by Anne Crawford
Monash University scientists and surgeons in the Alfred Hospital’s burns unit have edged closer to their goal of growing full thickness human skin to replace the need for skin grafts with the publication of two recent research papers.
The first paper reports on the findings of a three-year clinical study into an application of the procedure called cultured epithelial autograft (CEA). Regarded as the birth of skin tissue engineering, CEA takes skin cells from the patient needing the graft and grows the upper layer of skin (epidermis) in sheets in a laboratory.
A modified version of CEA was trialled at the burns unit in response to the need for improvement in wound closure in burns patients.
“We wanted to improve the system by introducing a modification so that the epithelial cells are actually grown on a fibrin gel, which makes it easier for the transfer of the skin sheets from a dish to a wound for grafting,” said Senior Scientist Dr Shiva Akbarzadeh.
It is important to close a wound as soon as possible. Under conventional CEA, the epidermal sheets need be matured prior to clinical application, taking up to four weeks. Introducing a fibrin gel carrier allows this production period to be shortened as well allowing easier application.
A phase 1 clinical trial of 10 patients who had more than 35% burns to their body was conducted to validate The Alfred’s process.
“The way the CEA/fibrin is applied plays a big role in the graft ‘take’ rate, and the best take rate was achieved when it was applied in combination with a widely meshed split skin graft,” Dr Akbarzadeh said. “This is an adjunct treatment that could be offered to the Alfred patients now,” she said.
The paper concluded that it was important to address the problem of contamination of the wound bed and that improved understanding of the biological processes involved was needed to inform a more targeted approach to skin tissue engineering.
The findings were published in the Journal of Plastic, Reconstructive & Aesthetic Surgery. First author was surgeon Dr Cheng Lo with Associate Professor Heather Cleland the senior author.
The second paper furthered work on ways to improve CEA, most notably by exploring a way to avoid using animal-derived (xeno) material in the manufacturing of skin tissue. “Right now there is actually no xeno-free cultured skin on the market in the world,” Dr Akbarzadeh said.
Dr Akbarzadeh said that although using animal-derived material was a safe method to date there was a potential risk of transmitting an animal-derived virus through the product.
The researchers outlined a step-by-step xeno-free method of cultivating and growing epithelial sheets using human derived serum and supporting feeder cells. This could be adapted to grow fully autologous epidermal sheets for burns and other type of wounds treatment. They recommended that the method be tested further for possible clinical application.
“Currently, we are developing a cultured full thickness skin graft, one step at a time and aiming to basically get to the point where we don’t actually have to use skin grafts and can bioengineer the patient’s skin in culture and graft the full thickness cultured skin rather than taking donor skin for treating deep burns,” Dr Akbarzadeh said.
The Victorian Adult Burns Service, the major burns care centre for adults in the state with serious burns injuries, is dedicated to constantly improving care for burns patients. Director Associate Professor Cleland, who also heads the Alfred Skin Bioengineering Laboratory, said translational research in the skin bioengineering laboratory was part of that drive.
“This research is providing insights into the mechanisms that determine successful skin grafting to produce wound healing and minimise scarring. We are focussed on harnessing those mechanisms to produce a reliable, true biosynthetic skin equivalent useful for the treatment of all kinds of skin injury and diseases,” she said.
Lo CH, Akbarzadeh S, McLean C, Ives A, Paul E, Brown WA, Cleland H. Wound healing after cultured epithelial autografting in patients with massive burn injury: A cohort study. J Plast Reconstr Aesthet Surg. 2018 Nov 13. pii: S1748-6815(18)30388-7. doi: 10.1016/j.bjps.2018.11.003. [Epub ahead of print]
Cheshire P, Zhafira AS, Banakh I, Rahman MM, Carmichael I, Herson M, Cleland H, Akbarzadeh S. Xeno-free expansion of adult keratinocytes for clinical application: the use of human-derived feeder cells and serum. Cell Tissue Res. 2019 Jan 21. doi: 10.1007/s00441-018-02986-5. [Epub ahead of print]
Monash University scientists and surgeons in the Alfred Hospital’s burns unit have edged closer to their goal of growing full thickness human skin to replace the need for skin grafts with the publication of two recent research papers.The first paper reports on the findings of a three-year clinical study into an application of the procedure called cultured epithelial autograft (CEA). Regarded as the birth of skin tissue engineering, CEA takes skin cells from the patient needing the graft and grows the upper layer of skin (epidermis) in sheets in a laboratory.
A modified version of CEA was trialled at the burns unit in response to the need for improvement in wound closure in burns patients.
“We wanted to improve the system by introducing a modification so that the epithelial cells are actually grown on a fibrin gel, which makes it easier for the transfer of the skin sheets from a dish to a wound for grafting,” said Senior Scientist Dr Shiva Akbarzadeh.
It is important to close a wound as soon as possible. Under conventional CEA, the epidermal sheets need be matured prior to clinical application, taking up to four weeks. Introducing a fibrin gel carrier allows this production period to be shortened as well allowing easier application.
A phase 1 clinical trial of 10 patients who had more than 35% burns to their body was conducted to validate The Alfred’s process.
“The way the CEA/fibrin is applied plays a big role in the graft ‘take’ rate, and the best take rate was achieved when it was applied in combination with a widely meshed split skin graft,” Dr Akbarzadeh said. “This is an adjunct treatment that could be offered to the Alfred patients now,” she said.
The paper concluded that it was important to address the problem of contamination of the wound bed and that improved understanding of the biological processes involved was needed to inform a more targeted approach to skin tissue engineering.
The findings were published in the Journal of Plastic, Reconstructive & Aesthetic Surgery. First author was surgeon Dr Cheng Lo with Associate Professor Heather Cleland the senior author.
The second paper furthered work on ways to improve CEA, most notably by exploring a way to avoid using animal-derived (xeno) material in the manufacturing of skin tissue. “Right now there is actually no xeno-free cultured skin on the market in the world,” Dr Akbarzadeh said.
Dr Akbarzadeh said that although using animal-derived material was a safe method to date there was a potential risk of transmitting an animal-derived virus through the product.
The researchers outlined a step-by-step xeno-free method of cultivating and growing epithelial sheets using human derived serum and supporting feeder cells. This could be adapted to grow fully autologous epidermal sheets for burns and other type of wounds treatment. They recommended that the method be tested further for possible clinical application.
“Currently, we are developing a cultured full thickness skin graft, one step at a time and aiming to basically get to the point where we don’t actually have to use skin grafts and can bioengineer the patient’s skin in culture and graft the full thickness cultured skin rather than taking donor skin for treating deep burns,” Dr Akbarzadeh said.
The Victorian Adult Burns Service, the major burns care centre for adults in the state with serious burns injuries, is dedicated to constantly improving care for burns patients. Director Associate Professor Cleland, who also heads the Alfred Skin Bioengineering Laboratory, said translational research in the skin bioengineering laboratory was part of that drive.
“This research is providing insights into the mechanisms that determine successful skin grafting to produce wound healing and minimise scarring. We are focussed on harnessing those mechanisms to produce a reliable, true biosynthetic skin equivalent useful for the treatment of all kinds of skin injury and diseases,” she said.
Lo CH, Akbarzadeh S, McLean C, Ives A, Paul E, Brown WA, Cleland H. Wound healing after cultured epithelial autografting in patients with massive burn injury: A cohort study. J Plast Reconstr Aesthet Surg. 2018 Nov 13. pii: S1748-6815(18)30388-7. doi: 10.1016/j.bjps.2018.11.003. [Epub ahead of print]
Cheshire P, Zhafira AS, Banakh I, Rahman MM, Carmichael I, Herson M, Cleland H, Akbarzadeh S. Xeno-free expansion of adult keratinocytes for clinical application: the use of human-derived feeder cells and serum. Cell Tissue Res. 2019 Jan 21. doi: 10.1007/s00441-018-02986-5. [Epub ahead of print]
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