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Abstract
Adult dermal wounds, in contrast to fetal wounds, heal with the formation of scar tissue. A crucial factor in determining the degree of scarring is the ratio of types I and III collagen, which regulates the diameter of the combined fibers. We developed a reaction-diffusion model which focuses on the control of collagen synthesis by different isoforms of the polypeptide transforming growth factor-β (TGFβ). We used the model to investigate the current controversy as to whether the fibroblasts migrate into the wound from the surrounding unwounded dermis or from the underlying subcutaneous tissue. Numerical simulations of a spatially independent, temporal model led to a value of the collagen ratio consistent with that of healthy tissue for the fetus, but corresponding to scarring in the adult. We investigated the effect of topical application of TGFβ and show that addition of isoform 3 reduces scar tissue formation, in agreement with the experiment. However, numerical solutions of the reaction-diffusion system do not exhibit this sensitivity to growth factor application. Mathematically, this corresponds to the observation that behind healing wavefront solutions, a particular healed state is always selected independent of transients, even though there is a continuum of possible positive steady states. We explain this phenomenon using a caricature system of equations, which reflects the key qualitative features of the full model but has a much simpler mathematical form. Biologically, our results suggest that the migration into a wound of fibroblasts and TGFβ from the surrounding dermis alone cannot account for the essential features of the healing process, and that fibroblasts entering from the underlying subcutaneous tissue are crucial to the healing process.
Nanoscale topography substrates have potential in guiding cell polarization and migration. Wound healing can be accelerated by nanotopographical substrates which provided appropriate direction to host cells around wound site. We fabricated biodegradable poly (lactic-co-glycolic acid) (PLGA) nanopatterned patch (nP-patch) using capillary force lithography method. Simple surface modification was applied using 3,4-dihydroxy-l-phenylalanine (LD), which has been reported as effective adhesion molecules with similar structure as mussel protein, to immobilize fibroblast growth factor-2 (FGF2) on PLGA patches. In present study, we hypothesized that nP-patch could be enhanced the cell migration in vitro by a guide of nanotopography and that nP-patch with soluble growth factor could accelerate skin wound healing in vivo. To investigate its nanotopographical effect on cell behavior, human dermal fibroblast (HDF) cells were cultured on nP-patch and flat PLGA patch (F-patch). The rate of surface coverage was measured on nP-patch with vertical or parallel orientation. The surface coverage rate was significantly enhanced by nP-patch with vertical orientation compared to the parallel orientation or the F-patch. We made a full thickness (Ø 18 mm) wound on the back of athymic mice and implanted PLGA patches with or without FGF2. FGF2-loaded nP-patch showed much faster wound closure in 21 days compared to others. Histological analysis showed that regenerated tissue had a similar structure as native skin. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2015.
Linear di¬usion is an established model for spatial spread in biological systems, including movement of cell populations. However, for interacting, closely packed cell populations, simple di¬usion is inappropriate, because di¬erent cell populations will not move through one another: rather, a cell will stop moving when it encounters another cell. In this paper, I introduce a nonlinear di¬usion term that re®ects this phenomenon, known as contact inhibition of migration. I study this term in the con- text of two competing cell populations, one of which has a proliferative advantage over the other; this is motivated by the very early stages of solid tumour growth. I focus in particular on travelling-wave solutions, corresponding to moving interfaces between the two cell populations. Numerical simulations indicate that there are wave- front solutions for wave speeds above a critical minimum value, and I present linear analysis that explains the selection of wave speeds by initial conditions. I obtain an approximation to the shape of these waves for high speeds, and show that the min- imum speed arises via quite new behaviour in the travelling-wave equations, with the proportion of cells of each type approaching a step function as the wave speed decreases towards the minimum. Exploiting this structure, I use singular perturba- tion theory to investigate the wave shape for speeds close to the minimum.
We report on the effect of synthetic extracellular matrix (ECM) scaffold in the form of uniformly-spaced nanogrooved surfaces in dermal wound healing. The rate of wound coverage was measured on various nanotopographical densities with vertical or parallel orientation using nanogrooves of 550 nm width with three different gaps of 550, 1100, and 2750 nm (spacing ratio: 1:1, 1:2 and 1:5). Guided by the nanotopographical cues in the absence of growth factors in wound healing process, the cultured NIH-3T3 cells demonstrated distinctly different migration speed, cell division, and ECM production as dictated by the topographical density and orientation, whereas the proliferation rate turned out to be nearly the same. Based on our experimental results, the nanopattern of 1:2 spacing ratio yielded the best wound healing performance in terms of migration speed, which seems similar to the natural organization of collagen fibers.
beta-catenin and transforming growth factor beta signaling are activated in fibroblasts during wound healing. Both signaling pathways positively regulate fibroblast proliferation during this reparative process, and the effect of transforming growth factor beta is partially mediated by beta-catenin. Other cellular processes, such as cell motility and the induction of extracellular matrix contraction, also play important roles during wound repair. We examined the function of beta-catenin and its interaction with transforming growth factor beta in cell motility and the induction of collagen lattice contraction.
Floating three dimensional collagen lattices seeded with cells expressing conditional null and stabilized beta-catenin alleles, showed a modest negative relationship between beta-catenin level and the degree of lattice contraction. Transforming growth factor beta had a more dramatic effect, positively regulating lattice contraction. In contrast to the situation in the regulation of cell proliferation, this effect of transforming growth factor beta was not mediated by beta-catenin. Treating wild-type cells or primary human fibroblasts with dickkopf-1, which inhibits beta-catenin, or lithium, which stimulates beta-catenin produced similar results. Scratch wound assays and Boyden chamber motility studies using these same cells found that beta-catenin positively regulated cell motility, while transforming growth factor beta had little effect.
This data demonstrates the complexity of the interaction of various signaling pathways in the regulation of cell behavior during wound repair. Cell motility and the induction of collagen lattice contraction are not always coupled, and are likely regulated by different intracellular mechanisms. There is unlikely to be a single signaling pathway that acts as master regulator of fibroblast behavior in wound repair. beta-catenin plays dominant role regulating cell motility, while transforming growth factor beta plays a dominant role regulating the induction of collagen lattice contraction.
The aim of this study was to investigate the collagen matrix in recurrent inguinal hernias. Total ribonucleic acid (RNA) was extracted from skin fibroblasts of three groups (control group I = healthy skin; control group II = plain skin scar; recurrent inguinal hernia group = skin of recurrent inguinal hernias; each n = 5). Reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis were used to investigate the expression of procollagen type I/- III, MMP-1, and MMP-13 mRNAs. Both ratios of procollagen types I to III mRNAs and collagen types I to III were apparently decreased in the recurrent hernia group compared to those of both control groups (p < 0.01). Significant differences were caused by the increase of both procollagen type III mRNA and collagen type III protein synthesis. A concomitant increase of MMP-1 and MMP-13 mRNAs and proteins was also observed in the recurrent hernia group and showed significant differences compared to those of both control groups I and II, respectively (p < 0.01). In conclusion, the decreased ratio of collagen types I to III seems not only to be the result of a relative increase in the levels of type III procollagen mRNA but also may be the result of an increase of MMP-1 and MMP-13. The data of the present study strongly suggest recurrent inguinal hernias to be a disease of the collagen matrix and result in a clearer understanding of the underlying pathophysiology and may support specific therapeutic strategies in hernia surgery (e.g., surgical meshes).
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