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Biodegradable Gelatin Microcarriers Facilitate Re-Epithelialization of Human Cutaneous Wounds - An In Vitro Study in Human Skin
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, e0128093- p.Article in journal (Refereed) Published
Abstract [en]

The possibility to use a suspended tridimensional matrix as scaffolding for re-epithelialization of in vitro cutaneous wounds was investigated with the aid of a human in vitro wound healing model based on viable full thickness skin. Macroporous gelatin microcarriers, CultiSpher-S, were applied to in vitro wounds and cultured for 21 days. Tissue sections showed incorporation of wound edge keratinocytes into the microcarriers and thicker neoepidermis in wounds treated with microcarriers. Thickness of the neoepidermis was measured digitally, using immunohistochemical staining of keratins as epithelial demarcation. Air-lifting of wounds enhanced stratification in control wounds as well as wounds with CultiSpher-S. Immunohistochemical staining revealed expression of keratin 5, keratin 10, and laminin 5 in the neoepidermal component. We conclude that the CultiSpher-S microcarriers can function as tissue guiding scaffold for re-epithelialization of cutaneous wounds.

Place, publisher, year, edition, pages
Public Library of Science , 2015. Vol. 10, no 6, e0128093- p.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-120232DOI: 10.1371/journal.pone.0128093ISI: 000355979500074PubMedID: 26061630OAI: oai:DiVA.org:liu-120232DiVA: diva2:842632
Available from: 2015-07-21 Created: 2015-07-20 Last updated: 2017-12-04
In thesis
1. Applications of human skin in vitro
Open this publication in new window or tab >>Applications of human skin in vitro
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic wounds are a substantial problem in today’s health care and place significant strains on the patient. Successful modelling of the wound healing process is pivotal for the advancement of wound treatment research. Wound healing is a dynamic and multifactorial process involving all constituents of the skin. The progression from haemostasis and inflammation to proliferation of epidermal  keratinocytes and dermal fibroblasts, and final scar maturation can be halted and result in a chronic wound that fails to re-epithelialise. The wound healing process constitutes an example of dynamic reciprocity in tissue where cellular changes take place on cues from the extracellular matrix and vice versa when tissue homeostasis is disturbed. The extracellular matrix provides a structural context for the resident cells and the epidermal keratinocytes, and a functioning interplay between the two tissue compartments is crucial for successful wound healing to take place. Work included in this thesis has applied viable human full thickness skin in vitro to investigate the re-epithelialisation process and barrier function of intact skin.The use of full thickness skin in vitro can take into account the contextual aspect of the process where the epidermal keratinocytes are activated and obtain a migratory phenotype, and are continuously dependent on the cues from the extracellular matrix and support of the dermis. When utilising skin for studies on re-epithelialisation, circular standardised full thickness wounds were created and cultured  for up to four weeks in tissue culture. In paper I, the organisation of a thick neoepidermis was investigated in the in vitro wound healing model when resident cells were provided with a porous suspended three dimensional gelatin scaffold. In paper II we investigated the use of a fluorescent staining conventionally used for proliferation studies to facilitate the tracing of transplanted epidermal cells in in vitro  wounds, in order to improve and expand the use of the model. In paper III the model was utilised to investigate the treatment approach of acidification of wounds to evaluate the suitability of such intervention in regards to keratinocyte function and re-epithelialisation. Studies on re-epithelialisation with the aid of the in vitro wound healing model provided insight in neoepidermal structure with porous gelatin scaffolding in the wound, a novel methodological approach to tracing cells and response to constrained wound healing environment. In paper IV, intact human skin was evaluated for modelling the cytotoxic response after exposure to a known irritant compound. To study barrier function, intact skin was exposed to irritants by restricting exposure topically, and full thickness skin in vitro was found suitable for modelling cytotoxicity responses. Employing human full thickness skin in vitro makes use of the actual target tissue of interest with epidermal and dermal cells, and full barrier function.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 99 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1493
National Category
Clinical Medicine Clinical Science
Identifiers
urn:nbn:se:liu:diva-123313 (URN)10.3384/diss.diva-123313 (DOI)978-91-7685-895-0 (ISBN)
Public defence
2016-01-29, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-12-10 Created: 2015-12-10 Last updated: 2015-12-18Bibliographically approved
2. Fibroblast Differentiation and Models of Human Skin
Open this publication in new window or tab >>Fibroblast Differentiation and Models of Human Skin
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis combines three publications and one manuscript, covering two principal topics: functional differentiation of human fibroblasts and laboratory models of human skin. The two topics favourably unite in the realm of tissue engineering. This thesis is therefore split into three main parts: 1. a discussion of phenotypic plasticity as it pertains to fibroblasts and the stem cell continuum; 2. a short review of engineered tissue, with particular focus on soluble factors and materials; and, 3. a motivated review of the biology, diversity and culture of skin, including skin construction.

The intended goal of our research endeavor was to achieve the  formulation of a bioactive therapy for skin regeneration. The main hypothesis was that fibroblast-to-keratinocyte differentiation would facilitate wound healing, and that the protocol for such a method could be adapted to clinical translation. The foundation for the hypothesis lay in the differentiation capabilities of primary dermal fibroblasts (Paper I). However, the goal has not yet been achieved. Instead, intermediate work on the construction of skin for the purpose of creating a model test-bed has resulted in two other publications. The use of excised human skin, a formidable reference sample for tissue engineered skin, has been used to investigate a gelatinbased material in re-epithelialization (Paper II). A first attempt at standardizing a constructed skin model also resulted in a publication: an evaluation of melanocyte influences on keratinocyte-mediated contraction (Paper III).

The introduction of melanocytes into a skin model raised questions about other appendages of the integumentary system. Our previous experience with preadipocyte isolation and identification, and our attempts at constructing three-dimensional adipose tissue, motivated further investigations into fibroblast-to-adipocyte differentiation. We investigated the possibility of activating thermogenesis in fibroblasts, a property otherwise reserved for cells of the adipogenic and myogenic lineages. Our attempts were successful, and are presently in manuscript form (Paper IV). Some further experiments and optimizations are necessary before establishing a reproducible protocol for thermogenic induction.

The knowledge obtained through these scientific inquiries have moved us closer to achieving our goals, but methodological advances are still necessary. In the meantime, we have new test-beds for investigating different interactions in skin, and that enables many new questions to be asked and answered.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 188 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1506
National Category
Cell Biology Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-125925 (URN)10.3384/diss.diva-125925 (DOI)978-91-7685-849-3 (ISBN)
Public defence
2016-04-08, Hasselquistsalen, ingång 76 pl 9, Campus US, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2016-03-09 Created: 2016-03-09 Last updated: 2016-04-12Bibliographically approved

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Lönnqvist, SusannaRakar, JonathanBriheim, KristinaKratz, Gunnar

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