4D printed hydrogel expanders use controlled buckling and low pressure to generate new soft tissue while preserving viability and activating early remodeling pathways for personalized reconstruction.
(Nanowerk Spotlight) Soft tissue reconstruction often begins with a simple but stubborn problem. When a wound is too large to close without distortion or loss of blood flow, surgeons must find extra skin somewhere else. Burns, tumor removal, and traumatic injuries can remove more tissue than the surrounding area can safely supply.
Traditional solutions involve grafting skin from another part of the body or repositioning nearby tissue. Both approaches can succeed, but they also introduce new wounds, visible differences in appearance, or structural weakness in the donor site. The underlying issue remains: many patients need more skin than they have.
A different insight emerged when clinicians observed how skin responds to steady and moderate stretching. Under the right conditions, it produces new cells and new matrix rather than tearing or thinning. This principle shaped the development of tissue expansion, where an implanted device gently stretches skin to encourage growth. The method has allowed surgeons to generate additional tissue that matches color, texture, and function in a way grafts often cannot.
Yet the devices that support this technique still present substantial limitations. Balloon like expanders must be filled repeatedly in a clinic, which increases discomfort and infection risk. Self-inflating hydrogel expanders avoid these visits but swell in all directions, which forces them to start thick and push outward in ways that can strain sensitive tissues.
During this same period, engineers have developed materials that can change shape in reliable and programmable ways. One of the most versatile examples is the hydrogel, a water absorbing polymer that can be patterned so different regions swell more or less when they absorb fluid. When designed carefully, a thin sheet can rise, curl, or fold into a controlled three-dimensional structure.
This transformation is known as 4D printing because the shape evolves over time. The basic idea is straightforward: the printed pattern determines how the sheet will move once it encounters moisture. Although these systems have gained attention for their precision, their use in medicine has been limited.
By combining a surgical need with a material that can be shaped at the microscopic level, the work aims to address long standing problems with current expanders, including incision size, force control, and compatibility with complex anatomy.
Fabrication and implantation of the 4D printed hydrogel expander. a) Fabrication process and chemical structures of the precursors. b) Implanting and expansion of the device. c) Molecular changes during the expansion. (Image: Reproduced with permission from Wiley-VCH Verlag) (click on image to enlarge)
The device begins as a flat sheet only 1.0 mm thick. Its structure comes from two light based curing steps. In the first step, a digital projector shines patterned light onto a thin layer of polyurethane acrylate, a plastic that solidifies when exposed to light. This forms a rigid frame that does not swell.
After removing the uncured material, the researchers fill the open areas with a second liquid mixture. This mixture contains 2 hydroxyethyl acrylate, which forms a water absorbing polymer, and poly(ethylene glycol) diacrylate, a crosslinker that connects polymer chains to control stiffness and water uptake. Ultraviolet light then cures this mixture into a hydrogel.
Before it cures fully, the hydrogel precursor seeps slightly into the edges of the polyurethane frame. When it solidifies, it forms a blended region that locks the two materials together. This prevents separation during swelling and gives the device structural stability.
When the sheet absorbs water, the hydrogel regions try to expand, but the frame prevents them from spreading outward. The only direction left is upward, so the sheet bends into a dome like shape. This buckling effect produces a controlled rise in height while keeping the footprint almost unchanged.
Tests show that the device reaches swelling equilibrium in about 30 min in water. With a crosslinker content of 0.5 wt.% the expanded height reaches 8.36 mm, which is about eight times the thickness of the original sheet. In contrast, standard hydrogel expanders swell uniformly in every direction and usually reach less than a threefold increase in any single axis. The ability to direct swelling into one dimension allows the device to start thin yet generate substantial height after implantation.
Mechanical testing reveals another key difference. At a displacement of 1.5 mm, the buckled device produces about 0.5 N of force. A cylindrical hydrogel expander made from the same chemistry produces nearly five times that amount. High pressure can compromise blood flow, so a lower and more controlled force profile makes the device safer for sensitive tissues. Based on the difference between its swollen height in water and in living tissue, the researchers estimate that the device applies about 0.78 N or 5.42 kPa to the scalp. A traditional cylindrical device at similar displacement produces about 32 kPa.
To evaluate performance in living tissue, the researchers implanted disc shaped expanders under the scalp of rats. The device began at 0.74 mm in height and rose to 6.3 mm within 10 h. The difference from the 8.1 mm height seen in water reflects the resistance of the surrounding skin. Blood flow above the device remained normal throughout. The expander stayed intact for 14 days, and tissue samples from major organs showed no unusual inflammation.
The skin above the expander increased in both area and mass. By day 5 the surface area had nearly doubled, and the mass had nearly tripled compared with untreated controls. Because both parameters rose together, the tissue likely maintained its thickness rather than thinning under stretch.
Microscopy provides detailed insight. The epidermis thickened by about 44 percent within 3 days. By day 14 it contained four layers of keratinocytes instead of two. Keratinocytes are the main cells in the outer skin layer. Staining for PCNA, a protein linked to cell division, showed more dividing cells in the expanded skin, especially in the basal layer where new cells form.
The dermis, the deeper layer, did not thin. Many earlier studies of traditional expanders reported dermal thinning. In this study, collagen content increased. Collagen type I and collagen type III, two major structural proteins, showed higher gene expression in expanded skin by day 14.
To understand the broader biological response, the researchers performed RNA sequencing after 3 days. They identified 1 685 up regulated and 931 down regulated genes. Many of these genes are involved in remodeling of the extracellular matrix, blood vessel formation, immune activity, and epithelial to mesenchymal transition. In this transition, epithelial cells loosen their attachments and take on more mobile characteristics that help tissues adapt to mechanical stress.
Markers of this process shifted in expected ways. The gene Cdh1, which produces the adhesion protein E cadherin, decreased. Genes that support mesenchymal traits, such as Vim, Fn1, and Snai1, increased. Protein measurements supported these findings. Levels of vimentin and fibronectin rose, while E cadherin fell.
Signaling pathways that regulate cell growth and survival also became active. The PI3K and AKT pathway showed increased phosphorylation of PI3K, AKT, and mTOR. Phosphorylation is a chemical modification that switches these proteins to their active state. Total protein levels remained similar between expanded and untreated skin, which indicates activation rather than increased production. Other pathways linked to mechanical sensing, including MAPK and Hippo signaling, also showed activity.
The researchers also tested how pattern design affects the device’s final shape. By changing the digital pattern that defines the frame, they produced sheets that rose into different forms. When implanted, these forms appeared as planned contours on the skin surface. The team also showed how to adjust the force the device produces. A sheet made from a 25 wt.% precursor applied about 0.36 N and produced less height. This tuning ability allows the expander to match different tissues or anatomical regions.
This study presents a system that connects programmable shape change with controlled tissue growth. The thin sheet generates significant height without requiring a large incision or exerting excessive pressure. It stimulates the growth of viable skin in an animal model and activates biological pathways associated with remodeling and recovery.
Further work will refine the expansion profile, broaden analysis across different tissues, and integrate digital planning. The approach points toward soft tissue expanders that can be tailored to individual anatomy and clinical need.
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