Scientists at RIKEN Center for Developmental Biology in Kobe grew skin in a laboratory that sprouted hair, produced oil, and connected to surrounding tissue like it belonged there. Published in Science Advances, their work represents the most advanced bioengineered skin ever achieved. Unlike current grafts that serve as biological bandages, this lab-grown tissue functions as skin should.

Burn victims currently face grim choices. Doctors harvest healthy skin from elsewhere on the body, creating a second wound that needs healing. For patients with severe burns covering large areas, donor sites run out. Even when grafts succeed, they lack the components that make skin work. No sweat glands to regulate temperature. No oil glands to prevent drying. No hair follicles or proper sensation. Just a protective covering that demands constant maintenance.

What if skin could be grown to order, complete with every component nature designed?

Why Current Skin Grafts Leave Burn Victims Applying Oil Daily

Skin does far more than cover bodies. As the largest organ, it protects against infection, regulates temperature through sweating, produces oils for waterproofing, and creates detailed sensation maps of the outside world. Hair follicles connect to tiny muscles. Glands secrete substances. Nerve endings transmit information. Fat provides cushioning. Blood vessels deliver nutrients.

Current artificial skin grafts fail to replicate this complexity. Labs grow sheets of epithelial cells, the outermost layer, but nothing deeper. Surgeons transplant these sheets onto burn patients, and they provide protection. Yet without sebaceous glands producing oil, grafts dry out. Patients must apply moisturizer constantly to prevent cracking and loss of waterproofing properties.

Temperature regulation fails without sweat glands. Bodies can’t cool properly in the heat. Touch sensation disappears when nerve connections don’t form. Grafted areas don’t match the surrounding skin in appearance, leaving patients with visible scarring and disfigurement.

John McGrath, professor of molecular dermatology at King’s College London, described the problem: “[Today’s skin grafts] function, but they don’t really look like or behave like skin. If you don’t have the hair follicles and you don’t have the sweat glands and things, it’s not going to function as skin.”

For severe burn victims, donor sites create additional problems. Surgeons must remove healthy skin from one area to graft onto another, creating a wound that requires healing. Patients with full-body burns have no donor sites available. Current treatments help people survive, but they leave lasting limitations.

From Gum Cells to Skin: How Scientists Turned Back the Clock

Dr. Takashi Tsuji and his team at RIKEN approached the problem differently. Instead of growing flat sheets of cells, they aimed to recreate the entire integumentary organ system, complete with all its complex structures.

Researchers started with adult cells from the mouse gums. Through chemical treatment, they reprogrammed these specialized cells into induced pluripotent stem cells (iPS). Like turning back a developmental clock, the process transformed adult cells into blank slates capable of becoming any tissue type in the body.

iPS cells offer advantages over embryonic stem cells. Scientists can harvest them from adult tissue without ethical concerns. Patients could theoretically provide their own cells, reducing rejection risks. Once reprogrammed, these cells divide indefinitely and can be guided down multiple developmental pathways.

Embryoid Bodies: Mini Clumps That Became Complex Organs

Tsuji’s team cultured iPS cells in special plates where they couldn’t attach to surfaces. Forced to cluster together, the cells formed three-dimensional structures called embryoid bodies (EBs). These clumps partially resembled developing embryos, containing a mix of cell types found in early development.

After culturing 3,000 cells per well for seven days, researchers had embryoid bodies ready for the next stage. Previous attempts to grow organs from stem cells failed because single cells or single embryoid bodies formed disorganized teratomas containing random tissues. Neural tissue, cartilage, muscle, and bronchial epithelia appeared jumbled together without proper structure.

Tsuji’s team developed a novel approach: the clustering-dependent embryoid body (CDB) transplantation method. Instead of transplanting single embryoid bodies, they encased more than 30 together in collagen gel. Multiple embryoid bodies clustering together allowed outer epithelial layers to connect through self-assembly, creating organized tissue rather than chaos.

Two-Stage Grafting Process Proved the Concept

Researchers transplanted clustered embryoid bodies into the subrenal capsules of immunodeficient mice. Protected inside these mice for 30 days, the cells differentiated following patterns seen in actual embryos. Unlike random teratoma formation, the clustering method produced organized epithelial tissue.

After a month, scientists removed the developing tissue and analyzed its structure. Results confirmed the formation of complex three-dimensional skin, complete with all three layers: epidermis, dermis, and subcutaneous fat. Hair follicles appeared. Sebaceous glands formed. Sweat glands developed.

For the final test, researchers transplanted small pieces of this bioengineered tissue onto the skin of other mice. Within 14 days, black hair erupted from the grafts, sprouting through the skin on white-haired nude mice. Hair kept growing. Follicles cycled through growth and rest phases just like natural hair.

Secret Ingredient That Tripled Hair Follicle Growth

One discovery proved particularly important. Researchers treated some embryoid bodies with Wnt10b, a signaling molecule that regulates dermal papilla and fat tissue development during hair follicle formation. Embryoid bodies receiving Wnt10b treatment produced far more hair follicles than untreated samples.

Wnt10b didn’t change the basic ability to form skin, but it controlled follicle frequency. Neural crest cells, which give rise to melanocytes that color hair, responded to Wnt signaling. Hair shafts in the bioengineered skin appeared black despite growing on white mice, proving neural crest cells had differentiated properly.

Signaling molecules like Wnt10b orchestrate organ development during embryogenesis. Understanding which signals control specific aspects of tissue formation allows scientists to guide stem cells down desired pathways.

Skin That Actually Connects: Nerves, Muscles, and Blood Vessels Hooked Up

Perhaps most impressive, the bioengineered skin didn’t just sit on top of host tissue. It made proper connections to surrounding structures. Hair follicles are connected to arrector pili muscles, the tiny smooth muscles that make hair stand up. Nerve fibers grew into the grafts, establishing connections to follicle stem cells in bulge regions where they belong.

Blood vessels penetrated the tissue. All three skin layers formed in the correct positions. Sebaceous glands appeared ready to secrete oil. Sweat glands developed structures needed for temperature regulation. Fat tissue is cushioned beneath the dermis.

Researchers confirmed origins by tracking Y-chromosomes. Male iPS cells transplanted into female mice allowed scientists to identify which tissue came from graft versus host. Y-chromosome-positive cells appeared throughout the transplanted areas in skin epithelium, dermis, sebaceous glands, intracutaneous adipose tissue, and hair follicles. Grafts came entirely from iPS cells, not host tissue growing over transplants.

Hair Follicles With All the Right Stem Cells in All the Right Places

Hair follicles contain multiple types of stem cells positioned in specific locations. CD34-positive and Sox9-positive follicle stem cells reside in the bulge region. Lrig1-positive epithelial stem cells occupy the upper bulge outer root sheath. Lgr5-positive cells drive hair cycling during the telogen-to-anagen transition.

Researchers examined whether bioengineered follicles reconstructed these niches correctly. Immunostaining revealed all the right cell types in all the right places. Stem cells populated bulge regions. Proper markers appeared in proper locations. Architecture matched natural follicles.

Hair cycled through growth and rest phases at least three times during the 90-day observation period. Anagen (growth) phases showed active follicles producing hair shafts. Telogen (rest) phases occurred when follicles stopped growing. Timing matched natural hair cycles in normal mice.

All three hair types found in mouse pelage appeared in bioengineered skin: zigzag, awl/auchene, and guard hairs. Distribution matched natural skin. The distance between follicles was measured similarly to normal mice. Lab-grown skin behaved like skin from birth.

No Tumor Formation After 3 Months: Safety Milestone Achieved

iPS cells raise safety concerns because they divide indefinitely. Uncontrolled growth could produce tumors. Researchers monitored 171 grafts for three months after transplantation. Zero cases of tumorigenesis occurred. Cells differentiated properly into specialized skin cells and stopped dividing uncontrollably.

Safety represents a major hurdle for any stem cell therapy. Demonstrating that bioengineered skin doesn’t form tumors after transplantation brings the technology closer to human application.

5 to 10 Years Before Human Trials Could Begin

Dr. Tsuji estimated the timeline to human application at 5 to 10 years. Mouse studies proved the concept works, but optimizing techniques for human cells requires additional research. Scaling up production to generate enough tissue for large burn areas presents engineering challenges.

Human skin has different properties from mouse skin. Follicle density differs. Hair types vary. Immune responses may differ. Researchers must validate every step using human iPS cells before clinical trials begin.

Current work focused on achieving proof of concept. Future work must address practical considerations for manufacturing, quality control, and clinical implementation.

Challenges That Remain

Two limitations emerged. Bioengineered skin can’t generate new nerve fibers. It connects to existing nerves from the host tissue, but doesn’t produce nerves itself. For patients with nerve damage, this limitation matters.

Hair color sometimes mismatched. White-haired mice occasionally grew black hair from grafts. For cosmetic applications, matching hair color to surrounding tissue becomes important. Controlling melanocyte differentiation and pigment production needs refinement.

Neither limitation prevents burn treatment applications where function matters more than perfect aesthetics. Both problems seem solvable with additional research.

Building Organs Layer by Layer

“Up until now, artificial skin development has been hampered by the fact that the skin lacked the important organs, such as hair follicles and exocrine glands, which allow the skin to play its important role in regulation. With this new technique, we have successfully grown skin that replicates the function of normal tissue,” Tsuji explained. “We are coming ever closer to the dream of being able to recreate actual organs in the lab for transplantation, and also believe that tissue grown through this method could be used as an alternative to animal testing of chemicals.”

When scientists rebuild skin from scratch, they confront how much intelligence gets embedded in tissues we barely consider. Every layer serves purposes beyond the obvious. Glands regulate temperature through evaporation. Follicles anchor muscles. Stem cells wait in specific niches ready to repair damage or cycle hair growth. Fat cushions and insulates. Nerves map sensation.

Building this complexity forces recognition that what seems simple contains genius developed across evolutionary timescales. Lab-grown skin that sweats and sprouts hair demonstrates humans can decode and reconstruct biological systems. Yet it also reveals how far current understanding falls short of replicating what bodies do automatically.

Cosmetic testing currently requires animals despite bans in many countries. Realistic skin samples with proper glands and permeability could replace mice and rats in safety testing for chemicals, cosmetics, and drugs. Animal-free testing methods gain traction as technology improves.

For burn victims facing limited options, bioengineered skin offers hope for functional grafts that behave like natural tissue. No more endless moisturizing. No more temperature regulation problems. No more donor site wounds. Just skin that works.

Each successful organ recreation pushes the boundary between living and manufactured, natural and engineered. Whether that distinction matters becomes an open question if function matches form. Bodies don’t care whether skin grew during development or in a laboratory if it sweats, grows hair, and heals wounds properly.

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