Adapting the Scar-in-a-Jar to Skin Fibrosis and Screening Traditional and Contemporary Anti-Fibrotic Therapies

Skin fibrosis still constitutes an unmet clinical need. Although pharmacological strategies are at the forefront of scientific and technological research and innovation, their clinical translation is hindered by the poor predictive capacity of the currently available in vitro fibrosis models. Indeed, customarily utilised in vitro scarring models are conducted in a low extracellular matrix milieu, which constitutes an oxymoron for the in-hand pathophysiology. Herein, we coupled macromolecular crowding (enhances and accelerates extracellular matrix deposition) with transforming growth factor beta 1 (TGF beta 1; induces trans-differentiation of fibroblasts to myofibroblasts) in human dermal fibroblast cultures to develop a skin fibrosis in vitro model and to screen a range of anti-fibrotic families (corticosteroids, inhibitors of histone deacetylases, inhibitors of collagen crosslinking, inhibitors of TGF beta 1 and pleiotropic inhibitors of fibrotic activation). Data obtained demonstrated that macromolecular crowding combined with TGF beta 1 significantly enhanced collagen deposition and myofibroblast transformation. Among the anti-fibrotic compounds assessed, trichostatin A (inhibitors of histone deacetylases); serelaxin and pirfenidone (pleiotropic inhibitors of fibrotic activation); and soluble TGF beta receptor trap (inhibitor of TGF beta signalling) resulted in the highest decrease of collagen type I deposition (even higher than triamcinolone acetonide, the gold standard in clinical practice). This study further advocates the potential of macromolecular crowding in the development of in vitro pathophysiology models.Peer reviewe

Wound healing and scar wars

Wound healing and scarring are highly conserved physiological responses to wounding in most tissues in higher organisms, consisting of a sequence of well-characterised stages (coagulation, inflammation, proliferation and remodelling [[1], [2], [3]]), with the aim to repair interrupted tissue structures and to restore tissue function [4]. However, this sequence can come to a halt before completion resulting in undesired outcomes, ranging from the formation of a large local scar to organ-encompassing fibrosis. Whilst the former causes cosmetic annoyance, the latter might lead to grave functional impairment or to chronic non-healing wounds.The authors would like to acknowledge for financial support the: Science Foundation Ireland, Career Development Award (Grant Agreement Number: 15/CDA/3629); Science Foundation Ireland / European Regional Development Fund (Grant Agreement Number: 13/RC/2073); H2020, Marie Skłodowska-Curie Actions, Innovative Training Networks 2015 Tendon Therapy Train project (Grant Agreement Number: 676338). The authors would also like to thank Mr Maciek Doczyk for designing Figure 1.2019-06-1

Wound healing and scar wars

Wound healing and scarring are highly conserved physiological responses to wounding in most tissues in higher organisms, consisting of a sequence of well-characterised stages (coagulation, inflammation, proliferation and remodelling [[1], [2], [3]]), with the aim to repair interrupted tissue structures and to restore tissue function [4]. However, this sequence can come to a halt before completion resulting in undesired outcomes, ranging from the formation of a large local scar to organ-encompassing fibrosis. Whilst the former causes cosmetic annoyance, the latter might lead to grave functional impairment or to chronic non-healing wounds.The authors would like to acknowledge for financial support the: Science Foundation Ireland, Career Development Award (Grant Agreement Number: 15/CDA/3629); Science Foundation Ireland / European Regional Development Fund (Grant Agreement Number: 13/RC/2073); H2020, Marie Skłodowska-Curie Actions, Innovative Training Networks 2015 Tendon Therapy Train project (Grant Agreement Number: 676338). The authors would also like to thank Mr Maciek Doczyk for designing Figure 1.peer-reviewed2019-06-1

Translational Research Symposium—collaborative efforts as driving forces of healthcare innovation

The 5th Translational Research Symposium was organised at the annual meeting of the European Society for Biomaterials 2018, Maastricht, the Netherlands, with emphasis on the future of emerging and smart technologies for healthcare in Europe. Invited speakers from academia and industry highlighted the vision and expectations of healthcare in Europe beyond 2020 and the perspectives of innovation stakeholders, such as small and medium enterprises, large companies and Universities. The aim of the present article is to summarise and explain the main statements made during the symposium, with particular attention on the need to identify unmet clinical needs and their efficient translation into healthcare solutions through active collaborations between all the participants involved in the value chain.This work was supported by the: European Commission Horizon 2020, Marie Skłodowska-Curie Actions, Innovative Training Networks 2015, Tendon Therapy Train project, under the grant agreement number 676338; Science Foundation Ireland, Career Development Award, under the grant agreement number 15/CDA/3629; Science Foundation Ireland and the European Regional Development Fund, under grant agreement number 13/RC/2073.2020-12-0

Dual drug delivery collagen vehicles for modulation of skin fibrosis in vitro

Single molecule drug delivery systems have failed to yield functional therapeutic outcomes, triggering investigations into multi-molecular drug delivery vehicles. In the context of skin fibrosis, although multi-drug systems have been assessed, no system has assessed molecular combinations that directly and specifically reduce cell proliferation, collagen synthesis and transforming growth factor β1 (TGFβ1) expression. Herein, a core-shell collagen type I hydrogel system was developed for the dual delivery of a TGFβ trap, a soluble recombinant protein that inhibits TGFβ signalling, and Trichostatin A (TSA), a small molecule inhibitor of histone deacetylases. The antifibrotic potential of the dual delivery system was assessed in an in vitro skin fibrosis model induced by macromolecular crowding (MMC) and TGFβ1. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and high performance liquid chromatography analyses revealed that ∼50% of the TGFβ trap and ∼30% of the TSA were released from the core and shell compartments, respectively, of the hydrogel system after 10 d (longest time point assessed) in culture. As a direct consequence of this slow release, the core (TGFβ trap)/shell (TSA) hydrogel system induced significantly (p < 0.05) lower than the control group (MMC and TGFβ1) collagen type I deposition (assessed via SDS-PAGE and immunocytochemistry), α smooth muscle actin (αSMA) expression (assessed via immunocytochemistry) and cellular proliferation (assessed via DNA quantification) and viability (assessed via calcein AM and ethidium homodimer-I staining) after 10 d in culture. On the other hand, direct TSA-TGFβ supplementation induced the lowest (p < 0.05) collagen type I deposition, αSMA expression and cellular proliferation and viability after 10 d in culture. Our results illustrate the potential of core-shell collagen hydrogel systems for sustained delivery of antifibrotic molecules.publishedVersionPeer reviewe

Current and upcoming therapies to modulate skin scarring and fibrosis

Skin is the largest organ of the human body. Being the interface between the body and the outer environment, makes it susceptible to physical injury. To maintain life, nature has endowed skin with a fast healing response that invariably ends in the formation of scar at the wounded dermal area. In many cases, skin remodelling may be impaired, leading to local hypertrophic scars or keloids. One should also consider that the scarring process is part of the wound healing response, which always starts with inflammation. Thus, scarring can also be induced in the dermis, in the absence of an actual wound, during chronic inflammatory processes. Considering the significant portion of the population that is subject to abnormal scarring, this review critically discusses the state-of-the-art and upcoming therapies in skin scarring and fibrosis.This work has been supported from the: Health Research Board, Health Research Awards Programme (grant agreement number: HRA_POR/2011/84); Science Foundation Ireland, Career Development Award Programme (grant agreement number: 15/CDA/3629); Science Foundation Ireland and the European Regional Development Fund (grant agreement number: 13/RC/2073); EU H2020, ITN award, Tendon Therapy Train Project (grant agreement number: 676338). The authors would like to thank Mr M. Doczyk for designing the figures of the manuscript. D.I.Z. would like to dedicate the manuscript to I.N.Z. who left.peer-reviewe

Current and upcoming therapies to modulate skin scarring and fibrosis

Skin is the largest organ of the human body. Being the interface between the body and the outer environment, makes it susceptible to physical injury. To maintain life, nature has endowed skin with a fast healing response that invariably ends in the formation of scar at the wounded dermal area. In many cases, skin remodelling may be impaired, leading to local hypertrophic scars or keloids. One should also consider that the scarring process is part of the wound healing response, which always starts with inflammation. Thus, scarring can also be induced in the dermis, in the absence of an actual wound, during chronic inflammatory processes. Considering the significant portion of the population that is subject to abnormal scarring, this review critically discusses the state-of-the-art and upcoming therapies in skin scarring and fibrosis