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Alternative to skin grafting


There is a growing burden in wound management. Stem cells will be instrumental in the development of skin substitutes. Novel hydrogel promotes skin regeneration in in vivo experiments.

Skin substitutes hold much potential for wound healing and will offer an alternative to skin grafting, according to a scientist at Sunnybrook Research Institute, Ross Tilley Burn Centre, Toronto, Ontario, Canada.

"We can make skin substitutes using cells from patients. There are adult stem cells in almost every organ of the body and these cells are potential sources of cells for skin regeneration," explains Saeid Amini-Nik M.Sc., M.D., Ph.D., a stem cell biologist who spoke during the annual meeting of the Canadian Association of Wound Care (November 2016, Niagra Falls, Ontario, Canada).

Growing burden

With the aging of the population and the rising incidence in diabetes, there is a growing burden in managing wounds with deficient healing, according to Dr. Amini-Nik. The cost of the treatment of chronic wounds in the United States has been put at more than $25 billion annually, he notes1.

There are an estimated two million burns annually in the United States, 70K of which require hospitalization. Dr. Amini-Nik notes that 10K patients in the United States die annually of infections or other complications associated with serious burns.

Even when patients survive burn injuries, there are some ongoing issues that they have to cope with such as pain and scarring, Dr. Amini-Nik notes.

"If patients survive, there is a high morbidity and a strong psychosocial impact," he says.

When there is an injury to the skin, normal healing with a scar does not always occur2,3, explains Dr. Amini-Nik, an assistant professor in the department of surgery at the University of Toronto in Toronto.

Skin healing can be deficient because of the presence of systemic conditions like diabetes, and it can be deficient in the elderly population4,5, Dr. Amini-Nik notes.

"Sometimes there can be excessive healing, and that is associated with scars like keloids," Dr. Amini-Nik says.

Human skin is a reservoir for stem cells. Here we see human skin stained with different markers of stem cells and differentiated cells. Photo: Saeid Amini-Nik M.Sc., M.D., Ph.D.

Restoring skin

Skin grafting is a means of restoring the skin so it can again perform multiple functions such as acting as a barrier and keeping the body hydrated, Dr. Amini-Nik says. However, bleeding, infection, and nerve damage can occur. Repeat skin grafts may be required, thus making skin grafting an inefficient process, Dr. Amini-Nik explains.

Skin substitutes have reduced morbidity and mortality associated with skin wounds, but there are some disadvantages with using cultured skin substitutes, according to Dr. Amini-Nik. Those include a wait time of three to 12 weeks after taking a biopsy before applying a cultured skin substitute, and the potentially significant cost of the application of a cultured skin substitute to a wound.

"The cost of a cultured skin substitute is about $15 per cm2," Dr. Amini-Nik says.

In addition, inadequate skin regeneration may result when wounds are very inflammatory, Dr. Amini-Nik explains.

Most skin substitutes that are used in wound healing are acellular and fail to use growth factors to aid in wound healing. Basic elements of an effective skin substitute would include scaffold materials, growth factor and cells, Dr. Amini-Nik6 says.

NEXT: Hydrogel skin substitute


Hydrogel skin substitute

Dr. Amini-Nik and colleagues have developed a cellularized bilayer pullulan-gelatin hydrogel to help regenerate the skin. They have performed in vivo experiments to demonstrate that cellularized pullulan-gelatin first generation hydrogel promotes skin regeneration and wound healing in wounds such as burns and chronic wounds7.

"We not only need proper material in the scaffold of a skin substitute which can provide a niche for stem cells to grow and differentiate, but also we need a technology to bring the stem cells together in a special formation which facilitates their growth and differentiation," Dr. Amini-Nik says.

The skin is a rich reservoir for stem cells from different lineages, with stem cells going through differentiation, regarded as a possible mechanism for the impact on wound healing, Dr. Amini-Nik explains.

Mesenchymal stem cells (MSCs) have been studied for their effect on wound healing. There are various sources of MSCs such as the bone marrow, adipose tissue, and the umbilical cord. Investigators have turned to the umbilical cord as a possible source of MSCs that would be preferable over bone marrow and adipose tissue because the umbilical cord stem cells offer a high yield and a lower level of immunogenicity.  

The value of human Wharton's jelly-derived MSCs had not been extensively studied in human normal skin. An investigation using an in vivo mouse model demonstrated that human Wharton's jelly-derived MSCs and their secretome offered improved wound healing8.

Delivery technology

"Once the right stem cells and the right scaffold is available, we need a technology that can assemble stem cells in spatial composition similar to the skin," Dr. Amini-Nik explains.

Biomedical engineering colleagues at the University of Toronto have developed a microfluidic device which allows controllable incorporation of material and cells within a flowing biopolymer sheet. Three-dimensional soft material assemblies are feasible with the technology9.

Using this technology and in collaboration with the biomedical engineering team, Dr. Amini-Nik and colleagues aimed to design a "skin printer" which allows for the formation of a skin substitute and can accommodate multiple stem cell populations in well-defined regions within the same skin substitute.

Dr. Amini-Nik is working with colleagues to determine the optimal combination of stem cells and scaffolding to produce layers of skin with the prototype design.

Disclosure: Dr. Amini-Nik reports no relevant disclosures.


1Brem H, Stojadinovic O, Diegelmann RF, et al. Molecular markers in     Patients with Chronic Wounds to Guide Surgical Debridement. Mol Med. 2007;13(1-2):30-9.

2Amini-Nik S, Cambridge, E, Yu W, et al. beta-Catenin-regulated myeloid cell adhesion and migration determine wound healing. J Clin Invest. 2014;    124(6):2599-610.

3 Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci.         2013;70(12):2059-81.

4Jeschke  MG, Patsouris D, Stanojcic M, et al. Pathophysiologic Response to         Burns in the Elderly. EBioMedicine. 2015; 2(10):1536-48.

5Jeschke MG, Pinto R, Costford SR, Amini-Nik S. Threshold age and burn size associated with poor          outcomes in the elderly after burn injury. Burns.         2016;42(2):276-81.     

6Nicholas MN, Jeschke MG, Amini-Nik S. Methodologies in creating skin   substitutes. Cell Mol Life Sci. 2016;73(18): 3453-72.

7Nicholas MN, Jeschke MG, Amini-Nik S. Cellularized Bilayer Pullulan-    Gelatin Hydrogel for Skin Regeneration. Tissue Eng Part A. 2016;22(9- 10):754-64.

8Arno AI, Amini-Nik S, Blit PH, et al. Human Wharton's jelly mesenchymal        stem cells promote skin wound healing through paracrine signaling. Stem    Cell Res Ther. 2014;5(1):28.

9Leng L, McAlister A, Zhang B, Radisic M, Gunther A. Mosaic hydrogels: one-step formation of multi-scale soft          materials. Adv Mater. 2012;24(27):    3650-8.



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