Handheld instrument for wound-conformal delivery of skin precursor sheets improves healing in full-thickness burns

Abstract

The current standard of care for patients with severe large-area burns consists of autologous skin grafting or acellular dermal substitutes. While emerging options to accelerate wound healing involve treatment with allogeneic or autologous cells, delivering cells to clinically relevant wound topologies, orientations, and sizes remains a challenge. Here, we report the one-step in-situ formation of cell-containing biomaterial sheets using a handheld instrument that accommodates the topography of the wound. In an approach that maintained cell viability and proliferation, we demonstrated conformal delivery to surfaces that were inclined up to 45 degrees with respect to the horizontal. In porcine pre-clinical models of full-thickness burn, we delivered mesenchymal stem/stromal cell-containing fibrin sheets directly to the wound bed, improving reepithelialization, dermal cell repopulation, and neovascularization, indicating that this device could be introduced in a clinical setting improving dermal and epidermal regeneration.

Skin regeneration is accelerated by a lower dose of multipotent mesenchymal stromal/stem cells—a paradigm change

“…However, the critical cell dosing of MSCs is unknown and difficult to compare based on previous reports. Publications utilizing the DRT for wound healing include MSCs cell dosages that vary between 5000 and 2,000,000 cells/cm 2 [9][10][11] and are tested on different models, such as rodents [11][12][13][14][15], pigs [9,10,16], and humans [17]. These studies were either given cell dosages once [9,10,16,18] or multiple times [11] on acute [9,10,16,18] and chronic wounds [17] either on partial [18] or full-thickness [9,10,16] (burn) wounds, making comparisons even more difficult.…”

“…However, we previously observed in an umbilical cord stem cell study using a bio-printer with direct cell depositioning onto burn wounds comparing to the cellularized DRT that even a lower dose regenerated the skin [10]. This raises the challenging question of which dose is optimal, as the general research hypothesis from these previous papers is that more cells lead to better wound healing outcomes.…”

Biological characteristics of stem cells derived from burned skin—a comparative study with umbilical cord stem cells

“…However, BD-MSCs did show a lower mesenchymal differentiation capacity compared to UC-MSCs for adipogenic and chondrogenic differentiation in the in vitro experiment. This could be due to the higher multipotent differentiation potential of the young UC-MSCs, which are faster in cell differentiation compared to the adult MSCs [ 6 , 34 ]. Another explanation could be that the extracted cells of the burn tissue contain a subpopulation [ 36 ] of very differentiated progenitor-MSC-like-fibroblasts [ 3 ] of the mesenchymal lineage.…”

“…Statistical significance was calculated on Δct values. We chose GAPDH as a housekeeping gene, since it is one of the most widely used reference genes in high-impact studies and considered a classical housekeeping gene [ 34 ].…”

An open-source handheld extruder loaded with pore-forming bioink for in situ wound dressing

“…This strategy provides a decent degree of freedom to the clinician using the device, allowing rapid adjustments to the wound shape/structure when using the bioprinting device as well as any potential patient movement during the operation, which cannot be conveniently accommodated by the robotic arm method. Several investigational studies have shown the potential of handheld bioprinting in intraoperative wound-dressing applications, such as healing of the skin [ 14 , 15 ], the muscle [ 16 ], and the bone [ 17 ], among others.…”