation and proliferation were investigated. We further analysed the formation of adhering and gap junctions, which are fundamental for tissue morphogenesis and cohesion. In this study, it was demonstrated that LaBP is an outstanding tool for the generation of multicellular 3D constructs mimicking tissue functions. These findings are promising for the realisation of 3D in vitro models and tissue substitutes for many applications in tissue engineering.