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Guided Regeneration of the Human Skin: in vitro and in vivo studies
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Every day and in all parts of the world, humans experience different grades of wounding and tissue loss of the skin, thus initiating one of the most complex biological processes. Acute and chronic wounds, as well as the additional problem of skin scarring, involve not only great suffering for the patient but also extensive health care costs for the society. Although the wound-healing process is a wellstudied field much knowledge must be gained to unlock the door to regenerative pathways in humans.

Epidermis heals by complete regeneration, but dermal and full thickness injuries heal with fibrosis and scar formation. In Papers I and II, we studied whether dermal scarring could be turned into regeneration by using two different types of threedimensional dermal scaffolds. In Paper I, we studied a solid scaffold made of poly(urethane urea), initially in vitro then followed by in vivo studies. In Paper II, we intradermally injected a liquid three-dimensional scaffold consisting of porous gelatin spheres in human healthy volunteers. Both materials showed ingrowth of functional fibroblasts and blood vessels and appeared to stimulate regeneration while slowly degrading. This finding could be of significant clinical importance, for example in burn wound care or after cancer surgery.

In Papers III and IV, we wanted to study the effects of amniotic fluid and hyaluronic acid on adult wound healing, because early fetal wounds re-epithelialize rapidly and naturally heal dermis by regeneration without the need of a dermal scaffold. Amniotic fluid, naturally rich in hyaluronic acid, induced an accelerated reepithelialization of adult human wounds in vitro, and hyaluronic acid seemed to be important for this effect. Stimulation with exogenous hyaluronic acid in vivo induced accelerated re-epithelialization and an altered protein expression in healthy human volunteers. The inflammatory phase of wound healing, as measured by tissue viability imaging, was not affected by hyaluronic acid. Elucidating the effects of amniotic fluid and hyaluronic acid on the wound-healing process may allow improved treatment of wounds with impaired healing.

Studies on finding new dermal scaffolds and studies on the positive effect of amniotic fluid or hyaluronic acid on the wound-healing process are two different ways of gaining insight that may lead to regeneration and improved wound healing for the patient.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. , 95 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1450
National Category
Medical Bioscience Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-115598DOI: 10.3384/diss.diva-115598ISBN: 978-91-7519-114-0 (print)OAI: oai:DiVA.org:liu-115598DiVA: diva2:795885
Public defence
2015-04-20, Berzeliussalen, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-03-17 Created: 2015-03-17 Last updated: 2015-03-17Bibliographically approved
List of papers
1. Characterisation of a new degradable polymer scaffold for regeneration of the dermis: In vitro and in vivo human studies
Open this publication in new window or tab >>Characterisation of a new degradable polymer scaffold for regeneration of the dermis: In vitro and in vivo human studies
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2008 (English)In: Organogenesis, ISSN 1547-6278, Vol. 4, no 3, 195-200 p.Article in journal (Refereed) Published
Abstract [en]

Full thickness skin wounds in humans heal with scars, but without regeneration of the dermis. A degradable poly(urethane urea) scaffold (PUUR), Artelon® is already used to reinforce soft tissues in orthopaedics, and for treatment of osteoarthritis of the hand, wrist and foot. In this paper we have done in vitro experiments followed by in vivo studies to find out whether the PUUR is biocompatible and usable as a template for dermal regeneration. Human dermal fibroblasts were cultured on discs of PUUR, with different macrostructures (fibrous and porous). They adhered to and migrated into the scaffolds, and produced collagen. The porous scaffold was judged more suitable for clinical applications and 4 mm Ø, 2 mm-thick discs of porous scaffold (12% w/w or 9% w/w polymer solution) were inserted intradermally in four healthy human volunteers. The implants were well tolerated and increasing ingrowth of fibroblasts was seen over time in all subjects. The fibroblasts stained immunohistochemically for procollagen and von Willebrand factor, indicating neocollagenesis and angiogenesis within the scaffolds. The PUUR scaffold may be a suitable material to use as a template for dermal regeneration. ©2008 Landes Bioscience.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-44440 (URN)76642 (Local ID)76642 (Archive number)76642 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2015-03-17Bibliographically approved
2. Use of macroporous gelatine spheres as a biodegradable scaffold for guided tissue regeneration of healthy dermis in humans: An in vivo study
Open this publication in new window or tab >>Use of macroporous gelatine spheres as a biodegradable scaffold for guided tissue regeneration of healthy dermis in humans: An in vivo study
2010 (English)In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, Vol. 63, no 5, 848-857 p.Article in journal (Refereed) Published
Abstract [en]

If a biodegradable scaffold is applied, the dermis can be regenerated by guided tissue regeneration. Scaffolds can stimulate in-growth of cells from the surroundings that migrate into them and start to produce autologous extracellular matrix as the scaffold is degraded. Several materials are available, but most of them are in the form of sheets and need to be laid on an open wound surface. A number of injectable fillers have been developed to correct soft-tissue defects. However, none of these has been used for guided tissue regeneration. We present a new technique that could possibly be used to correct dermal defects by using macroporous gelatine spheres as a biodegradable scaffold for guided tissue regeneration. In eight healthy volunteers, intradermal injections of macroporous gelatine spheres were compared with injections of saline and hyaluronic acid (Restylane (R)). Full-thickness skin biopsy specimens of the implants and surrounding tissue were removed 2, 8, 12 and 26 weeks after injection, and the (immuno) histological results were analysed. The Restylane (R) merely occupied space. It shattered the dermal tissue and compressed collagen fibres and cells at the interface between the implant and the dermis. No regeneration of tissue was found with this material at any time. The macroporous gelatine spheres were populated with fibroblasts already after 2 weeks. After 8 weeks the spheres were completely populated by fibroblasts producing dermal tissue. After 12 and 26 weeks, the gelatine spheres had been more or less completely resorbed and replaced by vascularised neodermis. There were no signs of capsular formation, rejection or adverse events in any subject. Further in vivo studies in humans are needed to evaluate the effect of the macroporous spheres fully as a matrix for guided tissue regeneration with and without cellular pre-seeding. However, the results of this study indicate the possibility of using macroporous gelatine spheres as an injectable, three-dimensional, degradable matrix for guided tissue regeneration.

Place, publisher, year, edition, pages
Elsevier Science B.V.amsterdam, 2010
Keyword
Filler, Soft-tissue defect, Guided tissue regeneration, Tissue engineering, Plastic surgery, Human
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54859 (URN)10.1016/j.bjps.2009.01.068 (DOI)000276199700021 ()
Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2015-03-17Bibliographically approved
3. Hyaluronic acid, an important factor in the wound healing properties of amniotic fluid: In vitro studies of re-epithelialisation in human skin wounds
Open this publication in new window or tab >>Hyaluronic acid, an important factor in the wound healing properties of amniotic fluid: In vitro studies of re-epithelialisation in human skin wounds
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2013 (English)In: Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, ISSN 2000-656X, E-ISSN 2000-6764, Vol. 47, no 2, 89-92 p.Article in journal (Refereed) Published
Abstract [en]

Foetal wounds are unique in their ability to heal rapidly without forming scars. The amniotic fluid, rich in nutrients, growth factors, and hyaluronic acid, surrounds the foetus and is essential to foetal wound healing. The wound healing properties of foetal wounds may be the result of high concentrations of hyaluronic acid. This study aimed to verify that amniotic fluid induces re-epithelialisation in human skin wounds in vitro and to study whether this ability is dependent on hyaluronic acid. Standard deep dermal wounds were produced in vitro in human skin. The skin samples, with a central wound, were incubated in different culture media. Varying concentrations of amniotic fluid and amniotic fluid with added hyaluronidase were tested, and re-epithelialisation was assessed at 3, 7, and 12 days using light microscopy, after staining with haematoxylin and eosin. Amniotic fluid 50% resulted in a significantly higher (p andlt; 0.05) grade of re-epithelialisation than Dulbeccos modified Eagles medium and 10% amniotic fluid at all time points. When 50% amniotic fluid was compared with 10% foetal calf serum, no significant difference was found in grades of re-epithelialisation on days 3 and 12 and significantly higher grades of re-epithelialisation on day 7 (p andlt; 0.05). Degradation of hyaluronic acid in the medium that contained 50% amniotic fluid gave significantly impaired re-epithelialisation (p andlt; 0.05) on culture days 3 and 7. In conclusion, amniotic fluid promotes accelerated re-epithelialisation and hyaluronic acid is an important ingredient.

Place, publisher, year, edition, pages
Informa Healthcare, 2013
Keyword
Amniotic fluid, fibroblasts, human, hyaluronic acid, hyaluronidase, in vitro, keratinocytes, wound healing
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91006 (URN)10.3109/2000656X.2012.733169 (DOI)000316362300002 ()
Note

Funding Agencies|Swedish Fund for Research without Animal Experiments||

Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
4. Exogenous hyaluronic acid induces accelerated re-epithelialization and altered protein expression in adult human skin wounds in vivo
Open this publication in new window or tab >>Exogenous hyaluronic acid induces accelerated re-epithelialization and altered protein expression in adult human skin wounds in vivo
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background

Hyaluronic acid, a large glycosaminoglycan involved in proliferation, migration, and tissue repair, is suggested to play an important role in ideal scarless fetal wound healing. This study aimed to investigate the effect of exogenous hyaluronic acid intradermal during deep dermal wound healing. Study parameters were erythema, re-epithelialization, and protein expression examined by using a previously described, minimally invasive in vivo human wound model in combination with tissue viability imaging, histology, and proteomics.

Methods

Standardized deep dermal wounds were created in the ventral forearm in ten healthy volunteers using blood collection lancets. The wound sites were injected with hyaluronic acid or saline solution, prior to wounding, or were left untreated. To quantify changes in red blood cell concentration as a measurement of inflammation, the study sites were photographed daily for two weeks using a tissue viability imaging system. At 24 hours and after 14 days, biopsy specimens were taken for histology and proteomics analysis.

Results

The inflammatory response was not affected by the injection of hyaluronic acid, as measured by tissue viability imaging. Hyaluronic acid significantly induced (p < 0.05) accelerated reepithelialization at 24 hours, and wounds treated with hyaluronic acid showed an altered protein expression.

Conclusion

The results from the present study are in concordance with  previous in vitro findings and suggest that exogenous hyaluronic acid has a  positive effect on the healing process of cutaneous wounds. We conclude that hyaluronic acid injected intradermally induces accelerated re-epithelialization and alters protein expression in vivo in human deep dermal skin wounds.

Keyword
Hyaluronic acid, hyaluronan, hyaluronate, Amniotic fluid, Wound healing, Human wound model, In vivo, Tissue viability imaging, Protein expression, proteomics
National Category
Medical Biotechnology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-115593 (URN)
Available from: 2015-03-17 Created: 2015-03-17 Last updated: 2015-03-17Bibliographically approved

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