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New treatment could reverse hair loss caused by an autoimmune skin disease

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Researchers at MIT, Brigham and Women’s Hospital, and Harvard Medical School have developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss and affects people of all ages, including children.

For most patients with this type of hair loss, there is no effective treatment. The team developed a microneedle patch that can be painlessly applied to the scalp and releases drugs that help to rebalance the immune response at the site, halting the autoimmune attack.

In a study of mice, the researchers found that this treatment allowed hair to regrow and dramatically reduced inflammation at the treatment site, while avoiding systemic immune effects elsewhere in the body. This strategy could also be adapted to treat other autoimmune skin diseases such as vitiligo, atopic dermatitis, and psoriasis, the researchers say.

“This innovative approach marks a paradigm shift. Rather than suppressing the immune system, we’re now focusing on regulating it precisely at the site of antigen encounter to generate immune tolerance,” says Natalie Artzi, a principal research scientist in MIT’s Institute for Medical Engineering and Science, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, and an associate faculty member at the Wyss Institute of Harvard University.

Artzi and Jamil R. Azzi, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, are the senior authors of the new study , which appears in the journal Advanced Materials . Nour Younis, a Brigham and Women’s postdoc, and Nuria Puigmal, a Brigham and Women’s postdoc and former MIT research affiliate, are the lead authors of the paper.

The researchers are now working on launching a company to further develop the technology, led by Puigmal, who was recently awarded a Harvard Business School Blavatnik Fellowship.

Direct delivery

Alopecia areata, which affects more than 6 million Americans, occurs when the body’s own T cells attack hair follicles, leading the hair to fall out. The only treatment available to most patients — injections of immunosuppressant steroids into the scalp — is painful and patients often can’t tolerate it.

Some patients with alopecia areata and other autoimmune skin diseases can also be treated with immunosuppressant drugs that are given orally, but these drugs lead to widespread suppression of the immune system, which can have adverse side effects.

“This approach silences the entire immune system, offering relief from inflammation symptoms but leading to frequent recurrences. Moreover, it increases susceptibility to infections, cardiovascular diseases, and cancer,” Artzi says.

A few years ago, at a working group meeting in Washington, Artzi happened to be seated next to Azzi (the seating was alphabetical), an immunologist and transplant physican who was seeking new ways to deliver drugs directly to the skin to treat skin-related diseases.

Their conversation led to a new collaboration, and the two labs joined forces to work on a microneedle patch to deliver drugs to the skin. In 2021, they reported that such a patch can be used to prevent rejection following skin transplant. In the new study, they began applying this approach to autoimmune skin disorders.

“The skin is the only organ in our body that we can see and touch, and yet when it comes to drug delivery to the skin, we revert to systemic administration. We saw great potential in utilizing the microneedle patch to reprogram the immune system locally,” Azzi says.

The microneedle patches used in this study are made from hyaluronic acid crosslinked with polyethylene glycol (PEG), both of which are biocompatible and commonly used in medical applications. With this delivery method, drugs can pass through the tough outer layer of the epidermis, which can’t be penetrated by creams applied to the skin.

“This polymer formulation allows us to create highly durable needles capable of effectively penetrating the skin. Additionally, it gives us the flexibility to incorporate any desired drug,” Artzi says. For this study, the researchers loaded the patches with a combination of the cytokines IL-2 and CCL-22. Together, these immune molecules help to recruit regulatory T cells, which proliferate and help to tamp down inflammation. These cells also help the immune system learn to recognize that hair follicles are not foreign antigens, so that it will stop attacking them.

Hair regrowth

The researchers found that mice treated with this patch every other day for three weeks had many more regulatory T cells present at the site, along with a reduction in inflammation. Hair was able to regrow at those sites, and this growth was maintained for several weeks after the treatment ended. In these mice, there were no changes in the levels of regulatory T cells in the spleen or lymph nodes, suggesting that the treatment affected only the site where the patch was applied.

In another set of experiments, the researchers grafted human skin onto mice with a humanized immune system. In these mice, the microneedle treatment also induced proliferation of regulatory T cells and a reduction in inflammation.

The researchers designed the microneedle patches so that after releasing their drug payload, they can also collect samples that could be used to monitor the progress of the treatment. Hyaluronic acid causes the needles to swell about tenfold after entering the skin, which allows them to absorb interstitial fluid containing biomolecules and immune cells from the skin.

Following patch removal, researchers can analyze samples to measure levels of regulatory T cells and inflammation markers. This could prove valuable for monitoring future patients who may undergo this treatment.

The researchers now plan to further develop this approach for treating alopecia, and to expand into other autoimmune skin diseases.

The research was funded by the Ignite Fund and Shark Tank Fund awards from the Department of Medicine at Brigham and Women’s Hospital.

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MIT researchers have developed microneedle patches that are capable of restoring hair growth in alopecia areata patients, reports Ernie Mundell for HealthDay . The team’s approach includes a, “patch containing myriad microneedles that is applied to the scalp,” writes Mundell. “It releases drugs to reset the immune system so it stops attacking follicles.” 

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Studies Uncover New Approaches to Combat Hair Loss in Men and Women

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Two recent studies highlight novel ways to combat pattern hair loss in men and women using small molecules such as JAK inhibitors that reawaken dormant hair follicles, as well as stem cell therapies aimed at growing new follicles. 

In the first study, researchers led by Angela Christiano, PhD , the Richard & Mildred Rhodebeck Professor of Dermatology at Columbia University Vagelos College of Physicians and Surgeons, discovered previously unknown cells that keep mouse hair follicles in a resting state and show that inhibiting the activity of these cells can reawaken dormant follicles.

In a second study, Christiano’s team created a way to grow human hair in a dish , which could open up hair restoration surgery to more people, including women, and improve the way pharmaceutical companies search for new hair-growth drugs.

Study Discovers Cells That Put Hair Follicles to Sleep

Cross section of a hair follicle. Image: Angela Christiano / Columbia University Irving Medical Center.

In male and female pattern baldness, many hair follicles still exist but are dormant. The search for new drugs that reawaken follicles and induce hair growth has been limited by the field’s focus on finding drugs that work along the same pathways as finasteride and minoxidil, the only two drugs currently available for men with male pattern baldness. 

Christiano and her colleagues previously discovered a new pathway, called JAK-STAT, that is active inside the stem cells of resting hair follicles and keeps them in a dormant state. They previously demonstrated that JAK inhibitors applied to mouse skin are a potent way to reawaken resting hair follicles in mice. 

In their latest study, the researchers wanted to get a detailed picture of the natural processes that keep follicles dormant, so they looked for factors that controlled the JAK pathway activity in the hair follicle. 

New Cells Called Trichophages

The search revealed a previously unknown immune-related cell type that produces a substance known as Oncostatin M that keeps the follicles in a state of dormancy. “Rare subsets of immune cells were previously difficult to identify in whole skin, but this work was facilitated by our ability to sequence individual cells and pinpoint the ones making Oncostatin M,” says Etienne Wang, PhD, first author of the study. These cells are most similar to macrophages, which are scavenger cells of the immune system, and the team found them in close association with resting hair follicles.

The researchers named these cells trichophages, after the Greek word tricho for hair.

Targeting the trichophages can also turn on the hair cycle. By using small molecule inhibitors and antibodies to block Csf1R, a receptor on the trichophages, the researchers could block the flow of Oncostatin M and restart the hair cycle. 

Reawakening Dormant Hair Follicles with New Drugs

“Our previous studies implicated JAK-STAT signaling as one potential new therapeutic pathway for hair loss disorders by targeting hair follicle stem cells with JAK inhibitors,” Christiano says. (A biotech company recently reported results of a small phase 2 trial of a topical JAK-STAT inhibitor based on these studies.) “Here, we show that blocking the source of the JAK activating signal outside the hair follicle is another way to target this mechanism.”

Most drug development has focused on treatments for male pattern hair loss, and the majority of clinical trials are conducted exclusively in men.  

“These new pathways may lead to new treatments for both men and women suffering from hair loss, since they appear to be acting independently of male hormone pathways,” Christiano says. “Especially if treatments are used topically, that could avoid the related side effects seen with finasteride and minoxidil.”

Growing New Hair Follicles in a Dish

In a second study, aimed at using stem cells for hair growth, the Columbia researchers have created a way to grow human hair in a dish, which could open up hair restoration surgery to more people, including women, and improve the way pharmaceutical companies search for new hair growth drugs.

It is the first time that human hair follicles have been entirely generated in a dish, without the need for implantation into skin.

Using 3D-Printing to Stop Hair Loss

For years it’s been possible to grow mouse or rat hairs in the lab by culturing cells taken from the base of existing follicles. 

“Cells from rats and mice grow beautiful hairs,” Christiano says. “But for reasons we don’t totally understand, human cells are resistant.”

To break the resistance of human hair cells, Christiano has been trying to create conditions that mimic the 3D environment human hair cells normally inhabit. The lab first tried creating little spheres of cells inside hanging drops of liquid. But when the spheres were implanted in mice, the results were unpredictable: The cells from some people created new hair while others didn’t.

3D Printing Creates Patterned Hair Follicles

In the new study, Christiano’s team exploited the unique capability of 3D printers to create a more natural microenvironment for hair follicle growth. 

The researchers used 3D printing to create plastic molds with long, thin extensions only half a millimeter wide. “Previous fabrication techniques have been unable to create such thin projections, so this work was greatly facilitated by innovations in 3D printing technology,” says Erbil Abaci, PhD, first author of this study. 

After human skin was engineered to grow around the mold, hair follicle cells from human volunteers were placed into the deep wells and topped by cells that produce keratin. The cells were fed a cocktail of growth factors spiked with ingredients, including JAK inhibitors, that the lab has found stimulates hair growth. 

After three weeks, human hair follicles appeared and started creating hair.

Hair Farms Could Expand Availability of Hair Restoration

Though the method needs to be optimized, engineered human hair follicles created in this way could generate an unlimited source of new hair follicles for patients undergoing robotic hair restoration surgery.

Hair restoration surgery requires the transfer of approximately 2,000 hair follicles from the back of the head to the front and top. It is usually reserved for male patients whose hair loss has stabilized and who have enough hair to donate.

“What we've shown is that we can basically create a hair farm: a grid of hairs that are patterned correctly and engineered so they can be transplanted back into that same patient's scalp,” Christiano says. 

“That expands the availability of hair restoration to all patients—including the 30 million women in the United States who experience hair thinning and young men whose hairlines are still receding. Hair restoration surgery would no longer be limited by the number of donor hairs.”

The engineered follicles also could be used by the pharmaceutical industry to screen for new hair growth drugs. Currently, high throughput screening for new hair drugs has been hampered by the inability to grow human hair follicles in a lab dish. No drugs have been found by screening; the only two approved for the treatment of pattern hair loss—finasteride and minoxidil—were initially investigated as treatments for other conditions.  

The team hopes that cultured hair farms will open up the ability to perform high throughput drug screens to identify new pathways that influence hair growth.

The first study, titled “ A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth ,” was published in Cell Stem Cell.

Other authors: Etienne C.E. Wang (Columbia University Irving Medical Center and National Skin Center, Singapore), Zhenpeng Dai (CUIMC), Anthony W. Ferrante (CUIMC), and Charles G. Drake (CUIMC).

The research was supported by the National Skin Center of Singapore, the National Medical Research Council of Singapore, the Locks of Love Foundation, and the National Institutes of Health (S10OD020056, P30AR069632, and P50AR070588).

Dr. Christiano is a consultant and shareholder for Aclaris Therapeutics Inc., a consultant for Dermira Inc., and recipient of grant funding from Pfizer Inc. Dr. Drake has served as a paid consultant for Agenus, Bayer, BMS, F-Star, Janssen, Merck, Pfizer, Pierre Fabre, Roche/Genentech, and Shattuck Labs. He has ownership interest in Compugen, Harpoon, Kleo, Potenza, Tizona, and Werewolf.

Columbia University has licensed intellectual property related to these studies to Aclaris Therapeutics Inc. 

The second study, titled “ Tissue engineering of human hair follicles using a biomimetic developmental approach ,” was published in Nature Communications. 

Other authors: Hasan Erbil Abaci, Abigail Coffman, Yanne Doucet, James Chen, Joanna Jacków, Etienne Wang, Zongyou Guo, Jung U. Shin (all from Columbia University Vagelos College of Physicians and Surgeons) and Colin A. Jahoda (Durham University, Durham, U.K.).

The research was supported by the NIH (National Center for Advancing Translational Sciences grant UH2EB017103; National Institute of Arthritis and Musculoskeletal and Skin Diseases grants K01AR072131 and P30AR069632); New York State Stem Cell Science (SDH C029550); an Ines Mandl Research Foundation Fellowship; and a CUIMC Precision Medicine Research Fellowship (with funds from NIH grant  UL1TR001873 ).

Dr. Christiano and Dr. Jahoda are founders of Rapunzel Bioscience Inc., which focuses on developing regenerative therapies for skin and hair disorders. The remaining authors declare no competing interests.

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Cure for hair loss? Breakthrough study may pave the way for new treatment

A single molecule may hold the key to battling male- and female-pattern hair loss, recent research suggests.

In mouse experiments, scientists showed that the molecule, dubbed SCUBE3, could spark hair growth in dormant mouse follicles, and even in human ones that had been grafted onto mice. The research was described in a study published in Developmental Cell.

Hair follicles in people who are bald still have the machinery to sprout new strands, study co-author Maksim Plikus, Ph.D., professor of developmental and cell biology at the University of California, Irvine, told TODAY.

All follicles have stem cells at their base that work together to produce strands of hair, Plikus said. In people who are bald or have thinning hair , some of those stem cells don’t seem to be working, he added.

“When it comes to growing hairs, follicle stem cells need to become activated,” Plikus said. “Once activated, they divide into daughter cells that mature and come together to form a strand.”

“Most people when they lose their hair wonder if the follicles are gone,” Plikus said. “They are there, but they are dormant. The reason they are inactive is that they are not hearing signaling molecules.”

That's where SCUBE3 comes in: The molecule carries the message that tells the follicles to activate. Plikus and his colleagues showed in their experiments that when mice were given microinjections of SCUBE3, their hair grew in thick . Even human follicles that were transplanted into the mouse skin turned on when exposed to SCUBE3. The findings suggest that, in people with thinning hair, there isn’t enough SCUBE3 present.

Plikus compares a head covered with dormant follicles to a huge factory filled with 3D printers that are idling and ready to print, but are waiting for someone to push their start buttons.

It’s likely, Plikus said, that it would take very small amounts of SCUBE3 to activate dormant human hair follicles. Moreover, he suspects that treatments would need to be given only two or three times a year.

While the research on SCUBE3 is promising, getting from mouse experiments to a human treatment for baldness isn’t guaranteed, and even if SCUBE3 turns out to grow hair in people, it takes a long time to take a treatment through all of the clinical trials needed to get Food and Drug Administration approval, Plikus said.

“Right now, we are very excited about it,” Dr. Brian Abittan, director of skin and hair rejuvenation at the Mount Sinai Health System, told TODAY. “With this SCUBE3 molecule, we’re hoping to have a more precise understanding of the signaling that controls hair growth. It would be great to have another pathway to treatments.”

But, Abittan said, this is still in the preclinical stage of development.

There is still a long way to go before this could become a baldness treatment, Rui Yi, Ph.D., professor of pathology and dermatology at Northwestern University's Feinberg School of Medicine, told TODAY. “There is a big difference between a human and a mouse. Mice have short hair that grows just long enough to cover their bodies.”

Before doing a clinical trial, the researchers probably will need to do more safety testing, Yi said.

Linda Carroll is a Peabody Award-winning journalist who is a contributing health and medicine writer for NBC News and TODAY. She is co-author of three books: “The Concussion Crisis: Anatomy of a Silent Epidemic”, “Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings” and “Duel for the Crown: Affirmed, Alydar, and Racing’s Greatest Rivalry”.  

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• Published: 17 February 2021

Functional hair follicle regeneration: an updated review

• Shuaifei Ji 1 ,
• Ziying Zhu 1 ,
• Xiaoyan Sun 1 &
• Xiaobing Fu 1  

Signal Transduction and Targeted Therapy volume  6 , Article number:  66 ( 2021 ) Cite this article

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• Regeneration
• Regenerative medicine

The hair follicle (HF) is a highly conserved sensory organ associated with the immune response against pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing. Although recent advances in lineage-tracing techniques and the ability to profile gene expression in small populations of cells have increased the understanding of how stem cells operate during hair growth and regeneration, the construction of functional follicles with cycling activity is still a great challenge for the hair research field and for translational and clinical applications. Given that hair formation and cycling rely on tightly coordinated epithelial–mesenchymal interactions, we thus review potential cell sources with HF-inducive capacities and summarize current bioengineering strategies for HF regeneration with functional restoration.

Similar content being viewed by others

Expansion and characterization of epithelial stem cells with potential for cyclical hair regeneration

Local and systemic mechanisms that control the hair follicle stem cell niche

Deciphering the molecular mechanisms of stem cell dynamics in hair follicle regeneration

Hair follicles (HFs) are a major skin appendage originating from the ectoderm. As a stem cell repository and a hair shaft factory, the HF contributes to remodelling its cutaneous microenvironment, including skin innervation and vasculature. 1 The HF participates in multiple functions, mainly physical protection, thermal insulation, camouflage, sebaceous dispersion, sensory perception and social interactions. In addition, hair in human society greatly affects the quality of life, attractiveness and self-esteem. However, destructive inflammation with various aetiologies and the subsequent replacement of fibres can involve the permanent loss of HFs, which impairs inherent skin function and, especially, psychological well-being. Thus, HF regeneration is in ever-increasing demand and has promising market prospects. HF morphogenesis and regeneration were shown to be dependent on the intensive cooperation of epithelial (epidermal stem cell [Epi-SCs]) and hair-inducive mesenchymal (dermal papilla [DP]) components, also called epithelial–mesenchymal interaction (EMI). EMI is a prerequisite for functional HF formation, regeneration and cycling, mainly through paracrine mechanisms, 2 and has become the theoretical basis of tissue engineering for HF regeneration. Current strategies to regenerate HF in vivo are aimed at simulating EMI, mostly adopting the principle of combining epithelial (Epi-SC and keratinocyte) and mesenchymal (DP cell [DPC] and skin-derived precursors [SKPs]) components. HFs are also a dynamic mini-organ, and their most notable feature is hair cycling (Fig. 1a ), from periods of organ regeneration and rapid growth (anagen) to apoptosis-driven regression (catagen); then, the HF moves back into anagen via an interspersed period of relative quiescence (telogen). 1 The interaction between HF stem cells (HFSCs) and DPCs plays a significant role in the regulation of hair cycling. 3 , 4 The activation, stability and sustainability of hair cycling are considered to be a key factor in achieving the longevity of HF function, but HF loss is often accompanied by the termination and elimination of hair cycling. Thus, the achievement of hair cycling regeneration is important for functional HF regeneration. Although hair transplantation has been widely applied, transplanted hair is not maintained in the long term. Moreover, clinical drugs still fail to meet the patents’ needs and even have drastic side effects. 5 Therefore, there is a need to explore alternative therapeutic solutions capable of generating functional HFs. Current techniques could make it possible to obtain potential cells in vitro (Fig. 1b ), such as DPCs (Fig. 1c ), SKPs, keratinocytes and other stem cells (Fig. 2 ), providing us with a series of cell sources. In addition, the optimization of the culture system also contributes to preserving the HF-inducive ability of potential cells. Based on these findings, we are able to regenerate functional HFs by the transplantation of potential cell mixtures, HF organoid construction in vitro, reprogramming induction and the establishment of a drug delivery system (Fig. 3 ). Here, we will review the potential cell sources and tissue engineering techniques that contribute to HF regeneration. In addition, the limitations and future of functional HF regeneration are summarized.

The process of hair cycling and DPCs in HF regeneration. a Mature and actively growing HFs anchored in the subcutis periodically regenerate by spontaneously undergoing anagen (repetitive cycles of growth), catagen (apoptosis-driven regression) and telogen (relative quiescence), which is termed hair cycling and is a typical characteristic of functional HFs. b Skeleton diagram of potential cells that contribute to regenerating HFs. c iPSCs share similar characteristics with embryonic stem cells in terms of morphology, self-renewal and differentiation capacity, and they can be induced into other potential cells in regenerative medicine. The transformation of fibroblasts into DPCs via lineage reprogramming. Optimization of the in vitro system to preserve the HF-inducive potential and the transplantation of cell-based biomaterials or HF organoids in vivo to regenerate HFs

Keratinocytes and SKPs in HF regeneration. a iPSCs were reprogrammed into keratinocytes, and biomaterials containing a mixture of fibroblasts and keratinocytes were embedded for de novo HF. b Fibroblasts were chemically induced into SKPs. A mixture of SKPs and epidermal stem cells or bioactive peptides was embedded in the hydrogel to regenerate HFs three-dimensionally

Strategies to achieve functional HF regeneration

Potential cell sources and mechanism for HF regeneration

DPCs, a kind of differentiated dermal cell at the base of HFs, 6 originate from blimp1+ fibroblasts (dermal stem cells [DSCs]) during embryonic development. 7 , 8 DPCs have the ability to stimulate epithelial HFSCs and are considered to be a master regulator of HF cycling. Past studies reported that DPCs isolated from rat and guinea pig vibrissae, as well as humans, could also induce HF formation when implanted into recipient non-hairy skin, 9 , 10 which indicates that DPCs could reprogramme non-hairy epidermis to a follicular fate. Subsequently, DPCs, either fresh or after tissue culture expansion, could also reproduce new HFs if placed in proximity to the epithelium. 11 , 12 Based on their strong HF-inducive ability, many attempts to coculture DPCs with other cell types to regenerate HFs have been studied, such as the two-dimensional juxtaposition of other epithelia, 13 cultured epithelial cells, 14 , 15 keratinocytes, 16 , 17 corneal epithelium 18 and amnion epithelium. 19 DPCs can secrete various factors to initiate HF formation by activating skin epithelial stem cells (Epi-SCs), so the mixture of DPCs and Epi-SCs also promotes functional HF regeneration in vivo. 20

DPCs with specific marker molecules possess HF-inducive capacity, including CD133 + DPCs and Versican + DPCs. CD133 + DPCs have been shown to be a specific subpopulation of cells in DPCs, and they can produce Wnt ligands and mediate signalling crosstalk between the mesenchyme and the epithelial compartment, further promoting adult HF growth and regeneration. 21 In addition, Versican + DPCs exhibit the typical characteristics of aggregation growth, 22 on which HF formation is highly dependent. 23 In addition, many functional molecules are involved in the positive regulation of DPC HF-inducive capacity (Fig. 4 ), such as endothelin-1 and stem cell growth factor , 24 insulin-like growth factor-1 (IGF-1) 25 and histidine decarboxylase , 26 but matricellular protein connective tissue growth factor (CCN2) negatively regulates HF regeneration, physiologically curbing HF formation by the destabilization of β-catenin . 27 In wound healing, hedgehog gene activation could shift the dermal fibroblast fate towards DPCs and result in extensive HF neogenesis. 28 Hoxc genes are able to reprogramme DPCs, and a single Hoxc gene is sufficient to activate dormant DP niches and promote regional HF regeneration through canonical Wnt signalling. 29 Monoterpenoid loliolide regulates the HF inductivity of human DPCs by activating the AKT/β-catenin signalling pathway. 30 Although DPCs possess the potential to regenerate HFs, freshly isolated human DPCs are not efficient in regenerating new HFs when they are directly transplanted. 31 To restore their intrinsic properties, three-dimensional (3D) spheres offer a more physiologically relevant system where cell–cell communication as well as microenvironments have been studied. It has been reported that sphere formation increases the ability of cultured human DPCs to induce HF from mouse epidermal cells, 32 in which glucose metabolism 33 and epigenetics 34 may be important regulators. The natural vitamin E form tocotrienol acts upstream of DP formation to induce HF anagen, dependent on the loss of E-cadherin and activation of β-catenin. 35 Pretreatment with 1α,25-dihydroxyvitamin D3 (VitD3) could significantly improve DPC functionality and hair folliculogenesis, which is mediated by the activation of Wnt10b, alkaline phosphatase (ALP) and transforming growth factor β2 (TGF-β2). 36 Consistent with VitD3, platelet-rich plasma has been shown to function in HF regeneration by enhancing DPC proliferation, 37 which may result from the downregulation of MYC, CCAAT/enhancer-binding protein beta and E2F transcription factor-1 gene. 38 Icariin promotes mouse HF growth by increasing IGF-1 secreted by DPCs. 39 Utilization keratinocyte-conditioned medium, 40 coculture with keratinocytes 40 , 41 or the addition of BMP6 42 and basic fibroblast growth factor (FGF) 43 to DPC expansion cultures could preserve their HF-inducive capacity. JAK inhibitor regulates the activation of key HF populations, such as the hair germ, and improves the inductive potential of DPCs by controlling a molecular signature enriched in intact, fully inducive DPs. 44

The regulatory factors of DPC HF-inducive capacity. Glucose metabolism and LncRNA-XIST/miR-424 axis in the regulation of HF-inducive potential of DP spheres

Skin-derived precursors

DSCs are stem cells located in the dermis of the skin. Based on distinct phenotypic properties and different cultural environments, DSCs can be divided into dermal fibroblasts and SKPs. 7 , 45 For instance, DPCs are differentiated dermal cells originating from blimp1 + dermal fibroblasts, 7 while SKPs are derived from Sox2 + follicle-associated dermal precursors. 46 SKPs are defined as DSCs that reside in the adult HF mesenchyme and can be isolated and expanded in vitro as self-renewing colonies. SKPs have the capacity to differentiate in vitro and in vivo into multiple lineages of different progeny. 47 Of note is that SKPs could regenerate the dermal sheath and repopulate DPCs in each growth cycle 48 to serially reconstitute HF when subcutaneously engrafted. 46 There are also various molecules affecting the inductive potential of SKPs. Trichostatin A, a potent and specific inhibitor of a histone deacetylase, could restore the HF-inducive capacity of SKPs by markedly alleviating culture expansion-induced SKP senescence, increasing the expression and activity of ALP and elevating the acetylation level of histone H3. 49 Platelet-derived growth factor (PDGF) could enhance SKP proliferation, increase SKP progeny and improve their HF-inducive capacity, but PDGF deficiency results in a progressive depletion of the stem cell pool and their progeny. 50 Many tentative methods to isolate and cultivate SKPs have also been explored, 51 , 52 particularly in computer-controlled stirred suspension bioreactors, which lead to a greater expansion of viable SKPs. 53 This technique allows a large number of SKPs that share a similar expression profile to that in static culture (fivefold greater than in static culture), and both static and bioreactor condition-derived SKPs are able to induce de novo HFs and repopulate their cellular niches. 53

Epidermis-derived cells

HFSCs are heterogeneous Epi-SCs compartmentalized along the longitudinal axis of HFs. They are divided into quiescent and primed HFSCs. For instance, relatively quiescent HFSCs in the follicular bulge region can serve as a reservoir for transient amplifying cells that are able to produce various cell types during HF regeneration. 54 Primed HFSCs have faster activation dynamics in the secondary hair germ of telogen HF. 55 The activation of primed HFSCs could trigger the subsequent activation of quiescent HFSCs, and the coordination of these two populations could fuel HF regeneration from telogen to anagen. 56 , 57 HFSCs express a panel of transcription factors, including Sox9, Tcf3, Lhx2 and Nfatc1. 57 , 58 , 59 HFSCs derived from a single rat vibrissa via organ culture could reconstitute HFs in vivo, 60 and even aged HFSCs still have the potential to regenerate HFs. 61 HFSCs could also differentiate into epidermal and sebaceous gland lineages, participating in the process of skin wound healing, and thus were considered ideal candidates for cutaneous repair and regeneration. Recent studies have reported that basal keratinocytes also have the capacity to facilitate HF regeneration under induction. Transgenic expression of the hairless gene ( HR ) in progenitor keratinocytes could rescue HF regeneration in Hr(−/−) mice, in which the new HFs resemble wild-type follicles and express markers of early anagen. 62 This process may be linked to the regulation of the precise timing of WNT signalling to HR. 62 , 63 Tuberous sclerosis complex 2 (TSC2)-null fibroblast-like cells grown from human TSC skin hamartomas could also induce neonatal foreskin keratinocytes to form HFs, complete with sebaceous glands, hair shafts, inner and outer root sheath (ORS) cells and the anagen-specific expression of versican, in which the TSC1/TSC2/mTORC1 pathway may play a significant role. 64

Reprogrammed cells

The differentiation of stem cells into adult cells in response to defined factors is an important application of cell reprogramming. Induced pluripotent stem cells (iPSCs) have similar characteristics to embryonic stem cells in terms of morphology, self-renewal and differentiation capacity. They are not only free from ethical issues but also able to be propagated as autologous cells, which can avoid the complication of immune rejection. Thus, reprogramming of iPSCs into potential cells could be an approach to providing cell sources for HF regeneration. Under retinoic acid (RA), an iPSC-derived LNGFR + Thy1 + subpopulation with high proliferation could be induced into DPCs in the DP medium. 65 The mixture of iPSC ectodermal precursor cells in keratinocyte culture medium with RA and bone morphogenetic protein (BMP) could also transform into new DPCs. 66 Intriguingly, iPSCs could also be generated from human DPCs upon lentiviral transfection with Oct4, Sox2, Klf4 and c-Myc. 67 In addition, iPSCs, post-culture on Matrigel, could differentiate into keratinocytes when treated with keratinocyte serum-free media supplemented with all- trans RA and BMP4. 68 Human hair follicular keratinocytes could also be reprogrammed into iPSCs, and keratinocyte-derived iPSCs are further capable of differentiating into keratinocytes, 69 which suggests a novel way to provide a source of keratinocytes. Lineage reprogramming is direct cellular reprogramming, which means that targeted cells could bypass the stem cell stage and convert directly to potential cells. Unlike traditional concepts regarding the epigenetic stability of differentiated cells, direct lineage reprogramming can transform one specialized cell type into another using defined factors, which is a more efficient and promising approach for producing functional cells. Treatment with the combination of FGF2, PDGF and 6-bromoindirubin-3′-oxime (BIO) could chemically transform human dermal fibroblasts into DPCs. 70 SKPs can be produced from healthy adult fibroblasts via lineage reprogramming, and their cryopreservation can largely preserve their properties and produce more significant yields. 71 Another way to rapidly expand SKPs via lineage reprogramming is to expose pre-established dermal fibroblasts to 30-min acid stress prior to isolating SKPs. 72 Acute acidic stress treatment of dermal fibroblast cultures greatly improves SKP isolation, growth, yield and multipotency.

With progress in HF developmental biology and cellular reprogramming techniques, several cells with the potential for HF regeneration have been identified. These results have greatly expanded the seed cell bank for HF regeneration and solved the problem of the lack of a cell source. However, the problems these cell sources have in common are that their potential to regenerate HF fails to be maintained during long-term culture in vitro. In addition, HFSCs are few in number and extremely difficult to obtain, and SKPs in vitro senesce soon when isolated from their physiological environments. 73 In addition, the efficiency of reprogramming by gene editing is still low. The optimization of the culture system in vitro and the improvement of reprogramming efficiency are challenges for HF regeneration. Therefore, we believe that the construction of 3D culture systems that simulate the in vivo environment may provide an alternative approach, similar to hydrogel scaffold-based cell culture, which contributes to maintaining cell proliferation and growth as well as the potential to regenerate HFs. In addition, chemical reprogramming, a new reprogramming technology, is characterized by high security and efficiency. 74 To improve the reprogramming efficiency, the replacement of chemical reprogramming with gene editing has broad prospects in HF regeneration.

Mechanisms for the restoration of HF-inducive capacity

After birth, mature and actively growing HFs eventually become anchored in the subcutis and then undergo hair cycling, periodically and spontaneously undergoing repetitive cycles of growth (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Therefore, the HF is regarded as a dynamic mini-organ. The activation and maintenance of hair cycling is a prerequisite for the functional regeneration of HFs. HFSCs play an indispensable role in maintaining hair cycling. The HFSC population remains largely quiescent during hair growth, but a subpopulation actively proliferates and promotes the production of the new hair shaft under the control of Axin2 expression. 75 At the onset of anagen following stimulation by growth-inducing signals from the DP, primed HFSCs also contribute to new hair shaft production. 76 Under induction by such signalling, primed HFSCs undergo rapid proliferation to fuel the initial stage of hair growth, and then, the quiescent HFSCs undergo a second round of activation that replenishes cells lost at the onset of anagen, finally supporting prolonged growth of the hair shaft. 56 At the beginning of anagen, activated HFSCs migrate from the bulge to the matrix area and become transit-amplifying cells that proliferate and differentiate to form the new hair shaft. 77 Therefore, the coordinated activation of primed HFSCs and quiescent HFSCs is instrumental for the maintenance of hair cycling. The mechanism underlying HFSC homeostasis and hair cycling regulation is a complex molecular controlling process (Table 1 ) that is highly dependent on hormonal action. 78 WNT/β-catenin and BMP signalling are considered to be the core pathways in the regulation of hair cycling. 79

The dynamic characteristics of HFs enable their sustainable and periodic regeneration. We think that the activation and maintenance of hair cycling are indispensable for achieving functional HF regeneration. Past studies have not only led to a better understanding of the molecular mechanisms of hair cycling, which makes it more possible to find the key molecules therein, but also have revealed the complexity of HF dynamic characteristics. Therefore, it is still difficult to discover the key molecular event in hair cycling.

In vivo strategies for functional regeneration of HFs

Cell transplantation and hf regeneration.

Cell-based transplantation without biomaterials is a minimally invasive approach to in vivo HF regeneration. Current cell transplantation mainly involves the transplantation of stem cells or a mixture of epidermal and dermal components. The injection of a mixture containing Epi-SCs and DPCs into nude mice could induce new HFs with the correct histological structures and form a multilayered stratified epidermis containing HF-like structures. 20 Although the new HFs are relatively small, this result proves again that the rearrangement of the EMI and the niches of the potential cells are essential and necessary for HF construction. A mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, and a bilayer structure resembling the epidermis and the dermis formed on the fifth day, followed by de novo HF. 80 In the regeneration process, the SKPs formed DPCs in neogenic HFs and abundant dermal cells in the dermis, and the Epi-SCs formed the epidermis and trunk of the HF. More importantly, this experiment also demonstrates that the PI3K-Akt signalling pathway plays a crucial role in the interactions between Epi-SCs and SKPs and de novo HF regeneration, which may suggest potential therapeutic applications in enhancing hair regeneration. 80 During the hair growth cycle, HFSCs periodically switch between the active and inactive stages to maintain stem cell populations and generate new HFs, while this potential is impaired in aged HFSCs. 81 However, in transplantation assays in vivo, aged HFSCs could still regenerate HFs when supported with the young dermis, while young HFSCs failed to regenerate HFs when combined with the aged dermis, which shows that the ageing skin microenvironment dictates stem cell behaviour and illustrates the dominant role of the niche microenvironment. 61 This research discovered that the HF regeneration potential of aged HFSCs can be rejuvenated by neonatal dermis during in vivo transplantation, providing promising new avenues for regenerative and geriatric medicine. In recent years, for the fully functional regeneration of ectodermal organs, a bioengineered organ germ has been developed by reproducing the embryonic processes of organogenesis, including bioengineered HFs. 82 Bioengineered HF germ could be reconstituted with embryonic skin-derived epithelial and mesenchymal cells and was able to develop histologically correct HFs when ectopically transplanted. The bioengineered HFs not only properly connected to the host skin epithelium by intracutaneous transplantation and reproduced the stem cell niche and hair cycling but also autonomously connected with nerves and the arrector pili muscle at the permanent region and exhibited piloerection ability. 83 Another way to construct bioengineered HF is with pelage and vibrissae reconstituted with embryonic skin-derived cells and adult vibrissa stem cells. After intracutaneous transplantation, this bioengineered HF germ not only develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres but also shows restored hair cycling and piloerection through the rearrangement of follicular stem cells and their niches, with fully functional hair organ regeneration. 84 It is worth mentioning that the in vivo transplantation of bioengineered HFs also achieves the partial restoration of hair cycling, which is a great step forward for functional HF regeneration.

Cellular reprogramming and HF regeneration

Cellular reprogramming is not only a tool for tissue engineering to enrich potential cell sources for the regeneration of HF but also a participant in physiological de novo HF induction. Secreted proteins (apolipoprotein-A1, galectin-1 and lumican) from embryonic skin conferred upon non-hair fibroblasts the competency to regenerate HF via the activation of IGF and WNT signalling, thereby endowing non-HF skin with the ability to reproduce HFs, which suggests the involvement of cellular reprogramming. 85 Because DPCs and dermal fibroblasts originate from common fibroblast progenitors in the developing embryonic mouse skin and have highly correlated gene expression profiles (96%), 86 adult dermal fibroblasts can be reprogrammed into a neonatal state, with the capacity of inducing ectopic HF formation similar to DPCs through the epidermal activation of β-catenin. 87 Furthermore, treatment with the combination of FGF2, PDGF and BIO in adherent culture followed by suspension culture could induce the generation of DP-like cells from foetus- or adult foreskin-derived fibroblasts. The integration of foetal/adult DP-like cells can be recruited to replenish DP of de novo generated HFs, and the regenerated HF structures were reconstructed in 65% nude mice implanted with foetal DP-like cells and in 70% nude mice with adult DP-like cells. 70 Finally, the combination of MITF, SOX10 and PAX3 could directly convert mouse and human fibroblasts into induced melanocytes, which have the ability to generate pigmented epidermis and HF in vivo when properly integrated into the dermal–epidermal junction. 88 Healed wounds with the loss of HF are usually filled with a large number of fibroblasts, so the exploration of fibroblast-based reprogramming holds great promise for HF regeneration in situ.

Cell-laden biomaterials for the establishment of HF equivalents

Biomaterials are implantable, inactive materials that can replace or repair damaged tissue with high biocompatibility. Biomaterials can create a 3D environment for cell-to-cell interactions, simulating the function of cell niches to a certain extent, and they have been widely used in wound repair and tissue regeneration. 89 The combination of potential cells with biomaterials, such as hydrogels, scaffolds and other self-assembled materials, could contribute to HF regeneration (Figs. 1c and 2 ). For in vivo HF regeneration, a 3D hydrogel with a mixture of epidermal keratinocytes, dermal cells and β-catenin-expressing CD133 + DPCs not only performed better than CD133 + DPCs alone (average of 28 ± 6 HF per field vs. 13 ± 6 HF per field) but also exhibited a more advanced hair cycling stage; 90 an average of 71% of the HFs reached anagen stage III, and 19% reached anagen stage IV in reconstituted skin containing β-catenin-expressing CD133 + DPCs, while 67.5% of the HFs in the control remained in anagen I and II, and only 27.5% reached anagen III. 90 The stable expression of β-catenin could promote the clonal growth of CD133 + DPCs in vitro in 3D hydrogel culture. An alternative strategy to reproduce EMI is to use a collagen-chitosan scaffold (CCS)-based 3D system containing dissociated epithelial cells and DPCs followed by treatment of the CCS with Wnt-CM from Wnt1a + bone marrow mesenchymal stem cells. The results suggested that the cell mixture was able to induce hair regeneration in nude mice, and Wnt-CM can maintain the hair induction ability of DPCs in expansion cultures, which may be associated with the activation of the Wnt/β-catenin signalling pathway. 91 Therefore, how to enhance the HF induction efficiency of cultured human DPCs is a priority in bioengineering for clinical HF regeneration. It has been reported that DPCs retain HF inductivity best when cultured and transplanted as multicellular aggregates, and DP spheroids could form a structure similar to the natural intercellular organization in vivo. 92 Therefore, another strategy is to achieve the scalable fabrication of controllable DP spheroids to regenerate HFs. Scalable production of controllable DP spheroids on polyvinyl alcohol surfaces has high viability and preserves DP characteristics, and at DPC numbers of 5 × 10 3 to 30 × 10 3 cells each, both human and rat DP spheroids are able to induce HF neogenesis. Larger DP spheroids exhibit higher HF inductivity. The researchers developed a method that can be automated for mass production of DP spheroids with controllable size and cell number in a wide range, 93 although the average diameter of regenerated hair fibre did not significantly change with increasing size of the transplanted DP spheroids. Likewise, the hanging-drop approach could also lead to a controllable 3D spheroid model for the scalable fabrication of inductive DP microtissues. That technique is based on surface tension and the interaction between surface tension and a gravity field that causes the convergence of liquid drops. With the converged drops, DP spheroids could endow high-passaged DP microtissues with many similarities to primary DP. Subcutaneous implantation of these microtissues mixed with new-born mouse epidermal cells has achieved reproducible HF induction in the hypodermis of nude mice, and a large amount of extracellular matrix (ECM) components is found in the intercellular space within the DP microtissue, similar to an anagen DP. 94 These models provide the potential to elucidate the native biology of human DP and show promise for the controllable and scalable production of inducive DPCs for future follicle regeneration. Exosomes derived from DP spheroids (3D DP-Exos) are also able to promote the proliferation of DPCs and ORS cells and accelerate anagen onset to influence hair cycling. Local injections of 3D DP-Exos (exosomes) could induce anagen from telogen and prolong anagen in mice. Moreover, DPC spheres treated with Exos could augment HF neogenesis when implanted with mouse epidermal cells, 95 which may be associated with high levels of miR-218-5p in Exos. 96 Cell surface engineering technology also advances HF regeneration by accurate micro/nanoscale control in cell-biomaterial ensembles and DP spheroid formation. Owing to the security and tuneable thickness at the nanoscale, the nanogel could encapsulate a single cell by layer-by-layer (LbL) self-assembly and further form DPC spheroids by physical cross-linking on nanogel-coated cells. LbL-DPC aggregation is akin to that of primary DPCs and has the capacity to restore HF induction potential in vitro and regenerate HFs in vivo. 97 Other biomaterials that contribute to the restoration of HF-inducive ability include human placenta ECM hydrogel, 98 synthesized ECM 99 and a chitosan/polyvinyl alcohol nanofibre sponge with an open-cell cellular structure, 100 which expands the biomaterial libraries for the optimization of the culture environment in vitro to restore the ability of DPCs to regenerate HFs. 3D printing technology for HF regeneration by recapitulating the physiological 3D organization of cells in the HF microenvironment is an innovative biomimetic approach. 101 It permits the controllable self-aggregating spheroid formation of DPCs in a physiologically relevant ECM, the initiation of EMI and further HF formation in human skin constructs. Remarkably, the vascularization of HF-bearing human skin constructs increases graft survival and enables efficient human hair growth in mice. 101 This method represents a novel bioengineering strategy for the feasible generation of hair-bearing human skin constructs entirely ex vivo from cultured human cells, and adaptation of this new technology by hair researchers, hair restoration surgeons and the pharmaceutical industries will have overwhelming implications in the maintenance and regeneration of HFs.

Similar to DPCs, long-term culture could also impair the HF-inducive capacity of SKPs. It is likely that SKPs rely on special environments for their self-renewal and stable gene expression. In tissue engineering, scaffolds are created to mimic environments for stem cells to survive, differentiate and form functional tissue structures. In this regard, scaffolds such as hydrogels and matrix could be candidates to support stem cells for organogenesis and regenerate HFs. 102 , 103 Self-assembling peptide nanofibres are made of natural amino acids and form hydrogels that surround cells in a manner similar to the ECM. RADA16 (Ac-(RADA)4-CONH2) is a representative example of such peptides that has been shown to promote nerve regeneration and wound healing. 104 , 105 A PRG (PRGDSGYRGDS) solution functionalized by mixing with RADA16 promoted the proliferation and migration of periodontal ligament fibroblasts. 106 The self-assembling peptide hydrogels formed by RADA16 and PRG (RADA-PRG) could facilitate the attachment, proliferation and survival of SKPs, ultimately supporting HF neogenesis in vivo. The transplantation of a combination of culture-expanded SKPs and neonatal epidermal cells into RADA-PRG hydrogel resulted in a significantly increased number of neogenic hairs compared to Matrigel and other peptide hydrogels. This may be attributed to the similarity of the properties of these designer peptide nanofibres to those of ECM molecules. 102 In addition, a mixture of culture-expanded Epi-SC and SKPs derived from the adult human scalp in a hydrogel was capable of reconstituting functional HFs, and the mechanisms of the expression of ALP in SKPs in vitro and the maintenance of HF-inducive properties in vivo may be associated with BMP4. 103 More importantly, Epi-SC implanted in wounds in combination with SKPs could also form functional sebaceous glands in association with HFs. Normal human neonatal foreskin keratinocytes were induced to differentiate into several cellular components that compose normal HFs, with the expression of anagen-specific versican when grown on a collagen matrix embedded with TSC2-null fibroblast-like cells or with fibroblasts. 64 Regenerated HFs were complete with sebaceous glands, hair shafts and inner and ORSs. 64

Drug delivery systems for HF construction

Drug delivery systems consist of molecules with pharmacological activity modified into advanced materials, which have been widely used in skin wound treatment. Currently, it has been reported that many drug delivery systems could promote wound healing as well as HF regeneration. Newly developed multidomain peptide hydrogels have exhibited regenerative potential in a diabetic wound healing model, resulting in wound closure, accelerated HF regeneration and a greater average number of HFs at both the edge and the centre. 107 Multifunctional Zn-doped hollow mesoporous silica/polycaprolactone electrospun membranes exhibit excellent antibacterial activity for wound healing and are ~20 times as likely to regenerate HFs as the control. 108 Most excitingly, the treatment of deep second-degree scalding injuries with human erythropoietin (EPO) to, whether by the local subcutaneous injection of nanosized rhEPO (recombinant human EPO)/infusion pumping or the topical application of rhEPO gel, achieved excellent skin repair with conical and HF structures, which was related to the combined expression of EPO receptor and β-subunit receptor. 109 , 110 A novel fibrous membrane (P/Qu/Cup, P: PCL, Qu: Quercetin, Cup: cuprorivaite, CaCuSi 4 O 10 ) containing quercetin-copper (Qu-Cu) chelates was fabricated by using quercetin and highly bioactive bioceramic (CaCuSi 4 O 10 ) incorporated in PCL/gelatine electrospun fibres. The fibrous membrane can effectively release Qu and Cu ions to induce the proliferation, migration and differentiation of skin- and HF-related cells, and the Qu, Cu ions and Si ions released from the composite membrane revealed synergistic activity to stimulate HF regeneration and wound healing in burned skin. 111 However, drug delivery systems mainly contribute to wound repair, accompanied by the acceleration of wound-induced HF neogenesis (WIHN). WIHN is a regenerative phenomenon separate from physiological regeneration, as its cellular origin is not from the HFSCs in the bulge at the wound edge. In WIHN, a fully functional follicle can regenerate in the centre of a full-thickness wound with a large enough size, and the cellular origin of this process is similar to an embryonic process. The neogenic follicles have similar functions to embryonic HFs, which also have a growth cycle. 63 Currently, there are few studies about drug delivery systems for HF regeneration alone outside the wound environment. However, because of their controllability, targeted delivery, sustained release and even intellectuality, we think drug delivery systems hold great promise for HF regeneration in the future.

Organoid technology and HF replacement

An organoid is defined as a 3D structure grown from organ-specific stem cell types. It can recapitulate key aspects of in vivo organs and avoid many of the disadvantages associated with cell lines. 112 HF organoids can be established from skin stem cells or a mixture of dermal and epidermal components. DP spheroids encapsulated by silk-gelatine hydrogel and HF keratinocytes as well as stem cells could be used to construct in vitro HF organoids. These organoids show enhanced DPC-specific gene expression and ECM production, and their structural features and cell–cell interactions are similar to those of in vivo HFs. 113 This simple in vitro DP organoid model system has the potential to provide significant insights into the underlying mechanisms of HF morphogenesis and distinct molecular signals relevant to different stages of the hair cycle and hence can be used for the controlled evaluation of the efficacy of new drug molecules to induce HF regeneration. To date, in vitro skin derivation strategies have focused on first generating keratinocytes and fibroblasts from iPSCs in separate cultures and then combining the two types of cells to form a skin-like bilayer. A major challenge is how to realize the synchronous construction of its appendages. Under initial treatment with the TGF-β inhibitor SB431542 (SB) and recombinant BMP4 and subsequent treatment with FGF2 (FGF) and a BMP inhibitor LDN-193189 (LDN), a homogeneous population of mouse pluripotent stem cells and constituting epidermal and dermal layers in a 3D culture formed skin organoids with a cyst conformation, in which HFs were spontaneously produced de novo. However, the new HFs entered catagen and degenerated during long-term culture. 114 These results suggest how skin organoid structures can be generated de novo without the use of embryonic tissue or undefined media, which will be useful for studying the minimal cellular and microenvironment requirements for HF induction. Scalp-derived dermal progenitor cells mixed with foreskin-derived Epi-SCs at a 2:1 ratio could aggregate in suspension to form a large number of HF organoids, and the dermal and epidermal cells self-assembled into distinct epidermal and dermal compartments. The addition of recombinant WNT3a protein to the medium enhanced the formation of these aggregates, and the transplantation of these organoids in vivo achieved HF formation. 115 Finally, a 3D integumentary organ system (IOS) obtained by the self-assembly of mesenchymal and Epi-SCs from iPSCs using the clustering-dependent embryoid body transplantation method also regenerated fully functional HF organoids. 116 After transplantation into nude mice, the HF organoid in that system could form proper connections to the surrounding host tissues, such as the epidermis, arrector pili muscles and nerve fibres, without tumorigenesis, and show appropriate hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches. 116 These findings reveal the generation of a bioengineered 3D IOS from iPSCs, including appendage organs such as HFs and sebaceous glands, with appropriate connections to surrounding tissues, which significantly advances the technological development of the bioengineered 3D IOS and its potential applications, including an in vitro assay system, an animal model alternative and bioengineered organ replacement therapy.

The transition from traditional culture to 3D culture constitutes excellent progress in HF regeneration. 3D culture enhances the proliferation and HF regeneration ability of potential cells, and a mixture of epidermal (Epi-SC) and dermal (SKP and DPCs) components in a 3D system simulates the characteristics of EMI, especially organoid technology and 3D printing technology. In 3D culture, regenerated HFs in vivo not only connect appropriately to surrounding host tissues but also undergo hair cycling activation. However, some problems are less thoroughly addressed. How long can the regenerated HFs last? Can the regenerated HFs go through full hair cycling? Will HF regeneration-induced hair be superior to transplanted hair? We think these are key questions and important challenges in functional HF regeneration.

Achievements, limitations and future perspectives

Much progress has been made in the developmental biology and regeneration of HFs. (1) A variety of cells with the potential to regenerate HFs have been identified, including DPCs, SKPs, HFSCs, keratinocytes and reprogrammed cells (iPSCs and fibroblasts), which provide a wide range of cell sources for HF regeneration. (2) We have gained a more comprehensive and in-depth understanding of the hair cycling-related mechanism, which provides the biological basis for finding key molecules to initiate and sustain the hair cycle. (3) Optimization of the in vitro culture system and the construction of a 3D culture environment could overcome the loss of the ability of potential cells to proliferate, self-renew and regenerate HFs caused by 2D culture. (4) The transplantation of a mixture of epidermal and dermal components, such as cell-based transplantation with or without biomaterials and HF organoids, could simulate EMI to a certain extent and successfully induce new HFs with the correct structure in vivo. (5) The HF organoid is a model for the exploration of mechanisms of HF morphogenesis and drug research to reproduce hair. (6) Drug delivery systems are characterized by strong controllability and high security, and they can promote wound healing accompanied by HF regeneration.

Since it is an architecturally and functionally complex organ, the HF is much more difficult to regenerate or reconstruct than many other organs. Due to this limitation, HF regeneration is still far from clinical transformation. (1) The sources of potential cells are still poor, largely because of cell ageing in vitro culture and inefficient reprogramming, so there is still a need to optimize the in vitro culture system. (2) The mechanism of hair cycling is very complex, and it is extremely difficult to identify the key molecules. (3) Current strategies simulating EMI are still insufficient. Both cell transplantation and organoid architecture lack the microenvironment of connective tissue, blood vessels and immune cells, which is still quite different from the physiological environment of normal tissues and organs. (4) It is unknown how many new HFs can be regenerated from biomaterials and tissue engineering. Do they allow other essential cells to be recruited to the new follicle? If so, do the attracted cells have the ability to affect organogenesis overall? 5) The cellular reprogramming techniques that contribute to HF regeneration still have low efficiency in vitro. (6) The 3D regeneration of HFs depends on biomaterials that need better external security, controllability and internal stability. Ideal biomaterials need to be safe and nontoxic. Under normal metabolism in the body, they can be kept in a stable state without biological degeneration, and the metabolism or degradation products are harmless and easily metabolized. (7) Whether the regenerated HFs function normally and how long they can last in vivo are less mentioned in past studies.

In summary, at the current stage, various attempts are only imitating a partial structure and/or function regeneration of HFs. The combination of different technologies and methodologies will hopefully lead to new progress. For example, the creation of transplantable HFs that closely mimic the structures and functions of native tissue may be accomplished by combining organoid technology with a drug delivery system. Depending on the controllable release of the relevant factors in hair cycling, such as WNT or BMP, hair cycling activation and maintenance of HF organs may be achieved. We also need to continue to optimize the in vitro culture systems of potential cells and look for more efficient reprogramming techniques, such as chemical reprogramming induced by small molecules or genetic reprogramming of genes delivered by biomaterials. Finally, we want to reiterate that, based on existing work, it is worth considering whether the achievement of the activation and maintenance of hair cycling in regenerated HFs could be the heart of the next phase.

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This work was supported, in part, by National Key Research and Development Plan (2018YFC1105704, 2017YFC1103304, 2016YFA0101000, 2016YFA0101002), the National Nature Science Foundation of China (81871569, 81830064, 81721092), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-059) and the Military Medical Research and Development Projects (AWS17J005, 2019-126).

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Shuaifei Ji, Ziying Zhu, Xiaoyan Sun & Xiaobing Fu

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S.J. conceived and drafted the manuscript. S.J. and X.S. discussed the concepts of the manuscript. S.J. and Z.Z. drew the figures and summarized the tables. X.S. and X.F. approved the version to be submitted.

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Ji, S., Zhu, Z., Sun, X. et al. Functional hair follicle regeneration: an updated review. Sig Transduct Target Ther 6 , 66 (2021). https://doi.org/10.1038/s41392-020-00441-y

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UC Irvine-led researchers reveal new molecular mechanism for stimulating hair growth

Findings may offer road map for next generation of therapies for androgenetic alopecia

Irvine, Calif., June 21, 2023 — The process by which aged, or senescent, pigment-making cells in the skin cause significant growth of hair inside skin moles, called nevi, has been identified by a research team led by the University of California, Irvine. The discovery may offer a road map for an entirely new generation of molecular therapies for androgenetic alopecia, a common form of hair loss in both women and men.

The study, published today in the journal Nature , describes the essential role that the osteopontin and CD44 molecules play in activating hair growth inside hairy skin nevi. These skin nevi accumulate particularly large numbers of senescent pigment cells and yet display very robust hair growth.

“We found that senescent pigment cells produce large quantities of a specific signaling molecule called osteopontin, which causes normally dormant and diminutive hair follicles to activate their stem cells for robust growth of long and thick hairs,” said lead corresponding author Maksim Plikus, UCI professor of developmental and cell biology. “Senescent cells are typically viewed as detrimental to regeneration and are thought to drive the aging process as they accumulate in tissues throughout the body, but our research clearly shows that cellular senescence has a positive side to it.”

The growth of hair follicles is well regulated by stem cell activation; these cells divide, enabling follicles to produce new hair in a cyclical manner. After each bout of hair growth, there’s a period of dormancy, during which the follicle’s stem cells remain inactive until the next cycle begins.

The study involved mouse models with pigmented skin spots that had hyperactivated hair stem cells and displayed accelerated hair growth, strongly resembling the clinical observations documented in human hairy skin nevi. Further detailed analysis of senescent pigment cells and the nearby hair stem cells revealed that the former produced high levels of a signaling molecule called osteopontin, for which hair stem cells had a matching receptor molecule called CD44. Upon molecular interaction between osteopontin and CD44, hair stem cells became activated, resulting in robust hair growth.

To confirm the leading role of osteopontin and CD44 in the process, mouse models lacking either one of these genes were studied; they exhibited significantly slower hair growth. The effect of osteopontin on hair growth has also been confirmed via hairy skin nevi samples collected from humans.

“Our findings provide qualitatively new insights into the relationship between senescent cells and tissue’s own stem cells and reveal positive effects of senescent cells on hair follicle stem cells,” said first and co-corresponding author Xiaojie Wang, UCI associate specialist in developmental and cell biology. “As we learn more, that information can potentially be harnessed to develop new therapies that target properties of senescent cells and treat a wide range of regenerative disorders, including common hair loss.”

The team included healthcare professionals and academics from the U.S., China, France, Germany, Korea, Japan and Taiwan.

“In addition to osteopontin and CD44, we’re looking deeper into other molecules present in hairy skin nevi and their ability to induce hair growth. It’s likely that our continued research will identify additional potent activators,” Plikus said.

This work was supported in part by LEO Foundation grants LF-AW-RAM-19-400008 and LF-OC-20-000611; Chan Zuckerberg Initiative grant AN-0000000062; W.M. Keck Foundation grant WMKF-5634988; National Science Foundation grants DMS1951144 and DMS1763272; and National Institutes of Health grants U01-AR073159, R01-AR079470, R01-AR079150, R21-AR078939 and P30-AR075047. Additional backing came from Simons Foundation grant 594598 and California Institute for Regenerative Medicine Shared Research Laboratory Grant CL1-00520-1.2.

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About the University of California, Irvine:  Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by  U.S. News & World Report . The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit  www.uci.edu .

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Diseases & conditions

Everyday care, darker skin tones, cosmetic treatments, public health programs, find a dermatologist.

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Both the CDC and the FDA warn against treating this common childhood condition on your own with non-prescription treatments. See what they recommend.

Find answers to questions patients ask about this newer treatment option, including, “What’s involved in switching from a biologic to a biosimilar?”

Everyone's at risk for skin cancer. These dermatologists' tips tell you how to protect your skin.

Find out what may be causing the itch and what can bring relief.

Find out why dark spots appear and what can fade them.

If you have what feels like razor bumps or acne on the back of your neck or scalp, you may have acne keloidalis nuchae. Find out what can help.

You can expect permanent results in all but one area. Do you know which one?

If you want to diminish a noticeable scar, know these 10 things before having laser treatment.

It can smooth out deep wrinkles and lines, but the results aren’t permanent. Here’s how long botox tends to last.

Use these professionally produced online infographics, posters, and videos to help others find and prevent skin cancer.

Free to everyone, these materials teach young people about common skin conditions, which can prevent misunderstanding and bullying.

You can search by location, condition, and procedure to find the dermatologist that’s right for you.

A dermatologist is a medical doctor who specializes in treating the skin, hair, and nails. Dermatologists care for people of all ages.

Hair loss: Diagnosis and treatment

Dermatologists have expertise in diagnosing hair loss and counseling their patients on what may help them regrow their hair.

This dermatologist is using a dermatoscope to examine a patient’s scalp.

Effective treatment for hair loss begins with finding the cause. To get an accurate diagnosis, it helps to see a board-certified dermatologist. These doctors have in-depth knowledge about the many causes of hair loss and experience treating the diverse causes.

How do dermatologists find out what’s causing hair loss?

To pinpoint the cause of your hair loss, a dermatologist begins by gathering information. Your dermatologist will:

Ask questions . It’s important to know how long you’ve had hair loss and whether it came on quickly.

Look closely at your scalp, nails, any other area with hair loss . This exam provides vital clues about what’s happening.

Test the health of your hair . Gently pulling on your hair tells your dermatologist a lot about how your hair is growing and whether it’s prone to breaking.

If your dermatologist suspects that the cause of your hair loss could be a disease, vitamin deficiency, hormone imbalance, or infection, you may need a blood test or scalp biopsy. These tests can be done in your dermatologist’s office.

Once your dermatologist has this information, it’s often possible to tell you what’s causing your hair loss.

Sometimes, your dermatologist needs more information. This might be the case if someone has more than one cause. For example, a woman may have had a baby a few months ago, and this may be causing obvious hair shedding. She may also have early hereditary loss, which isn’t so obvious.

No one hair loss treatment works for everyone

Once your dermatologist finds the cause(s), your dermatologist will tell you whether treatment is recommended. Sometimes, your hair will regrow on its own, making treatment unnecessary.

When hair may regrow on its own

Yes, your hair may regrow on its own. This can happen if you recently:

Recovered from a major illness or had surgery

Underwent cancer treatment

Lost 20 pounds or more

Developed a mild case of a disease called alopecia areata , which causes your immune system to attack your hair follicles

Got rid of psoriasis on your scalp

Your dermatologist can tell you whether your hair may start to grow again on its own.

Sometimes to see regrowth, you need to make some changes.

Changing your hair care (or hairstyle) may help

Some hairstyles and hair care habits can damage hair, leading to hair loss. If your dermatologist finds that this may be causing your hair loss, your dermatologist can recommend changes that will help you stop damaging your hair.

You’ll find tips that dermatologists give their patients at:

African American hair: Tips for everyday care

Hairstyles that pull can lead to hair loss

How to stop damaging your hair

When do dermatologists recommend treatment for hair loss?

While your hair may regrow on its own, your dermatologist may recommend treatment to help it grow more quickly. Sometimes, treatment is essential to prevent further hair loss.

A treatment plan for hair loss may include one or more of the following.

At-home treatments for hair loss

At-home treatments offer convenience, and you can buy many of them without a prescription. Because studies show that the following can help, your dermatologist may include one (or more) in your at-home treatment plan.

Minoxidil (Rogaine®) : Minoxidil can help early hair loss; it cannot regrow an entire head of hair.

To use minoxidil, you apply it to the scalp as directed, usually once or twice a day.

When used as directed, minoxidil can:

Stimulate hair growth

Prevent further hair loss

Minoxidil tends to be more effective when used along with another treatment for hair loss. Many people see some regrowth when using minoxidil, but it takes time to see results, usually about 6 to 12 months.

Should you see regrowth, you will need to keep using it every day.

If you stop applying minoxidil, you lose its benefits. Because minoxidil helps you maintain your hair’s thickness, some hairs may look and feel thinner. You’ll also gradually notice that you’re shedding more hair.

Laser for at-home use : You can buy laser caps and combs to treat hair loss at home. While only a few studies have looked at these devices, the results are promising.

In one study, more than 200 men and women who had hereditary hair loss were given either a laser hair comb or a sham device that looked like a laser comb. The patients used the device that they were given 3 times per week for 26 weeks.

The researchers found that some patients using the laser rather than the sham device saw overall thicker and fuller hair.

It’s important to understand that not everyone who used a laser saw regrowth.

More studies are needed to find out who is most likely to benefit from this treatment and whether these devices cause long-term side effects.

Microneedling : A microneedling device contains hundreds of tiny needles. A few studies have shown that it can help stimulate hair growth. In one study, men between the ages of 20 and 35 years old who had mild or moderate hereditary hair loss were treated with either:

5% minoxidil twice a day

5% minoxidil twice a day plus weekly microneedling

After 12 weeks of treatment, the patients treated with minoxidil and microneedling had significantly more hair growth.

Other studies have shown that using microneedling along with another treatment, including platelet-rich plasma or a corticosteroid that you apply to the thinning area, helps improve hair growth.

While you can buy a microneedling device without a prescription, it’s best to check with your dermatologist first. Microneedling can worsen some conditions. It’s also important to get the right microneedling device.

The devices used for hair loss contain longer needles than the those used to treat the skin.

Procedures to help regrow hair

While at-home treatments offer convenience, a procedure performed by a board-certified dermatologist tends to be more effective. For this reason, your dermatologist may include one of the following in your treatment plan.

Injections of corticosteroids : To help your hair regrow, your dermatologist injects this medication into the bald (or thinning) areas. These injections are usually given every 4 to 8 weeks as needed, so you will need to return to your dermatologist’s office for treatment.

This is considered the most effective treatment for people who have a few patches of alopecia areata , a condition that causes hair loss. In one study of 127 patients with patchy alopecia areata, more than 80% who were treated with these injections had at least half of their hair regrow within 12 weeks.

Hair transplant : If you have an area of thinning or balding due to male (or female) pattern baldness, your dermatologist may mention a hair transplant as an option. This can be an effective and permanent solution.

To learn more, go to: A hair transplant can give you permanent, natural-looking results .

Laser therapy : If using minoxidil every day or taking medication to treat hair loss seems unappealing to you, laser therapy may be an option. Also called low-level laser therapy, a few studies suggest that this may help:

Hereditary hair loss

Alopecia areata

Hair loss due to chemotherapy

Stimulate healing and hair growth after a hair transplant

Studies indicate that laser therapy is safe and painless but requires many treatment sessions. To see a bit of hair growth, you may need several treatments a week for many months.

Platelet-rich plasma (PRP) : Studies show that this can be a safe and effective hair loss treatment. PRP involves drawing a small amount of your blood, placing your blood into a machine that separates it into parts, and then injecting one part of your blood (the plasma) into the area with hair loss.

The entire procedure takes about 10 minutes and usually doesn’t require any downtime.

You will need to return for repeat injections. Most patients return once a month for 3 months and then once every 3 to 6 months.

Within the first few months of treatment, you may notice that you are losing less or minimal amounts of hair.

Prescription medication that can regrow hair

Another treatment option is to take prescription medication. The type of medication prescribed will depend on your:

Hair loss cause

Overall health

Expected results

Plans for getting pregnant

With any medication, side effects are possible. Ask your dermatologist about possible side effects that you might experience while taking one of these medications to treat hair loss. The medications include:

Finasteride (Propecia®) : The U.S. Food and Drug Administration (FDA) approved this medication to treat male pattern hair loss. When taken as directed, finasteride can:

Slow down hair loss

Stimulate new hair growth

Finasteride is a pill that you take once a day. Taking it at the same time each day seems to produce the best results.

Finasteride: Before and after

This man took finasteride to treat his male pattern hair loss, and within 1 year (B), he had noticeable improvement. After 2 years (C), he had regrown most of his hair.

Like other treatments for hair loss, this, too, takes time to work. It usually takes about 4 months to notice any improvement.

Finasteride tends to be more effective if you begin taking it when you first notice hair loss. A dermatologist may also prescribe this medication to treat a woman who has hereditary hair loss and cannot get pregnant.

If finasteride works for you, you will need to keep taking it to continue getting results. Once you stop, you’ll start losing hair again. Before taking this medication, be sure to discuss possible side effects with your dermatologist.

Spironolactone : For women who have female pattern hair loss, this medication may be an option. It can:

Stop further hair loss

Increase hair thickness

Studies indicate that this medication is effective in about 40% for women who have female pattern hair loss. In one study of 166 women taking spironolactone, 42% said they had mild improvement, and 31% reported increased thickness.

It’s essential that you not become pregnant while taking spironolactone. This medication can cause birth defects. To prevent pregnancy, your dermatologist will also prescribe a birth control pill if it’s possible for you to get pregnant.

Other medications : If you have an infection or painful inflammation, your dermatologist can prescribe medication to treat these.

For example, if you have a type of hair loss called frontal fibrosing alopecia (FFA), which can cause painful inflammation, your dermatologist may prescribe an antibiotic and antimalarial medication. Scalp ringworm, which is caused by a fungus, requires antifungal medication.

Vitamins, minerals, and other supplements

If your blood test reveals that you’re not getting enough biotin, iron, or zinc, your dermatologist may recommend taking a supplement. If you’re not getting enough protein, your dermatologist can tell you how to boost your intake.

You should only take biotin, iron, or zinc when your blood test shows that you have a deficiency. If your levels are normal, taking a supplement can be harmful. For example, if you take too much iron, you can develop iron poisoning. Early signs of this include stomach pain and vomiting.

Other supplements meant to help with hair loss tend to contain a lot of one nutrient. Because this can cause you to get too much of the nutrient, many dermatologists recommend taking a multivitamin instead.

Wigs and concealers

Do you feel uncomfortable taking medication? Does your schedule limit the amount of time you have for treatment? Is the cost of treatment, which insurance generally will not cover, too expensive?

If you answered yes to any of these questions, your dermatologist may recommend a wig or concealer.

While these cannot slow hair loss or help you regrow hair, they can boost your self-esteem. Another advantage is that a wig or concealer offers immediate results.

Many types of wigs, including ones that can be custom-made for you, are available. If you’re looking for a concealer, such as a spray or powder that can hide hair loss, you’ll find many products available online. With endless choices, it can be helpful to have a dermatologist guide you in selecting one.

What is the outcome for someone who has hair loss?

With an accurate diagnosis, many people who have hair loss can see hair regrowth. If you need treatment for regrowth, the earlier you start, the more likely you are to see regrowth.

It’s important to understand that:

Not every type of hair loss can be treated, but a dermatologist may be able to prevent further hair loss.

It can take months before you see results from treatment.

No one treatment works for everyone, even two people with the same type of hair loss.

Sometimes, hair loss is stubborn and requires trying different treatments before finding one that works.

Self-care also plays an essential role in preventing and treating hair loss. To find out what dermatologists recommend, go to Hair loss: Self-care .

Images Images 1 and 2: Getty Images

Image 3: Property of the American Academy of Dermatology, A to Z Video Series

Image 4: Image used with permission of Journal of the American Academy of Dermatology: J Am Acad Dermatol . 1998; 39:578-89.

References Adil A, Godwin M. “The effectiveness of treatments for androgenetic alopecia: A systematic review and meta-analysis.” J Am Acad Dermatol . 2017;77:136-141.

American Academy of Dermatology:

“Research demonstrates potential of platelet-rich plasma therapy for hair loss” News release issued March 1, 2019. Last accessed May 22, 2019.

New generation of laser and light therapies could provide future treatment options for skin, hair and nail conditions,” News release issued March 16, 2012. Last accessed May 22, 2019.

Avci P, Gupta GK, et al . “Low-level laser (light) therapy (LLLT) for treatment of hair loss.” Lasers Surg Med . 2014;46:144-51.

Dhurat R, Sukesh M, et al . “A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: A pilot study.” Int J Trichology . 2013;5:6-11.

Donovan J. (2019, March) “Medically maximizing male and female hair loss.” In: Rogers NE (Director) Session S032: Alopecia: Work-up and treatment.” Symposium conducted at the 2019 Annual Meeting of the American Academy of Dermatology, Washington, DC.

Freites-Martinez A, Shapiro J, et al . “Hair disorders in cancer survivors.” J Am Acad Dermatol . 2019;80:1199-1213.

Goren A, Shapiro J, et al . “Clinical utility and validity of minoxidil response testing in androgenetic alopecia.” Dermatol Ther. 2015;28:13-6.

Jimenez JJ, Wikramanayake TC, et al . “Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study.” Am J Clin Dermatol . 2014;15:115-27.

Kumar MK, Inamadar AC, et al . “A randomized controlled, single-observer blinded study to determine the efficacy of topical minoxidil plus microneedling versus topical minoxidil alone in the treatment of androgenetic alopecia.” J Cutan Aesthet Surg . 2018;11:211-6.

Paus R, Olsen EA, et al . “Hair growth disorders.” In: Wolff K, Goldsmith LA, et al. Fitzpatrick’s Dermatology in General Medicine (seventh edition). McGraw Hill Medical, New York, 2008:753-74.

Ring CM, Keller MS. “Research letters: Effect of camouflaging agents on psychologic well-being: A cross-sectional survey of hair loss patients.” J Am Acad Dermatol . 2017;76:1186-9. Funding sources: None. Conflicts of interest: None declared

Rodrigues BL, Montalvão SAL, et al. “Treatment of male pattern alopecia with platelet-rich plasma: A double-blind controlled study with analysis of platelet number and growth factor levels.” J Am Acad Dermatol . 2019;80:694-700.

Shannon F, Christa S, et. al . “Demographics of women with female pattern hair loss and the effectiveness of spironolactone therapy.” J Am Acad Dermatol . 2015;73: 705-6.

Last updated: 12/13/22

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JSmol Viewer

Innovative strategies for hair regrowth and skin visualization.

Graphical Abstract

1. Introduction

2. structure of the skin and hair follicles, 3. molecular mechanisms of hair regrowth, 4. innovative strategies for hair regrowth, 4.1. external stimulation, 4.1.1. photostimulation, 4.1.2. ultrasound stimulation, 4.1.3. electrical stimulation, 4.1.4. stretch stimulation, 4.2. microneedles for hair regrowth, 4.3. regenerative medicine for hair regrowth, 4.3.1. biomimetic extracellular matrix, 4.3.2. extracellular vesicles, 4.3.3. organoid culture, 5. skin visualization, 6. claims for hair regrowth, 7. natural products for hair regrowth, 8. patent applications and clinical trials for hair loss treatment.

9. Conclusions and Outlook

Conflicts of interest.

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Mai, Q.; Han, Y.; Cheng, G.; Ma, R.; Yan, Z.; Chen, X.; Yu, G.; Chen, T.; Zhang, S. Innovative Strategies for Hair Regrowth and Skin Visualization. Pharmaceutics 2023 , 15 , 1201. https://doi.org/10.3390/pharmaceutics15041201

Mai Q, Han Y, Cheng G, Ma R, Yan Z, Chen X, Yu G, Chen T, Zhang S. Innovative Strategies for Hair Regrowth and Skin Visualization. Pharmaceutics . 2023; 15(4):1201. https://doi.org/10.3390/pharmaceutics15041201

Mai, Qiuying, Yanhua Han, Guopan Cheng, Rui Ma, Zhao Yan, Xiaojia Chen, Guangtao Yu, Tongkai Chen, and Shu Zhang. 2023. "Innovative Strategies for Hair Regrowth and Skin Visualization" Pharmaceutics 15, no. 4: 1201. https://doi.org/10.3390/pharmaceutics15041201

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• People Tested

The 6 Best Hair Loss Treatments of 2024, Tested by People with Thinning Hair

Our top pick is the Advanced Trichology NutraM DHT Blocking Hair Serum

Jessie Quinn is a Los Angeles-based contributing shopping writer at PEOPLE with over 10 years of experience covering all things beauty, fashion, and lifestyle. At PEOPLE, she collaborates with the PEOPLE Tested team to share our top recommendations for everything from the best shapewear to the best dark spot correctors.

In This Article

• Our Top Picks
• What to Know

Behind The Scenes

Why trust people.

• What Is PEOPLE Tested?

People / Taylor Calta

If your hair seems thinner than usual, you're not alone: 50 percent of women and 80 percent of men experience hair loss in their lifetime. But thanks to impressive hair loss treatments designed to thicken up your ‘do while also shielding against hair-thinning hormones, you can put an end to excessive hair fall and even help your hair grow back .

The More You Know

Since there are so many causes of hair loss, treatment results can differ person to person. And while they might not solve the issue altogether, board-certified dermatologist Dr. Dendy Engelman says individuals experiencing hair loss caused by factors like genetics, hormonal imbalances, or lifestyle choices can still benefit from hair loss treatments.

With so many different hair care products that claim to make your hair thicker and longer, finding one that actually does the trick takes time, research, and resources. Our PEOPLE Tested team dedicated nearly 1,000 hours testing 20 formulas and uncovered which treatments were effective and, ultimately, worth the money.

Best Overall

Advanced trichology topical melatonin hair growth serum.

Advanced Trichology

Easy to apply

Quick-drying and not greasy

Saw hair growth after one month

Excellent value

Has a strong scent

After testing 20 hair loss treatments, this serum received top marks and was a clear winner for top spot. The dropper makes application super easy (you can apply it directly to the scalp) and the quick-drying formula is never greasy so it doesn’t mess up your hairstyle or require extra washing. It absorbed easily and never caused irritation.

When testing this hair loss treatment, we noticed results within just one month of use . At the end of the testing period, our hair looked and felt a lot thicker, with new growth in some of the thinner areas as well as along our hairline.

Ingredients: Melatonin, minoxidil | Size: 2 ounces | Supply: 90 days

Best Overall (Cheaper)

Hers minoxidil foam for women.

Comes in 2, 4, and 6-month supplies

Costs around $15 per month

A little goes a long way

Saw results in one month

Hard to clean the cap after using

For another quick-acting hair loss treatment, we also loved the Minoxidil Foam from hers. This treatment comes in 2-, 4-, and 6-month supplies and costs around $15 per month (the 4- and 6-month plans are even cheaper). It has a mousse-like consistency that is easy to work into the scalp and doesn’t interfere with style, though there is a little bit of a sheen upon application.

After just one month of testing, we began to see a difference in our root growth. At the end of the testing period, our hair looked and felt a lot thicker and healthier . It also has a soothing and cooling touch that feels nice on irritated scalps and is scent-free so it’s great for sensitive noses. 

Ingredients: Minoxidil | Size: 2.11 ounces | Supply: 2-6 months

People / Alexa Jade Frankelis

Easiest Application

Keranique hair regrowth treatment.

Easy to target specific areas

Doesn’t leave hair greasy

Saw results after two months

Takes a little longer to absorb and dry

As much as we love the Advanced Trichology NutraM DHT Blocking Hair Serum for its application process, we found that this solution from Keranique was even easier to use. The serum features applicator caps with long nozzles that apply directly to the scalp, making it less messy and easier to target specific areas versus the entire head. It takes a little longer to absorb and dry (around five minutes), but it doesn't dry greasy.

While we didn’t see results as quickly as some of the other formulas on our list, we still noticed improvements before the end of the testing period. After around eight weeks, our hair looked and felt a lot thicker and we noticed new growth in some of the sparser areas of our scalp . 

Ingredients: Minoxidil | Size: 2 ounces | Supply: 60 days

People / Allison Vancura

Best for Men

Nioxin 5% minoxidil hair regrowth treatment for men.

Quick to absorb and dry

Noticeable results after nine weeks

Improved bald spot hair growth

Messy application process

Not ideal for sensitive scalps

This serum from Nioxin is the best hair loss treatment for men. We tested this on a bald spot, and after nine weeks of twice daily use some baby hairs started to sprout . The scalp serum features a dropper that is relatively easy to use but can get a bit awkward when targeting a specific area, especially on the back of the head.

While it absorbs quickly, the serum is a bit runny which can make for a messy application process (this formula in spray form would have been much more ideal). Nonetheless, we were impressed by the regrowth and think it’s worth using over a longer period of time to maximize the hair growth benefits. 

Ingredients: Minoxidil | Size: 2 ounces | Supply: 30 days

Best for Color-Treated Hair

Virtue minoxidil 5% hair growth treatment.

Virtue Labs

It comes with shampoo, conditioner, and treatment

Available in 30 and 90 days supply

Less hair fall

If want a hair loss treatment that won’t interfere with your color-treated hair , try this regimen from Virtue. The kit comes with hair loss shampoo , conditioner, and a minoxidil treatment designed to support hair growth. Despite using the product just every two weeks, we still experienced growth along the hairline and our strands felt a lot thicker with less fall, too. 

Ingredients: Minoxidil, gamma keratin, alpha keratin | Size: Varies, depending on product | Supply: 30-90 days

People / Chantia Murphy

Best Thickening

Rogaine women's 2% minoxidil topical solution hair regrowth treatment.

Only takes seconds to absorb

Hair looked thicker and longer after 6 weeks

Doesn’t have a greasy residue

Messier application process

Whether you have experienced some fall or want to thicken up your strands, this treatment from Rogaine is worth considering for its thickening benefits. The minoxidil-infused formula absorbs into the scalp within seconds and doesn’t leave the roots feeling greasy or fade color-treated hair. It’s also one of the more efficient formulas we tried, as we noticed thicker and longer hair after just six weeks of use. 

People / Alisa Hale

What to Know About Hair Loss Treatments

Ingredients.

Dr. Engelman says to look for hair growth promoters like minoxidil , biotin , and keratin , as these can promote regeneration and strengthen hair. “Scalp treatments containing ingredients like caffeine or palmetto can also block the effects of dihydrotestosterone (DHT), a hormone associated with hair thinning,” she says.

All six treatments on our list contain minoxidil for growth, including our top pick for the best hair loss treatment, the Advanced Trichology NutraM DHT-Blocking Hair Serum (90-Day Supply) . If you want something with some extra oomph, the Virtue Hair Growth Treatment also has gamma and alpha keratin to strengthen strands and improve growth efforts. 

Long-Term Use 

While there are some hair styling products that can create the illusion of thicker, fuller hair, there is no such thing as an overnight solution for hair loss. When adding hair loss treatments to your regimen, Dr. Jacobs says to use them consistently and long-term for best results.

With that said, if you are hoping to achieve some noticeable improvements in a shorter amount of time, we found that the Advanced Trichology NutraM DHT-Blocking Hair Serum made our hair thicker after just one month of regular application (though of course, results were more noticeable after a longer testing period). 

Underlying Causes of Hair Loss

Hair loss treatments can help improve thickness and length with regular use. However, Dr. Jacobs and Dr. Engelman both express the importance of knowing the underlying cause of your loss and working with a medical professional to help address the concern.

“Hair loss can be the result of various factors, including hormonal fluctuations (such as pregnancy and postpartum), genetic predispositions, aging, stress, and seasonal changes,” says Dr. Jacobs. 

Vitamin and mineral deficiencies can also lead to hair loss, especially if you have lower levels of iron, vitamin B12, vitamin D, and biotin. “Lack of these nutrients might cause hair thinning or shedding because they are essential for sustaining healthy hair growth,” says Dr. Engelman. “Vitamin D affects the hair growth cycle by inhibiting the proliferation of hair follicle cells, and iron deficiencies can lead to anemia causing reduced oxygen delivery to the hair follicles and subsequent hair loss.” Dr. Engelman says biotin is also important because it is essential for the production of keratin, which is the protein that makes up the hair shaft. 

Additionally, Dr. Engelman says environmental factors “like exposure to pollutants or harsh chemicals in hair care products can damage the hair follicles,” which can result in hair loss over time. 

By addressing the underlying causes of hair loss and using a treatment regularly in your regimen, you can begin to reverse the side effects and achieve desired results. 

We researched dozens of formulas before taking 20 products out for a real-world spin. We spent 12 weeks and 960 hours testing each treatment, carefully considering the application process, effectiveness, and overall results.

• Application: During the testing period, we considered the packaging and required application process to get a general idea of convenience. We carefully looked at the applicator itself, plus the required treatment time, usage, and amount required to achieve desired results. We also made note of ease-of-use, the consistency, and if the process was messy or not. 
• Effectiveness: When using a hair loss treatment, you of course want it to be effective. Witht his in mind, we marked down which formulas gave us the best results, how long it took to experience said results, and if the products matched their claims. We also considered which ones worked best for thickening and which ones promoted growth. 
• Overall Results: After considering the application process and effectiveness, we compared our notes and looked at the overall results of all 20 formulas. In addition to the hair growth outcomes, we also considered which formulas had the best absorption, were quick-drying, and didn’t leave behind any greasy residue. 

Once our results were in, we compared and rated each product before narrowing down our selection to these six best hair loss treatments on the market.

Jessie Quinn is a contributing commerce writer for PEOPLE and has written for publications such as Byrdie, InStyle, The Spruce, NYLON, and more. Jessie has spent years trying to improve her hair health and promote growth. While she might have long and healthy strands today, she’s gone through phases of hair loss and has tried everything from supplements to serums to achieve her current ‘do. 

She considered her own experiences as well as those of our PEOPLE Tested team to highlight the formulas that are worth spending your energy and money on. Jessie also reached out to board-certified dermatologists Dr. Michael I. Jacobs and Dr. Dendy Engelman to learn more about what causes hair loss and what to look for in effective treatments.

Our Expert Panel

• Dr. Michael I. Jacobs is a board-certified dermatologist and associate professor of dermatology at Weill Cornell Medical College.
• Dr. Dendy Engelman is a board-certified cosmetic dermatologist and Mohs surgeon Shafer Clinic in New York City.

What Is PEOPLE Tested? 

We created the PEOPLE Tested seal of approval to help you find the very best products for your life. We use our unique methodology to test products in three labs across the country and with our network of home testers to determine their effectiveness, durability, ease of use, and so much more. Based on the results, we rate and recommend products so you can find the right one for your needs.

But we don’t stop there: We also regularly re-review the categories in which we’ve awarded the PEOPLE Tested seal of approval — because the best product of today might not be the best of tomorrow. And by the way, companies can never buy our recommendation: Their products must earn it, fair and square.

In short, PEOPLE Tested provides recommendations you can trust — every day, every purchase.

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Patients With AGA Treated With PRP Display Hair Regrowth, Potential Microbiome Rebalance

Platelet-rich plasma (PRP) treatment increased hair regrowth in patients with androgenetic alopecia (AGA) and may help rebalance the scalp microbiome, although the link between the microbiome changes and hair growth needs future investigations.

Male pattern baldness | Image Credit: Oksana - stock.adobe.com

Patients with androgenetic alopecia (AGA) found platelet-rich plasma (PRP) treatment led to increased hair growth and showed potential in scalp microbiome rebalancing.

A small sample study was performed on 14 participants with AGA to analyze the clinical efficacy while observing results before treatment (TB) and after treatment (TA). 1

The study focused on scalp microbiome because research points to the imbalance in microbiota as a trigger for AGA, while the most common form of bacteria found in scalp swabs of healthy individuals are Cutibacterium spp . and Staphylococcus spp ., accounting for approximately 90% of the total gene sequence.

Currently there are only 2 drugs approved by the US FDA for AGA treatment, oral finasteride and topical minoxidil, both of which come with serious adverse effects and are oftentimes not effective among patients. PRP treatment has been a successful method in treating AGA, proving so through basic research and clinical trials over the past decade.

Research has suggested an interplay between the gut and skin microbiome in relation to hair biology. 2 While it is still unknown how the gut microbiota may influence AA pathogenesis, the association of AA and gut dysbiosis diseases is prominent as seen in inflammatory bowel disease, ulcerative colitis, and Crohn disease.

Prior to treatment, patients had 36 mL of peripheral blood extracted from each AGA volunteer. 1 Then, PRP was categorized into 3 parts, prefrozen at –80 °C for a 24 hour period. Afterwards, PRP was freeze-dried using a freeze-drying machine for 48 hours. Participants were treated once a month and blood samples were collected after 3 months to isolate the PRP. Overall, treatment took place over a 6-month duration.

Clinical efficacy of PRP in AGA was evaluated through photography and dermascopy. Swab sampling was conducted using the scalp area of the patients with AGA. Following procedure, every swab was put into a 50 mL centrifuge tube and stored at –80 °C until the DNA was extracted from the sample.

Patients with AGA showed an increased level of macroscopic hair regrowth following 6 treatments with PRP. Dermatoscopes showed significant changes in a multitude of parameters in hair growth. Before treatment, 14 patients with AGA were sampled and after treatment, 8 samples were collected. Bacterial population was slightly higher in the TA group compared with the TB group but there were no statistically significant differences between the 2 groups.

While there were differences among the TA and TB groups, there were no major differences observed ( P = .203).

Looking at the major types of bacteria, like phylum, the TB group was dominated by Firmicutes (39.4%), followed by Proteobacteria (23.4%) and Actinobacteriota (21.5%).

In the bacterial communities like genera, both the TB and TA groups had high levels of Staphylococcus (TB: 28.3%, TA: 21.7%), Lawsonella (TB: 10%, TA: 6.7%), Cutibacterium (TB: 8.5%, TA: 13.9%), and Bacteroides (TB: 5.1%, TA: 4.1%).

When examining individual bacterial species, uncultured_bacterium was the most abundant in both groups (TB: 39.1%, TA: 41.5%). This was followed by uncultured Staphylococcus (TB: 12.2%, TA: 7.4%) and Staphylococcus warneri (TB: 7.4%, TA: 2.4%).

The scalp microbial composition of the scalp before and after treatment expressed discernible differences at the species and genus levels.

Throughout the TB group, 3 bacterial genera were abundant, Brevundimonas, uncultured, and Eremococcus. There were 14 genera overall that were enriched in the TA group, known as Paenibacillus, Aeribacillus, Spirosoma, Comamonas, Cereibacter, Massilia, Nocardioides, Hydrogenophilus, Granulicatella, Geobacillus, Meiothermus, Pseudomonas, Thermus, and Brevibacillus .

Data found Pseudomonas_sp . was more abundant in the TA group (2.05%) compared with the TB group (0.68%).

The study highlighted the distinct role microbial ecological imbalance plays in scalp diseases because the skin hosts a diverse community of microbes. Following treatment for AGA, hair density grew instantly, scalp composition improved, and the ratio of g_Cutibacterium and g_Staphylococcus were normal. Additionally, Lawsonella was elevated in the TB group compared with the TA group for the first time in scalp microbiota.

Similarly, a 2-sample Mendelian randomization study suggested that certain types of bacteria, like Olsenella , Ruminococcaceae UCG-004 , and Ruminococcaceae UCG-010 , might increase the risk of AGA. 3 On the other hand, bacteria belonging to Ruminiclostridium 9 , Anaerofilum , and the Acidaminococcaceae family seemed to have a protective effect. These findings suggest a connection between specific gut microbes and AGA, opening the door for developing more targeted probiotics to potentially help manage hair loss.

While PRP treatment does show signs of positive impacts on the composition of scalp microbiota, further research is necessary to investigate the impact microbial communities have on patients with AGA to determine whether PRP has a therapeutic role after altering the composition of the scalp.

1. Zhang Q, Wang Y, Ran C, et al. Characterization of distinct microbiota associated with androgenetic alopecia patients treated and untreated with platelet-rich plasma (PRP). Animal Model Exp Med . 2024;7(2):106-113. doi:10.1002/ame2.12414

2. Carrington AE, Maloh J, Nong Y, Agbai ON, Bodemer AA, Sivamani RK. The gut and skin microbiome in alopecia: associations and interventions. J Clin Aesthet Dermatol . 2023;16(10):59-64.

3. Fu H, Xu T, Zhao W, Jiang L, Shan S. Roles of gut microbiota in androgenetic alopecia: insights from Mendelian randomization analysis.  Front Microbiol . 2024;15. doi:10.3389/fmicb.2024.1360445

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15 Home Remedies for Hair Growth

• Common Causes
• Home Remedies
• When to Seek Care

Some hair loss (called shedding) is expected. On average, people lose 50 to 100 strands of hair a day. Depending on the cause of your hair loss , some home remedies, such as massage, herbs, and nutritional changes, may help regrow hair naturally.

However, some cases of hair loss are permanent. This could be due to genes, health conditions, medications, or hairstyles and products. Hair loss can take an emotional toll since hair is often a significant part of people's identity.

This article discusses common causes of hair loss, home remedies, prevention, and when to contact a healthcare provider.

rparobe / Getty Images

Common Causes of Hair Loss

Some causes of hair loss are:

• Genetics ( androgenic alopecia )
• Age (hair growth slows as you age)
• Chemotherapy
• Hormonal fluctuations (following childbirth or as a result of stress)
• Using damaging hair care products
• Wearing tight hairstyles ( traction alopecia )
• Hormonal imbalance from polycystic ovary syndrome (PCOS)
• Scalp infection
• Medication side effects
• Scalp psoriasis
• Hair pulling
• Untreated syphilis
• Thyroid disease
• Nutrient deficiency
• Friction (from tight hats , boots, or socks)
• Poison (arsenic, thallium, mercury, and lithium)

There are two categories of hair loss: Scarring and non-scarring. Scarring hair loss is permanent and called cicatricial alopecia .

There are two types of cicatricial alopecia. In primary cicatricial alopecia, the hair follicle is destroyed by an inflammatory process. In secondary cicatricial alopecia, the hair follicle is destroyed by an injury like a burn, infection, radiation, or a tumor.

Non-scarring hair loss is called alopecia areata . An autoimmune disorder causes this type of patchy hair loss. It may be helped with home remedies or medical treatments.

Home Remedies for Hair Loss

The good news is several natural home remedies may help with hair regrowth , including scalp massage, different essential oils, herbs, and more.

In one study, participants noted an increase in hair thickness after 24 weeks of using scalp massage for four minutes daily. Researchers say the stretching of the skin involved in scalp massage changes gene expression and transmits mechanical stress to cells, increasing hair thickness.

Eating More Protein

You might try increasing your protein intake if you want your hair to grow faster naturally. That's because a protein deficiency can result in hair loss. Since the hair shaft is composed of keratin (a protein on the skin's surface), increasing protein might help you develop healthier hair. However, more studies are needed.

Increasing Iron Intake

Increasing your iron intake may be another way to make your hair thicker and fuller naturally. Researchers evaluated participants with iron deficiency -related alopecia and found that initiating iron supplements within six months of diagnosis would improve the prognosis.

However, iron supplementation may interact with some medications. It's important to speak with a healthcare provider before taking iron supplements.

Aloe vera gel applied topically may be another strategy for naturally growing hair. In one study, aloe ferox gel loaded with finasteride (a prescription hair loss medication) and oregano oil effectively treated alopecia areata .

Coconut Oil

Coconut oil is used worldwide for scalp and hair health. In African and Asian countries, coconut oil is the most widely used product to help with scalp health and hair growth. Researchers point to biotin as the primary nutrient in coconut oil that helps with scalp health and hair growth.

Biotin is vitamin B7, and ingesting it promotes hair and nail health.

Viviscal is a supplement that promotes hair growth. A study evaluated whether these oral supplements promote hair growth. Researchers found that after 90 and 180 days of treatment, participants who took Viviscal significantly increased the number of hair strands.

They also noted improved hair volume, scalp coverage, and thickness.

Another supplement to try for hair loss is fish oil . A trial examined the effect of nutritional supplements, including fish oil, on hair loss. It was found that when participants took omega-3 and omega-6 fatty acids and antioxidants, they acted efficiently against hair loss.

Some research has found that the herb ginseng may prevent hair loss and promote hair growth by preventing cell death. Ginseng stimulates the anagen (hair growth) phase and delays the phase of the catagen (end of active growth).

Onion Juice

The phytochemicals in onion juice have hair growth–stimulating properties. Researchers say these phytochemicals are so potent they may be more effective than conventional hair loss treatments, like minoxidil and finasteride.

Rosemary Oil

Another herb that may help with hair regrowth is rosemary oil. One study compared rosemary oil and minoxidil. After six months, participants in both groups experienced a significant increase in hair count. Researchers conclude that rosemary oil is an effective treatment for androgenetic alopecia.

Geranium Oil

Research looked at the effect of geranium oil extract in human cells and mice. It found that it promoted hair growth in vivo by regulating growth and cellular response.

Some people also use lemon oil for hair growth. They bellieve it may strengthen hair follicles and promote hair growth. However, there is little evidence to support these claims.

Pumpkin Seed Oil

Pumpkin seed oil offers promising potential in treating hair loss. One study compared pumpkin seed oil to minoxidil. Participants with female hair loss reported that the number of upright regrowing hairs significantly increased from before treatment to after.

Saw Palmetto

Saw palmetto is another plant that holds promise for hair regrowth. A study found that saw palmetto oil reduced hair fallout by up to 29% and hair density (thickness) by almost 8%.

Green tea has many health benefits, including hair health. In one study, researchers found that when combined with persimmon leaf extract and sophora fruit extracts, hair density, and diameter significantly increased after 24 weeks compared with the placebo group (those given an intentionally ineffective treatment to act as a control group).

A Word From Verywell

Hair, like skin and nails, can reflect a person's general state of health. In primary care, I always look at the hair, skin, and nails as important elements of an assessment. This can help connect the dots in diagnosis or, when needed, indicate a referral to a dermatologist.

How to Prevent Hair Loss

In addition to treating hair loss, there are also things you can do to prevent hair loss . These include:

• Establish a gentle hair care routine.
• Reduce how often you use heated products.
• Avoid chemical hair treatments.
• Avoid tightly pulled ponytails, braids, pigtails, and buns.
• Avoid pulling or tugging your hair.
• Quit smoking ,
• Eat nutritious foods.
• Consider blood tests to determine if you are getting enough vitamins and minerals.

When to Contact a Healthcare Provider About Hair Loss

If you’re losing more hair than average, especially if you have other symptoms, you should contact a healthcare provider. Since hair loss can have many causes, getting to the root of the problem is critical for identifying the best course of treatment.

Dermatologists (doctors specializing in skin and hair) may recommend at-home treatments like those mentioned in this article for mild cases. However, for more severe hair loss, there are other options, including:

• Laser treatment
• Microneedling
• Steroid injections
• Hair transplant
• Platelet-rich plasma

There are many different home remedies for hair loss, such as scalp massage, essential oils, herbs, and more. Some have more scientific backing than others. In addition to diet and supplements, you can also take steps to reduce or prevent hair loss, like having a gentle hair care routine.

If your hair loss is significant or you don't see results from at-home treatment, see a dermatologist to determine the cause of your hair loss.

American Academy of Dermatology Association. Do you have hair loss or hair shedding? .

American Academy of Dermatology Association. Hair loss: Who gets and causes .

National Organization for Rare Disorders. Cicatricial alopecia .

Koyama T, Kobayashi K, Hama T, Murakami K, Ogawa R. Standardized scalp massage results in increased hair thickness by inducing stretching forces to dermal papilla cells in the subcutaneous tissue .  Eplasty . 2016;16:e8. Published 2016 Jan 25.

Guo EL, Katta R. Diet and hair loss: effects of nutrient deficiency and supplement use .  Dermatol Pract Concept . 2017;7(1):1-10. doi:10.5826/dpc.0701a01

Lin CS, Chan LY, Wang JH, Chang CH. Diagnosis and treatment of female alopecia: Focusing on the iron deficiency-related alopecia .  Tzu Chi Med J . 2023;35(4):322-328. doi:10.4103/tcmj.tcmj_95_23

Qadir MI. Medicinal and cosmetological importance of aloe vera . J Nat Med . 2009;2:21-26.

Hosny KM, Rizg WY, Alfayez E, et al. Preparation and optimization of aloe ferox gel loaded with Finasteride-Oregano oil nanocubosomes for treatment of alopecia .  Drug Deliv . 2022;29(1):284-293. doi:10.1080/10717544.2022.2026534

Saxena R, Mittal P, Clavaud C, et al. Longitudinal study of the scalp microbiome suggests coconut oil to enrich healthy scalp commensals .  Sci Rep . 2021;11(1):7220. doi:10.1038/s41598-021-86454-1

Ablon G, Dayan S. A randomized, double-blind, placebo-controlled, multi-center, extension trial evaluating the efficacy of a new oral supplement in women with self-perceived thinning hair .  J Clin Aesthet Dermatol . 2015;8(12):15-21.

Le Floc'h C, Cheniti A, Connétable S, Piccardi N, Vincenzi C, Tosti A. Effect of a nutritional supplement on hair loss in women .  J Cosmet Dermatol . 2015;14(1):76-82. doi:10.1111/jocd.12127

Choi BY. Hair-growth potential of ginseng and its major metabolites: A review on its molecular mechanisms .  Int J Mol Sci . 2018;19(9):2703. doi:10.3390/ijms19092703

Kesika P, Sivamaruthi BS, Thangaleela S, Bharathi M, Chaiyasut C. Role and mechanisms of phytochemicals in hair growth and health .  Pharmaceuticals (Basel) . 2023;16(2):206. doi:10.3390/ph16020206

Panahi Y, Taghizadeh M, Marzony ET, Sahebkar A. Rosemary oil vs minoxidil 2% for the treatment of androgenetic alopecia: a randomized comparative trial .  Skinmed . 2015;13(1):15-21.

Boisvert WA, Yu M, Choi Y, et al. Hair growth-promoting effect of Geranium sibiricum extract in human dermal papilla cells and C57BL/6 mice .  BMC Complement Altern Med . 2017;17(1):109. doi:10.1186/s12906-017-1624-4

Alyoussef A. Comparative study of the online over-the-counter hair loss products . J Dermatol Res Ther 6:077. doi:10.23937/2469-5750/1510077

Ibrahim IM, Hasan MS, Elsabaa KI, Elsaie ML. Pumpkin seed oil vs. minoxidil 5% topical foam for the treatment of female pattern hair loss: A randomized comparative trial .  J Cosmet Dermatol . 2021;20(9):2867-2873. doi:10.1111/jocd.13976

Sudeep HV, Rashmi S, Jestin TV, et al. Oral and topical administration of a standardized saw palmetto oil reduces hair fall and improves the hair growth in androgenetic alopecia subjects - A 16-week randomized, placebo-controlled study .  Clin Cosmet Investig Dermatol . 2023;16:3251-3266. doi:10.2147/CCID.S435795

Ham S, Lee YI, Kim IA, et al. Efficacy and safety of persimmon leaf formulated with green tea and sophora fruit extracts (BLH308) on hair growth: A randomized, double-blind, placebo-controlled clinical trial .  Skin Res Technol . 2023;29(9):e13448. doi:10.1111/srt.13448

American Academy of Dermatology Associates. Hair loss: Tips for managing .

By Kathi Valeii Valeii is a Michigan-based freelance writer with a bachelor's degree in communication from Purdue Global.

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Hair loss (alopecia) can affect just your scalp or your entire body, and it can be temporary or permanent. It can be the result of heredity, hormonal changes, medical conditions or a normal part of aging. Anyone can lose hair on their head, but it's more common in men.

Baldness typically refers to excessive hair loss from your scalp. Hereditary hair loss with age is the most common cause of baldness. Some people prefer to let their hair loss run its course untreated and unhidden. Others may cover it up with hairstyles, makeup, hats or scarves. And still others choose one of the treatments available to prevent further hair loss or restore growth.

Before pursuing hair loss treatment, talk with your doctor about the cause of your hair loss and treatment options.

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• Male-pattern baldness

Male-pattern baldness typically appears first at the hairline or top of the head. It can progress to partial or complete baldness.

• Female-pattern baldness

Female-pattern baldness typically starts with scalp hairs becoming progressively less dense. Many women first experience hair thinning and hair loss where they part their hair and on the top-central portion of the head.

• Patchy hair loss (alopecia areata)

In the type of patchy hair loss known as alopecia areata, hair loss occurs suddenly and usually starts with one or more circular bald patches that may overlap.

• Traction alopecia

Hair loss can occur if you wear pigtails, braids or cornrows, or use tight hair rollers. This is called traction alopecia.

• Frontal fibrosing alopecia

Early treatment of a receding hairline (frontal fibrosing alopecia) might help avoid significant permanent baldness. The cause of this condition is unknown, but it primarily affects older women.

Hair loss can appear in many different ways, depending on what's causing it. It can come on suddenly or gradually and affect just your scalp or your whole body.

Signs and symptoms of hair loss may include:

• Gradual thinning on top of head. This is the most common type of hair loss, affecting people as they age. In men, hair often begins to recede at the hairline on the forehead. Women typically have a broadening of the part in their hair. An increasingly common hair loss pattern in older women is a receding hairline (frontal fibrosing alopecia).
• Circular or patchy bald spots. Some people lose hair in circular or patchy bald spots on the scalp, beard or eyebrows. Your skin may become itchy or painful before the hair falls out.
• Sudden loosening of hair. A physical or emotional shock can cause hair to loosen. Handfuls of hair may come out when combing or washing your hair or even after gentle tugging. This type of hair loss usually causes overall hair thinning but is temporary.
• Full-body hair loss. Some conditions and medical treatments, such as chemotherapy for cancer, can result in the loss of hair all over your body. The hair usually grows back.
• Patches of scaling that spread over the scalp. This is a sign of ringworm. It may be accompanied by broken hair, redness, swelling and, at times, oozing.

When to see a doctor

See your doctor if you are distressed by persistent hair loss in you or your child and want to pursue treatment. For women who are experiencing a receding hairline (frontal fibrosing alopecia), talk with your doctor about early treatment to avoid significant permanent baldness.

Also talk to your doctor if you notice sudden or patchy hair loss or more than usual hair loss when combing or washing your or your child's hair. Sudden hair loss can signal an underlying medical condition that requires treatment.

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People typically lose 50 to 100 hairs a day. This usually isn't noticeable because new hair is growing in at the same time. Hair loss occurs when new hair doesn't replace the hair that has fallen out.

Hair loss is typically related to one or more of the following factors:

• Family history (heredity). The most common cause of hair loss is a hereditary condition that happens with aging. This condition is called androgenic alopecia, male-pattern baldness and female-pattern baldness. It usually occurs gradually and in predictable patterns — a receding hairline and bald spots in men and thinning hair along the crown of the scalp in women.
• Hormonal changes and medical conditions. A variety of conditions can cause permanent or temporary hair loss, including hormonal changes due to pregnancy, childbirth, menopause and thyroid problems. Medical conditions include alopecia areata (al-o-PEE-she-uh ar-e-A-tuh), which is immune system related and causes patchy hair loss, scalp infections such as ringworm, and a hair-pulling disorder called trichotillomania (trik-o-til-o-MAY-nee-uh).
• Medications and supplements. Hair loss can be a side effect of certain drugs, such as those used for cancer, arthritis, depression, heart problems, gout and high blood pressure.
• Radiation therapy to the head. The hair may not grow back the same as it was before.
• A very stressful event. Many people experience a general thinning of hair several months after a physical or emotional shock. This type of hair loss is temporary.
• Hairstyles and treatments. Excessive hairstyling or hairstyles that pull your hair tight, such as pigtails or cornrows, can cause a type of hair loss called traction alopecia. Hot-oil hair treatments and permanents also can cause hair to fall out. If scarring occurs, hair loss could be permanent.

More Information

Hair loss care at Mayo Clinic

Risk factors

A number of factors can increase your risk of hair loss, including:

• A family history of balding on your mother's or father's side
• Significant weight loss
• Certain medical conditions, such as diabetes and lupus
• Poor nutrition

Most baldness is caused by genetics (male-pattern baldness and female-pattern baldness). This type of hair loss is not preventable.

These tips may help you avoid preventable types of hair loss:

• Be gentle with your hair. Use a detangler and avoid tugging when brushing and combing, especially when your hair is wet. A wide-toothed comb might help prevent pulling out hair. Avoid harsh treatments such as hot rollers, curling irons, hot-oil treatments and permanents. Limit the tension on hair from styles that use rubber bands, barrettes and braids.
• Ask your doctor about medications and supplements you take that might cause hair loss.
• Protect your hair from sunlight and other sources of ultraviolet light.
• Stop smoking. Some studies show an association between smoking and baldness in men.
• If you're being treated with chemotherapy, ask your doctor about a cooling cap. This cap can reduce your risk of losing hair during chemotherapy.

Living with hair loss?

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• AskMayoExpert. Alopecia. Mayo Clinic; 2019.
• Malki L, et al. Variant PAD13 in central centrifugal cicatricial alopecia. New England Journal of Medicine. 2019; doi:10.1056/NEJMoa1816614.
• Briggs JK. Hair loss. Triage Protocols for Aging Adults. Waloters Kluwer; 2019.
• Warner KJ. Allscripts EPSi. Mayo Clinic, Nov. 25, 2019.
• Office of Patient Education. Hair replacement surgery. Mayo Clinic; 2017.
• Hair loss. American Academy of Dermatology. https://www.aad.org/public/diseases/hair-loss/treatment/causes/fall-out. Accessed Jan. 31, 2020.
• Hair loss. American Cancer Society. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/hair-loss.html. Accessed Jan. 2, 2020.
• Van Zuuren EJ, et al. Interventions for female pattern hair loss. JAMA Dermatology. 2017; doi:10.1001/jamadermatol.2016.5790.
• Shapiro J, et al. Evaluation and diagnosis of hair loss. https://www.uptodate.com/contents/search. Accessed Jan. 2, 2020.
• Shapiro J, et al. Alopecia areata: Clinical manifestations and diagnosis. https://www.uptodate.com/contents/search. Accessed Jan. 2, 2020.
• Hereditary hair loss. Mayo Clinic Health Letter. 2016;4:1.
• Cold caps and scalp cooling systems. https://www.breastcancer.org/tips/hair_skin_nails/cold-caps. Accessed Jan. 31, 2020.
• Mirmirati P. Age-related hair changes in men: Mechanisms and management of alopecia and graying. Maturitas. 2015; doi.10.1016/j.maturitas.2014.10.008.
• Chemotherapy and you: Support for people with cancer. National Cancer Institute. https://www.cancer.gov/publications/patient-education/chemotherapy-and-you.pdf. Accessed Feb. 3, 2020.
• Shapiro J. Lichen planopilaris. https://www.uptodate.com/contents/search. Accessed March 26, 2020.
• Gibson LE (expert opinion). Mayo Clinic. March 26, 2020.
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Microneedling and Its Use in Hair Loss Disorders: A Systematic Review

Robert s. english, jr..

Perfect Hair Health, 2021 Fillmore, Ste 98, San Francisco, CA 94115 USA

Sophia Ruiz

Pedro doamaral, associated data.

Data availability is not applicable to this article as no datasets were generated or analyzed during the current study.

Introduction

Microneedling (MN) is a minimally invasive procedure involving the induction of percutaneous wounds with medical-grade needles. In this literature review, we investigate clinical data on MN for the treatment of hair loss disorders.

A literature search was conducted through PubMed up to November 2021 to identify original articles evaluating the use of MN on hair loss disorders. The database was searched using the following keywords: “microneedling,” “micro needling,” “micro needle,” “microneedle,” “needle,” “dermaroller” and “alopecia,” “hair loss,” “alopecia,” “areata,” “cicatricial,” or “effluvium.”

A total of 22 clinical studies featuring 1127 subjects met our criteria for inclusion. Jadad scores ranged from 1 to 3, with a mean of 2. As an adjunct therapy, MN improved hair parameters across genders and a range of hair loss types, severities, needling devices, needling depths of 0.50–2.50 mm, and session frequencies from once weekly to monthly. Across 17 investigations totaling 911 androgenic alopecia (AGA) subjects, MN improved hair parameters when paired with 5% minoxidil, growth factor solutions, and/or platelet-rich plasma (PRP) topicals, or when introduced to subjects whose hair count changes had plateaued for ≥ 6 months on other treatments. Across four investigations on 201 alopecia areata (AA) subjects, MN improved hair parameters as a standalone therapy versus cryotherapy, as an adjunct to 5-aminolevulinic acid and photodynamic therapy, and equivalently when paired with topical PRP versus carbon dioxide laser therapy with topical PRP. Across 657 subjects receiving MN, no serious adverse events were reported.

Conclusions

Clinical studies demonstrate generally favorable results for MN as an adjunct therapy for AGA and AA. However, data are of relatively low quality. Significant heterogeneity exists across interventions, comparators, and MN procedures. Large-scale randomized controlled trials are recommended to discern the effects of MN as a standalone and adjunct therapy, determine best practices, and establish long-term safety.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-021-00653-2.

Key Summary Points

Alopecia is a common cosmetic concern affecting over 50% of adults throughout a lifetime [ 1 ]. Hair loss disorders are typically categorized into scarring and nonscarring alopecias, with treatments dependent on the pathogenesis and diagnosis determined during dermatological evaluation [ 2 ]. While drug and nondrug interventions often help to improve many hair loss disorders, treatments for androgenic alopecia (AGA) are typically relegated to stopping the progression of the condition [ 3 ]. Moreover, treatments for alopecia areata (AA) and alopecia totalis (AT) remain limited, with recurrence rates high [ 4 ]. Consequently, there remains demand for novel and effective hair loss treatments.

Microneedling (MN) is a minimally invasive procedure involving the induction of percutaneous wounds with 0.25–5.00 mm medical-grade needles. First described by Orentreich in 1995 for the use of wrinkles and atrophic scars, MN purportedly releases platelet-derived growth factor and vascular endothelial growth factor to promote wound-healing responses, improve angiogenesis, and attenuate or partially reverse fibrosis resulting from acute injury and skin aging [ 5 , 6 ]. MN can be administered at-home or in-clinic, with devices ranging from needling stamps, manual rollers, and automated pens with or without fractional radiofrequency. Across a range of devices, needling depths, and session frequencies, MN has demonstrated clinical improvements as a standalone and/or adjunct therapy for patients with atrophic scars, actinic keratoses, and pigmentation disorders such as vitiligo and melasma [ 6 , 7 ].

In the last decade, studies have demonstrated that MN may enhance transdermal delivery, promote anagen-initiating Wnt/ β -catenin signaling, and improve dermal papillae stem cell proliferation—thus potentiating therapeutic effects for a variety of hair loss disorders [ 8 – 10 ]. In 2013, the landmark study by Dhurat et al. on 100 AGA subjects found that over a 12-week period, once-weekly MN combined with twice-daily 5% minoxidil increased hair counts significantly versus minoxidil monotherapy [ 11 ]. Since then, investigators have continued to assess the effects of MN as both a standalone and adjunct therapy for hair loss.

In this systematic review, we investigate the use of MN as a standalone, adjunct, and comparator therapy on hair loss disorders. We evaluate patient populations, interventions, comparators, MN procedures, outcomes, and adverse events—as well as evidence quality using Jadad scoring. We discuss possible mechanisms by which MN may improve hair loss disorders as a monotherapy and an adjunct intervention. Finally, we identify limitations in the current body of research and provide recommendations for future clinical trials.

Literature Search

A broad literature search was conducted through PubMed up to November 2021 to identify original articles that evaluate the use of MN on hair loss disorders. The database was searched using combinations of the following keywords: “microneedling,” “micro needling,” “micro needle,” “microneedle,” “needle,” “dermaroller” and “alopecia,” “hair loss,” “alopecia,” “areata,” “cicatricial,” or “effluvium.” This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Inclusion and Exclusion Criteria

All search hits were screened and examined for relevant titles and abstracts. Full texts were reviewed to determine eligibility. Articles were included if they featured all of the following: (a) human subjects with scalp hair loss, (b) MN as a standalone or adjunct therapy, and (c) endpoint measurements related to scalp hair. Articles were excluded if they did not feature (a) original data, (b) human data, (c) endpoint measurements for hair parameters, and/or (d) designs that adequately evaluated the effects of MN on hair. This literature review is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Full inclusion and exclusion criteria can be found in Table ​ Table1 1 .

PICOS inclusion and exclusion criteria

A table summarizing the inclusion and exclusion criteria in our systematic review for clinical studies investigating the use of MN for the treatment of hair loss disorders

RE and SR each independently identified 367 records for screening. RE, SR, and PD each independently screened all 367 titles and abstracts to assess eligibility, and the 42 full texts to determine inclusion. RE, SR, and PD each independently assessed Jadad scores. Any disagreements in identifications, screenings, selections, and/or Jadad scores were discussed by RE and PD and resolved by RE.

Of the 42 full texts accessed to assess eligibility, 20 were excluded on the basis of the wrong intervention ( n  = 2), outcome ( n  = 4), or study design ( n  = 14). A total of 22 clinical studies met our criteria for inclusion: 17 trials with randomization and 5 nonrandomized prospective cohorts (Fig.  1 ). Jadad scores ranged from 1 to 3, with a mean score of 2 (Table S1).

PRISMA flowchart. A PRISMA flowchart detailing the process of eligibility for all records reviewed for the literature review, as well as the number of studies identified, screened, excluded, and included

Of the 22 studies, 16 were conducted on AGA subjects, 4 on alopecia areata subjects, 1 on alopecia totalis subjects, and 1 on both AGA and telogen effluvium (TE) subjects. A total of 1127 subjects (856 males and 269 females) were included featuring the following hair loss types: AGA ( n  = 911), AA ( n  = 201), AT ( n  = 8), and TE ( n  = 7) [ 11 – 32 ].

Within studies featuring AGA subjects, enrollment ages ranged from 18 to 70 years, with a subject-weighted average of 33.75 years. Of the 15 studies with male AGA subjects, 1 did not enroll subjects based on a classification system, while 14 included males with hair loss based on the Norwood–Hamilton scale: I (0.0%), II (46.7%), III (93.3%), IV (93.3%), V (60%), and VI (26.7%). Of the seven studies with female AGA subjects, one did not enroll subjects based on any classification system, one enrolled based on Sinclair scores, and five enrolled females with hair loss determined by the Ludwig scale: I (80.0%), II (60.0%), and III (60.0%) (Table ​ (Table2 2 ).

Parameter summaries for studies assessing the use of MN on AGA subjects

A table summarizing all included studies assessing the use of MN on AGA subjects. Each study summary features parameters regarding author, year of publication, total subjects, gender, study type, treatment regimen, MN procedure, number of MN sessions, treatment duration, assessment endpoints, effectiveness, adverse events, and Jadad score

Interventions and Comparators

In total, 536 subjects received MN therapy, while 375 received other hair loss interventions. Across all study groups, MN was included as a standalone therapy in 6 groups ( n  = 105). As an adjunct therapy, MN was evaluated alongside topical minoxidil in 10 groups ( n  = 234), proprietary topicals and/or growth factor solutions in 3 groups ( n  = 46), PRP in 2 groups ( n  = 61), continued medication use in 1 group ( n  = 50), PRP and systemic medications in 1 group ( n  = 42), PRP with topical minoxidil in 1 group ( n  = 25), topical minoxidil and continued medications in 1 group ( n  = 11), and topical minoxidil alongside growth factors in 1 group ( n  = 10) (Table ​ (Table2 2 ).

MN Procedures

MN devices tested included manual rollers ( n  = 8), automated pens ( n  = 7), manual stamps ( n  = 1), and automated fractional radiofrequency pens ( n  = 1). Needle lengths ranged from 0.25 to 2.50 mm, with a mean needle length of 1.39 mm.

The frequency of MN sessions ranged from twice weekly to once monthly, with a mean session frequency of once per 2.64 weeks. The number of MN sessions ranged from 3 to 52, with a mean of 9.53 MN sessions per study. Treatment durations averaged 20.01 weeks.

While four studies did not specify MN session endpoints, 13 studies standardized endpoints by a number of passes, directions, and/or taps ( n  = 3), mild erythema ( n  = 3), a number of passes and/or bleeding ( n  = 3), or passes until hemorrhage ( n  = 4) (Table ​ (Table2 2 ).

In total, 15 of 17 studies assessed hair parameters through phototrichograms (i.e., hair counts, hair diameters, and/or hair densities). Of the 17 studies, 6 included MN-only groups, whereas all studies tested MN alongside other hair loss interventions.

Of the six MN monotherapy groups, two noted significant increases to total hair counts, one found significant increases to hair diameters and total hair density, and three showed no effect [ 13 , 18 – 20 , 25 , 27 ].

Of the seven studies testing MN with 5% minoxidil, six found statistically significantly increased hair counts versus 5% minoxidil alone, and for a range of devices and needle lengths: rollers, automated pens, and fractional radiofrequency devices with depths from 0.60 to 2.50 mm [ 11 , 15 , 18 , 19 , 21 , 23 , 25 ]. However, Sohng et al. tested 5% minoxidil with a 0.25 mm needling stamp twice-weekly and found no effect on hair parameters [ 13 ]. When comparing 5% minoxidil with 0.60 mm or 1.20 mm needle lengths, Faghihi et al. found that 0.60 mm needle lengths led to significant hair count and diameter increases versus 5% minoxidil, whereas 1.20 mm needle lengths only saw hair count increases versus 5% minoxidil [ 21 ].

All three studies testing MN alongside proprietary topicals and/or growth factors noted increases to hair counts [ 16 , 18 , 27 ]. Lee et al. and Yu et al. demonstrated improved hair parameters but no differences across groups when comparing MN use with topical versus intradermal delivery of proprietary products and/or growth factors [ 18 , 27 ]. Conversely, Ozcan et al. found that MN alongside either topical or injectable PRP significantly increased hair counts and diameters similarly across groups, but that subjects receiving MN alongside topical PRP saw greater improvements to anagen:telogen hairs [ 17 ]. Interestingly, in a split-scalp study, Aggarwal et al. showed that both MN and MN with PRP injections increased hair diameters and density equivalently—with no significant differences noted across groups [ 20 ].

Two studies tested the introduction of MN alongside ongoing hair loss medications [ 14 , 22 ]. Burns et al. found that twice monthly MN combined with 5% minoxidil improved Ludwig scores for 11/11 females who had previously plateaued for ≥ 6 months on other hair loss treatments [ 14 ]. Starace et al. showed that the addition of MN improved hair counts in those already using hair loss treatments for > 1 year (Table ​ (Table2) 2 ) [ 22 ].

Adverse Events

Across 536 subjects receiving MN, no serious adverse events were reported. Of mild adverse events, transient pain, scalp irritation, and mild erythema were most commonly reported. Withdrawal rates across MN groups were low and comparable to non-MN groups.

Of the five studies with AA and AT subjects, enrollment ages ranged from 16 to 45 years, with a subject-weighted average of 28.34 years. Three investigations enrolled subjects with hair loss gradients according to Severity Of Alopecia Tool (SALT) score, one study enrolled on the basis of severe AA, and one study enrolled on the basis of AT (Table ​ (Table3 3 ).

Parameter summaries for studies assessing the use of MN on AA and AT subjects

A table summarizing all included studies assessing the use of MN on AA and AT subjects. Each study summary features parameters regarding author, year of publication, total subjects, gender, study type, treatment regimen, MN procedure, number of MN sessions, treatment duration, assessment endpoints, effectiveness, adverse events, and Jadad score

In total, 114 subjects received MN therapy while 95 received other hair loss interventions. Of the five studies featuring AA and AT subjects, three compared treatments across patients ( n  = 181), while two compared treatments across lesions within the same patients ( n  = 28).

Across all study groups, MN was included as a standalone therapy in three groups ( n  = 68). As an adjunct therapy, MN was evaluated alongside a PRP topical in one group ( n  = 20), and with 5-aminolevulinic acid or methyl 5-aminolevulinic acid alongside photodynamic therapy in two groups ( n  = 25). As a comparator, MN was included as a control against cryotherapy in one group ( n  = 40), PRP injections in one group ( n  = 20), fractional CO 2 laser alongside a PRP topical in one group ( n  = 20), triamcinolone acetonide injections in one group ( n  = 20), 5% minoxidil injections in one group ( n  = 20), and 5-aminolevulinic acid or methyl 5-aminolevulinic acid alongside photodynamic therapy in two groups ( n  = 23) (Table ​ (Table3 3 ).

MN devices tested included manual rollers ( n  = 3) and automated pens ( n  = 2). Needle lengths ranged from 1.00 to 5.00 mm, with a mean needle length of 2.25 mm.

The frequency of MN sessions ranged from once every 2 weeks to once monthly, with a mean session frequency of once every 3.46 weeks. The number of MN sessions ranged from three to six, with a mean of 4.40 MN sessions per study. Treatment durations averaged 14.20 weeks.

While one study did not specify MN session endpoints, four studies standardized endpoints by a number of passes ( n  = 2), a number of passes and/or mild erythema ( n  = 1), or minutes of passes in affected areas ( n  = 1) (Table ​ (Table3 3 ).

In total, two of five studies assessed hair parameters through objective measurements (i.e., phototrichograms or 4 mm punch biopsies). Subjective measurements for the remaining three studies included Severity of Alopecia Tool (SALT) scores ( n  = 2), Lesional Area & Density (LAD) scores ( n  = 1), and/or a four-point scale ( n  = 1).

Of the three studies testing standalone MN groups, Aboeldahab et al. and Abdallah et al. showed that MN alone increased hair density and improved SALT scores, respectively [ 28 , 30 ]. However, Giorgio et al. demonstrated no changes to hair parameters using a four-point scale to evaluate MN alone [ 31 ].

When comparing MN with cryotherapy, Aboeldahab et al. found significant increases to hair counts and hair densities across both interventions, with MN demonstrating greater changes to SALT scores versus cryotherapy [ 28 ]. Conversely, Abdallah et al. found that triamcinolone acetonide injections with and without 5% intradermal minoxidil led to greater improvements to SALT and LAD scores versus controls than MN alone [ 30 ].

As an adjunct therapy, Giorgio et al. showed that MN alongside 5-aminolevulinic acid and photodynamic therapy improved 94% of AA lesions versus 53% of lesions receiving only 5-aminolevulinic acid and photodynamic therapy [ 31 ]. However, Yoo et al. found that in AT subjects, methyl 5-aminolevulinic acid and photodynamic therapy with and without MN led to no hair parameter improvements according to 4 mm punch biopsies [ 32 ].

Finally, Ragab et al. demonstrated that, over a 3-month period, MN alongside topical PRP improves SALT scores similarly to fractional CO 2 laser therapy alongside topical PRP (Table ​ (Table3) 3 ) [ 29 ].

Among 114 subjects receiving MN, no serious adverse events were reported. Of mild adverse events, transient pain and mild erythema were most common. Of the five studies, no withdrawals were reported in MN or non-MN groups.

Clinical studies demonstrate generally favorable results for MN as an adjunct therapy for AGA and AA. However, data are of relatively low quality and should be interpreted with caution. Due to significant heterogeneity across interventions, comparators, and MN procedures (i.e., devices, needle lengths, session frequencies, and session endpoints), we could not conduct a meta-analysis. Here we discuss the proposed mechanisms of MN, limitations in the current body of research, and design considerations for future studies.

In AGA-affected hair follicles, dihydrotestosterone dysregulates the Wnt/ β -catenin pathway, induces transforming growth factor β 1, and triggers apoptosis in dermal papillae and epithelial cells. This leads to a shortened anagen phase, reductions to dermal papillae cell cluster sizes with each re-entry into anagen and, consequently, microvascular degradation alongside progressive hair follicle miniaturization [ 33 – 36 ]. In mid-to-late stages of miniaturization, perifollicular fibrosis is often observed and may reduce the effectiveness of both systemic and topical AGA treatments [ 37 ].

As a monotherapy for AGA, data on MN are limited, and the mechanisms by which MN might improve AGA remain speculative. In a pooled linear regression across six subgroups, Gupta et al. found that MN significantly increased total hair counts, by more than 5% topical minoxidil [ 38 ]. However, two of the subgroups were a part of split-scalp studies assessing MN versus PRP injections or topical growth factor solutions [ 20 , 27 ]. Therefore, the possibility of percutaneous treatment diffusion across scalp zones cannot be discounted.

Animal models suggest that MN may promote anagen-initiating Wnt/ β -catenin signaling and dermal papillae stem cell proliferation. In particular, percutaneous wounds from MN appear to activate hair follicle stem cells, platelet-derived growth factor, and vascular endothelial growth factor—potentiating the initiation of angiogenesis, neocollagenesis, and a new anagen cycle [ 5 – 7 , 9 , 10 ]. Clinical data show that MN reduces scarring and improves the density and thickness of epidermal and dermal skin layers [ 39 , 40 ]. In two randomized controlled clinical trials, Bao et al. found that MN alone increased terminal hair counts—with their latter study analyzing biopsies from a subset of AGA subjects showing that MN alone upregulated protein levels of both FZD3 and LEF-1 but not β -catenin [ 19 , 25 ]. However, RT-PCR testing revealed no statistical increases to mRNA expression—with the authors postulating that the inconsistent results might be due to small sample sizes, infrequent needling sessions, shallow needling depths, and/or posttranscriptional modifications [ 25 ].

As an adjunct therapy, MN may improve AGA by enhancing transdermal delivery, and by improving sulfation and Wnt pathway expression when paired with topical minoxidil. Henry et al. demonstrated in vitro that 0.15 mm needles inserted into human skin for 10 seconds enhanced transdermal permeability of calcein by more than 1000-fold [ 41 ]. These effects may partly explain the equivalent and/or additive improvements to hair parameters from intradermal growth factors or PRP injections versus MN alongside their topical applications [ 16 , 17 ]. Additionally, MN may enhance topical minoxidil activation. Topical minoxidil is a pro-drug that requires sulfation by sulfotransferase enzymes in the outer root sheath of hair follicles [ 8 ]. Goren et al. demonstrated that reduced sulfotransferase activity in hair follicles predicted topical minoxidil nonresponders [ 42 ]. More recently, Sharma et al. found that, over 21 days, once-weekly microneedling led to a median increase in sulfotransferase activity of 37.5% [ 8 ]. Finally, Bao et al. demonstrated that MN with 5% minoxidil upregulated the expression of FZD3, LEF-1, and β -catenin in mRNA and protein more than MN or 5% minoxidil monotherapy—suggesting that the addition of MN might amplify the effects of minoxidil on the Wnt pathway [ 19 ].

AA and AT are autoimmune forms of alopecia resulting from the collapse of immune privilege in affected hair follicles. In particular, peribulbar lymphocytic infiltrates appear to induce apoptosis in hair follicle keratinocytes—leading to inflammation, impaired hair shaft production, and sometimes hair shaft miniaturization within the same hair cycle. While the histologic features of AA and AT are well studied, their underlying pathogenesis remain poorly understood—with researchers speculating the involvement of immunological shifts related to genetic and environmental factors [ 4 ].

As a monotherapy for AA and AT, data on MN are unrobust. While Aboeldahab et al. and Abdallah et al. noted improvements to AA from MN alone, these results should be interpreted with caution due to relatively small sample sizes, as well as the 50% spontaneous recoveries observed in many AA studies with adequate controls [ 28 , 30 ]. Moreover, Giorgio et al. found no effect from MN alone in AA subjects [ 31 ]. As an adjunct therapy, Giorgio et al. suggested that the release of growth factors from MN may induce immunosuppressive actions that amplify the effects of substances such as 5-aminolevulinic acid [ 31 ]. Ragab et al. found that MN alongside topical PRP improved hair parameters similarly to PRP injections, and suggested that MN may also enhance transdermal delivery for AA [ 29 ].

Limitations

Due to significant heterogeneity across MN studies regarding interventions, comparators, MN devices, needle lengths, session frequencies, and session endpoints, our systematic review does not include a meta-analysis and cannot establish best practices for MN procedures.

Faghihi et al. found hair parameters improved more when pairing 5% minoxidil with fortnightly MN using an automated pen with needle lengths of 0.60 mm versus 1.20 mm [ 21 ]. Faghihi et al. postulated that puncture depths of 0.60 mm still generate enough of an inflammatory response for stem cell and growth factor recruitment, but without damaging the hair follicle bulge residing 1.00–1.80 mm from the skin surface [ 43 ]. Interestingly, Sasaki found that with MN automated pens, needling lengths matched penetration depths up to 1.50 mm [ 44 ]. Due to user pressure variability and needle entry angulation, Lima et al. estimated that a 3.00 mm MN manual roller only penetrates to skin depths 50–70% of its needle length [ 45 ]. Taken together, equivalent MN penetration depths of 0.60–0.80 mm may be achievable with MN automated pens and MN manual rollers set to needle lengths of 0.60–0.80 mm and 1.25–1.50 mm, respectively. Relatedly, Fernandes postulated that MN device preferences do not matter so long as the skin is penetrated to the same depths [ 46 ]. Regardless of standardizations for MN devices or needle lengths, additional methodological considerations—i.e., session durations, frequencies, and endpoints—still likely exert influence over the degree of inflammation induced, and thereby the magnitude of outcomes across a variety of hair parameters. As such, no procedural best practices can be ascertained with the current body of evidence.

While 8 of 22 clinical studies on MN included groups to evaluate MN alone ( n  = 174), only 1 study compared MN monotherapy against an untreated control patch for AA ( n  = 20). Moreover, 21 of 22 clinical studies on MN assessed hair parameter changes over periods of less than 52 weeks. Study durations of less than 52 weeks often do not allow investigators to separate the effects of any intervention against seasonal fluctuations to hair cycling—particularly in the absence of untreated control groups [ 47 , 48 ].

Finally, 4 out of 22 clinical studies utilized split-scalp study designs to evaluate MN against or as an adjuvant to topicals and/or injectables. Since MN is suspected to enhance transdermal drug delivery, split-scalp study designs leave open the possibility of percutaneous drug diffusion across scalp zones, thus limiting the interpretability of endpoint assessments.

Recommendations

Large-scale, randomized, placebo-controlled clinical trials assessing the use of MN for hair loss are needed. Future investigations should consider study durations of at least 12 months, include groups for MN as a monotherapy, and evaluate MN against a placebo (i.e., manual rollers with removed needles, automated pens with uninstalled needle cartridges, and/or an untreated control group). Split-scalp studies should be avoided, particularly when evaluating MN against or as an adjuvant to topicals and/or injectables. Finally, studies evaluating the use of MN across different procedural standards (i.e., shorter needle lengths and more frequent sessions versus longer needle lengths and less frequent sessions) will help toward establishing best practices.

Among 22 clinical studies featuring 1127 subjects, MN as an adjunct therapy improved hair parameters across genders as well as a range of hair loss types, hair loss severities, needling devices, needling depths of 0.50–2.50 mm, and session frequencies from once weekly to once monthly—with no serious adverse events reported. However, results should be interpreted with caution due to significant heterogeneity across study interventions, comparators, and MN procedures (i.e., devices, needle lengths, session frequencies, and session endpoints). Large-scale randomized controlled trials are needed to discern the effects of MN as a standalone and adjunct therapy, determine best practices for MN procedures, and establish long-term safety data. Study designs should consider 12-month durations, include groups using MN as a monotherapy, and evaluate MN against a placebo and/or untreated group.

Below is the link to the electronic supplementary material.

Acknowledgements

No funding or sponsorship was received for this study or publication of this article.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

RE contributed to the concept/design, systematic review process, and writing of the manuscript. RE, SR, and PD contributed to the systematic review process.

Disclosures

Robert S. English, Sophia Ruiz, and Pedro DoAmaral have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability

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FDA Approves New Medication for Chronic Weight Management

FDA News Release

Today, the U.S. Food and Drug Administration approved Zepbound (tirzepatide) injection for chronic weight management in adults with obesity (body mass index of 30 kilograms per square meter (kg/ m2) or greater) or overweight (body mass index of 27 kg/m2 or greater) with at least one weight-related condition (such as high blood pressure, type 2 diabetes or high cholesterol) for use, in addition to a reduced calorie diet and increased physical activity. Tirzepatide, the active ingredient in Zepbound, is already approved under the trade name Mounjaro to be used along with diet and exercise to help improve blood sugar (glucose) in adults with type 2 diabetes mellitus.

“Obesity and overweight are serious conditions that can be associated with some of the leading causes of death such as heart disease, stroke and diabetes,” said John Sharretts, M.D., director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “In light of increasing rates of both obesity and overweight in the United States, today’s approval addresses an unmet medical need.” 

Approximately 70% of American adults have obesity or overweight, and many of those overweight have a weight-related condition. Losing 5% to 10% of body weight through diet and exercise has been associated with a reduced risk of cardiovascular disease in adults with obesity or overweight.

Zepbound activates receptors of hormones secreted from the intestine (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) to reduce appetite and food intake. Zepbound is administered by injection under the skin once weekly, and the dosage must be increased over four to 20 weeks to achieve the target dosages of 5 milligram (mg), 10 mg or 15 mg once weekly. The maximum dosage of Zepbound is 15 mg once weekly.

Zepbound’s effectiveness for chronic weight management (weight reduction and maintenance) in combination with a reduced-calorie diet and increased physical activity was established in two randomized, double-blind, placebo-controlled trials of adults with obesity or overweight with at least one weight-related condition. These studies measured weight reduction after 72 weeks in a total of 2,519 patients who received either 5 mg, 10 mg or 15 mg of Zepbound once weekly and a total of 958 patients who received once-weekly placebo injections. In both trials, after 72 weeks of treatment, patients who received Zepbound at all three dose levels experienced a statistically significant reduction in body weight compared to those who received placebo, and greater proportions of patients who received Zepbound achieved at least 5% weight reduction compared to placebo.   The larger of the two trials enrolled adults without diabetes. At the start of the trial, the average body weight was 231 pounds (105 kg) and average body mass index was 38 kg/m2. In this trial, those randomized to receive the highest approved dosage of Zepbound (15 mg once weekly) lost on average 18% of their body weight compared to those randomized to placebo. 

At the start of the trial in adults with type 2 diabetes, the average body weight was 222 pounds (101 kg) and average body mass index was 36 kg/m2. Those randomized to receive the highest approved dosage of Zepbound (15 mg once weekly) lost on average 12% of their body weight compared to those randomized to placebo.

Zepbound can cause side effects such as nausea, diarrhea, vomiting, constipation, abdominal (stomach) discomfort and pain, injection site reactions, fatigue, hypersensitivity (allergic) reactions (typically fever and rash), burping, hair loss and gastroesophageal reflux disease.

Zepbound causes thyroid C-cell tumors in rats. It is unknown whether Zepbound causes such tumors, including medullary thyroid cancer, in humans. Zepbound should not be used in patients with a personal or family history of medullary thyroid cancer or in patients with Multiple Endocrine Neoplasia syndrome type 2. 

Zepbound has not been studied in patients with a history of pancreas inflammation (pancreatitis) or severe gastrointestinal disease (including severe gastroparesis, a condition that affects normal movement of the muscles in the stomach). It should not be used in combination with Mounjaro or a GLP-1 receptor agonist. The safety and effectiveness of coadministration of Zepbound with other medications for weight management have not been established. 

Zepbound should not be used in patients with a history of severe allergic reaction to tirzepatide (its active ingredient) or to any of its other ingredients. Patients should stop Zepbound immediately and seek medical help if a severe allergic reaction is suspected. Zepbound also contains warnings for inflammation of the pancreas (pancreatitis), gallbladder problems, hypoglycemia (blood sugar that is too low), acute kidney injury, diabetic retinopathy (damage to the eye’s retina) in patients with type 2 diabetes mellitus and suicidal behavior or thinking. Patients should discuss with their health care provider if they have symptoms of pancreatitis or gallstones. If Zepbound is used with insulin or a medication that causes insulin secretion, patients should speak to their health care provider about potentially lowering the dose of these other medicines to reduce the risk of hypoglycemia. Health care providers should monitor patients with kidney disease, diabetic retinopathy and depression or suicidal behaviors or thoughts. 

Zepbound received Priority Review and Fast Track designations for this indication.

The FDA granted this approval to Eli Lilly and Co.

Related Information

• NIH: Overweight & Obesity Statistics

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