Although prevention strategies have reduced the incidence of serious burns since the 20th century, burns remain a leading cause of trauma worldwide.1 Each year, more than 11 million people globally and 1 million people in the United States require medical treatment for burns.1,2 Other types of chronic wounds, such as diabetic and pressure ulcers, also affect a substantial number of Americans.3

Although split thickness autografts remain the gold standard treatment approach for addressing severe wounds, adequate coverage depends on the availability of healthy donor skin, and the use of allografts confers the risk for immune rejection.3 The development of dermal substitutes has led to improvements in survival and full-thickness wound closure, and cellular therapy techniques including manual cell seeding and cell spraying have demonstrated superior results in terms of rapid wound coverage, accelerated healing, and cosmetic outcomes compared with noncellular techniques. However, due to low delivery precision, these strategies are currently not capable of generating the complex skin structure required for optimal functional and aesthetic outcomes in patients with extensive wounds.3

Conversely, bioprinting — typically using inkjet printers — enables the fabrication and direct delivery of skin cells to specific sites in a layered manner. In murine and porcine models, researchers at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, have shown promising results using skin bioprinting for severe wounds. In a proof-of-concept study published in 2019 in Scientific Reports, they validated a novel mobile skin bioprinting system that deposits skin cells directly into full-thickness wounds.3

Compared with other treatments, the deposition of “layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier” was associated with a 3-week acceleration in wound closure, 50% reduction in wound contraction, and 4- to 5-week acceleration in wound re-epithelialization. “These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes,” according to the study authors.3


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In another porcine preclinical study published in February 2020 in Biofabrication, researchers at the Sunnybrook Research Institute at the University of Toronto in Ontario demonstrated similar success using a handheld instrument for the direct, wound-conformal delivery of mesenchymal stem/stromal cell-containing fibrin sheets to the wound bed of full-thickness burns.4 This technique was found to improve “re-epithelialization, dermal cell repopulation, and neovascularization, indicating that this device could be introduced in a clinical setting [to improve] dermal and epidermal regeneration,” the study authors wrote.

Ultimately, the use of skin bioprinting for the treatment of burns and other severe wounds could significantly accelerate wound closure and healing, reduce the risk for infection, minimize scarring, and improve cosmetic outcomes. Consequently, these improvements would likely reduce the number of required surgeries and length of hospital stay for many patients requiring wound care.1

To learn more about developments in skin bioprinting, we spoke with Marc Jeschke, MD, PhD, director of the Ross Tilley Burn Centre in Toronto, Ontario, senior scientist at the Sunnybrook Research Institute, and professor in the department of surgery and plastic surgery and the department of immunology at the University of Toronto; and Adam Jorgensen, an MD/PhD candidate who works on the bioprinting research team at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina.

What does the available evidence suggest thus far regarding skin bioprinting for wound healing?

Dr Jeschke: Bioprinting, or 3-dimensional printing of skin for wound healing and wound recovery, is of major interest and major importance, particularly in patients with burns. This is reflected by research and advances in burn patients during the last 2 to 3 decades. Their survival depends on wound healing, and the conventional gold standard of taking grafts and placing it on wounds creates more wounds. Hence, there is the concern of inflicting more pain, increasing wound sizes, and causing harm.

However, this is a necessary intervention, so it seems quite logical to create tissue-engineered or novel skin replacement approaches. Similarly, this is the case for patients with large and complex wounds. Wound coverage and wound regeneration are essential, so our goal is to not induce new wounds or cause more pain by taking donor sites. Therefore, the evidence is very strong that bioprinting or skin regenerative medicine are imperative for patients’ survival.

In addition to survival, long-term outcomes such as scarring, itch, and tightness are also important. Poor quality of life is one of the major challenges remaining in burn care. Therefore, the hope is that this can be significantly improved through the use of regenerative medicine and skin printing.

Jorgensen: The advantage of using bioprinting to create skin as a substitute or for wound healing includes the ability to precisely place the cells where they are needed, thus creating tissue structures that are layered appropriately. Bioprinting also allows for reproducibility, so the skin can be engineered in the same manner each time. Bioprinting can also be used for rapid manufacturing scale-up once the technology is proven to be clinically effective, allowing for increased availability to patients at decreased costs.

Tell us a bit about the work underway at Wake Forest. What are some of the most notable findings and future plans?

Jorgensen: Studies at the Wake Forest Institute for Regenerative Medicine have shown that bioprinting allows for recapitulation of the epidermis, dermis, and hypodermis in an anatomically relevant manner. A recent study showed that bioprinted skin provides permanent wound closure, with restoration of the skin barrier, and achievement of functional and cosmetic results.2 In this technology, the skin is bioprinted in vitro and matured before implantation. Bioprinted skin accelerated full-thickness wound closure by promoting epidermal barrier formation without increasing contraction. Our next step with this technology is to scale up to clinically relevant sizes in a preclinical model of wound healing.

A second approach we have investigated is bioprinting skin at the patient’s bedside. The bioprinter uses integrated imaging to scan and facilitate the precise delivery of cells directly into an injured area, replicating the layered skin structure. These preclinical studies showed rapid wound closure, reduced contraction, and accelerated re-epithelialization.3 The next steps for this technology include development and testing of an in situ skin bioprinter for clinical use and further validation in a preclinical model.

What will it take to advance this technology toward clinical use?

Dr Jeschke: Advancing the technology to clinical trials seems quite straightforward. The technology — the cell composition, cell flow, and printing — needs to be optimized. Once we determine how these cells should be incorporated and structured, and which matrix to use, a clinical safety trial will be conducted. I foresee this happening in 5 to 10 years for wound regeneration and recovery. In addition, our knowledge about cellular components and interaction will significantly increase during the coming years, likely leading to further advances in bioprinted skin for use in clinical trials.

Jorgensen: The next steps towards clinical use include standardizing the scale-up process for cell culture and expansion from autologous tissue. Facilitating simplified isolation methods and improving cell expansion techniques will reduce costs and improve the turnaround time from the time of biopsy to implantation.

What are remaining needs in this area in terms of research or technological advances?

Dr Jeschke: As indicated above, there are many needs. We need to have a better understanding of interactions and of acute and long-term outcomes. Can we print functionally identical skin to a patient, which would be composed of autologous cells? What source do those cells have to be? What dosing? What ink? These are essential questions, but once we initiate a clinical safety trial, I believe this will then further advance the technology, which ultimately will be a clinically introduced technology in the future.

Jorgensen: Key items include improvements in the microstructure of the skin, such as sweat, sebaceous glands, and hair follicles, that will continue to improve the functional characteristics of bioprinted skin.

References

1. Varkey M, Visscher DO, van Zuijlen PPM, Atala A, Yoo JJ. Skin bioprinting: the future of burn wound reconstruction? Burns Trauma. 2019;7:4.

2. Jorgensen AM, Varkey M, Gorkun A, et al. Bioprinted skin recapitulates normal collagen remodeling in full-thickness wounds. Tissue Eng Part A. 2020;26:9-10.

3. Albanna M, Binder KW, Murphy SV, et al. In situ bioprinting of autologous skin cells accelerates wound healing of extensive excisional full-thickness wounds. Sci Rep. 2019;9(1):1856.

4. Cheng RY, Eylert G, Gariepy J-M, et al. Handheld instrument for wound-conformal delivery of skin precursor sheets improves healing in full-thickness burns. Biofabrication. 2020;12(2):025002.