Hair follicle–containing punch grafts accelerate chronic ulcer healing: A randomized controlled trial

doi:10.1016/j.jaad.2016.02.1161

Journal of the American Academy of Dermatology

Volume 75, Issue 5, November 2016, Pages 1007-1014

https://doi.org/10.1016/j.jaad.2016.02.1161 Get rights and content

Background

A prominent role of hair follicle–derived cells in epidermal wound closure is now well established but clinical translation of basic research findings is scarce. Although skin punch grafts have been used as a therapeutic intervention to improve healing of chronic leg ulcers, they are normally harvested from nonhairy areas, thus not taking advantage of the reported role of the hair follicle as a wound-healing promoter.

Objective

We sought to substantiate the role of hair follicles in venous leg ulcer healing by transplanting hair follicle–containing versus nonhairy punch grafts.

Methods

This was a randomized controlled trial with intraindividual comparison of hair follicle scalp grafts and nonhairy skin grafts transplanted in parallel into 2 halves of the same ulcer.

Results

Ulcer healing measured as the average percentage reduction 18 weeks postintervention was significantly increased (P = .002) in the hair follicle group with a 75.15% (SD 23.03) ulcer area reduction compared with 33.07% (SD 46.17) in the control group (nonhairy grafts).

Limitations

Sample size was small (n = 12).

Conclusion

Autologous transplantation of terminal hair follicles by scalp punch grafts induces better healing than punch grafts harvested from nonhairy areas. Hair punch grafting is a minimally invasive surgical procedure that appears to be effective as a therapeutic tool for chronic venous leg ulcers.

Section snippets

Study design

This study was designed as an open, single-center, randomized controlled trial with intraindividual comparison. Each patient had 1 leg ulcer that was divided into 2 halves of as similar a size as possible. To avoid bias ulcers were divided vertically in 2 halves because the venous return flows upwards from bottom to top. The 2 halves were randomized for each wound into an experimental and control area by a methodologist blinded to study data (Fig 1). The random allocation sequence was concealed

Results

Patients had a mean age of 73 years; 33.3% were men and 66.7% were women. Average initial ulcer size was 23.34 cm². Average initial size for the experimental group was 11.35 cm² and 11.99 cm² for the control group. Average duration of the ulcers before surgery was 6 years.

Discussion

This study demonstrates that the half of the ulcer transplanted with scalp punch grafts experienced a statistically significant better outcome than the half transplanted with nonhairy grafts.

The fact that follicle-rich scalp punches improve wound healing reflects the clinical translation of the latest discoveries in hair follicle biology related to wound healing.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 Considering that the hair follicle is a well-known reservoir of several types of stem cell,1, 4, 31,

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Chronic ulcers significantly affect the quality of life of patients and impose a high cost on the healthcare system. The therapeutic management should be comprehensive, taking into consideration the etiological diagnosis of the wound and the characteristics of the wound bed when deciding on a therapeutic proposal appropriate to the healing phase, correcting factors that delay healing. During the epithelialization phase, repair techniques with grafts are recommended to shorten re-epithelialization time, improve the quality of scar tissue, and achieve adequate pain management. Currently, due to the reported benefits of skin appendages, the technique of follicular unit auto-grafting obtained with a scalp punch is among the chosen strategies for wound repair. This is a minimally invasive, outpatient practice, whose technique has advantages over the donor site, patients recovery and well-being.
Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment
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The therapeutic potential of human BMSCs, ADSCs and amnion-derived MSCs in a murine model of cutaneous wounds was directly compared, and it was found that ADSCs had the most pronounced effect on wound closure [35]. Dermal MSCs have also demonstrated promising effects on wound healing in pre-clinical in vitro and animal studies and in several clinical trials [33,36,37]. In conclusion, the source of MSCs most likely has an impact on the ability of the cells to home to wounded tissue, engraft and exert anti-inflammatory wound healing effects [38–41].
Mesenchymal stromal cells (MSCs) are multi-potent stromal-derived cells capable of self-renewal that possess several advantageous properties for wound healing, making them of interest to the field of dermatology. Research has focused on characterizing the unique properties of MSCs, which broadly revolve around their regenerative and more recently discovered immunomodulatory capacities. Because of ease of harvesting and expansion, differentiation potential and low immunogenicity, MSCs have been leading candidates for tissue engineering and regenerative medicine applications for wound healing, yet results from clinical studies have been variable, and promising pre-clinical work has been difficult to reproduce. Therefore, the specific mechanisms of how MSCs influence the local microenvironment in distinct wound etiologies warrant further research. Of specific interest in MSC-mediated healing is harnessing the secretome, which is composed of components known to positively influence wound healing. Molecules released by the MSC secretome can promote re-epithelialization and angiogenesis while inhibiting fibrosis and microbial invasion. This review focuses on the therapeutic interest in MSCs with regard to wound healing applications, including burns and diabetic ulcers, with specific attention to the genetic skin disease recessive dystrophic epidermolysis bullosa. This review also compares various delivery methods to support skin regeneration in the hopes of combating the poor engraftment of MSCs after delivery, which is one of the major pitfalls in clinical studies utilizing MSCs.
Hair transplantation: Basic overview
2021, Journal of the American Academy of Dermatology
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The technique is similar to the punch grafting technique used for many years in chronic ulcers,99 with the difference that the punch graft source is the hairy scalp. A study comparing transplantation in chronic leg ulcers of grafts harvested from hairy scalp versus nonhairy areas showed a greater healing response with hair grafts.95 Another study showed that hair transplantation into chronic wounds achieved better skin/scar quality than split-thickness skin grafts,100 suggesting a scar remodeling effect induced by the transplanted follicles that needs further investigation.
Modern hair restoration surgery is based on a technique known as follicular unit transplantation, in which follicular units are the exclusive structures used as hair grafts. In Part 1 of this 2-part review, we describe how the techniques employed in hair transplantation have evolved into their present forms. Anatomic concepts of specific relevance for dermatologists are discussed, including the distribution and ex vivo morphology of scalp follicular units. Male androgenetic alopecia and female pattern hair loss are the most common reasons for hair loss consultations with dermatologists and will be the primary focus of this review. However, because not all hair disorders are suitable for transplantation, this review will also describe which scalp conditions are amenable to surgery and which are not. Guidelines are provided to help dermatologists better define good and bad candidates for hair transplantation. Other conditions for which hair transplantation surgery is indicated are reviewed.
Hair Follicle Grafting Therapy Promotes Re-Emergence of Critical Skin Components in Chronic Nonhealing Wounds
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An exploding public health crisis is the exponential growth in the incidence of chronic nonhealing ulcers associated with diseases such as diabetes. Various modalities have been developed to stimulate wound closure that is otherwise recalcitrant to standard clinical treatments. However, these approaches primarily focus on the process of re-epithelialization and are often deficient in regenerating the full spectrum of structures necessary for normal skin function. Autologous hair follicle grafting is a recent therapy to stimulate the closure of such nonhealing wounds, and we observed effects beyond the epidermis to other important components of the dermis. We found that hair follicle grafting facilitated the reappearance of various undifferentiated and differentiated layers of the epidermis with the restoration of epidermal junctions. In addition, other important structures that are critical for cutaneous health and function such as the blood and lymph vasculature, nerve fibers, and sweat gland structures were restored in postgrafted wounds. Interestingly, both immune cells and inflammatory signals were substantially decreased, indicating a reduction in the chronic inflammation that is a hallmark of nonhealing wounds. Our observation that punch wounds created on the postgrafted area likewise healed suggests that this is a self-sustaining long-term therapy for patients with chronic wounds.
Transplantation of autologous single hair units heals chronic wounds in autosomal recessive dystrophic epidermolysis bullosa: A proof-of-concept study
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Hair follicles contain epithelial and mesenchymal stem cells, both of which play a role in wound healing. Terminal hair follicle-containing punch grafts from the scalp have been shown to accelerate healing of chronic venous leg ulcers [10]. We herein report the successful treatment of many chronic non-healing ulcers in a 54-year-old female patient with an intermediate RDEB (previously known as RDEB generalized intermediate, non-Hallopeau-Siemens RDEB) by grafting single hair follicular units extracted from her scalp.
Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is characterized by recurrent mucocutaneous blistering with non-healing ulcers which are often complicated by squamous cell carcinoma (SCC). Despite having as high as 80% death rate from SCC, RDEB still does not have an effective treatment. We report on the efficacy of single follicular unit extract (FUE) grafting to heal chronic ulcers of intermediate RDEB in a 54-year-old woman with extensive chronic wounds covering around 30% of the body surface area. On Day 17 post first graft session, the area of treated ulcers on her right upper back was reduced by 80%. Immunofluorescence study revealed positive type VII collagen expression along the epidermal and follicular basement membrane zone in the donor and recipient sites. A few grafted follicles continued to grow hair on the recipient sites. A total of 360 FUEs were grafted in nine sessions over five years, resulting in healing of most treated ulcers and reduced significantly her time for daily wound dressing. Importantly, FUE grafting using patient's own scalp follicles does not require any laboratory manipulation. It is safe and easy to perform. Autologous follicular grafting appears efficacious for healing of recalcitrant wounds and provides an innovative solution for RDEB patients with such wounds.
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Almost from all organs, both mesenchymal stromal cells and fibroblasts can be isolated. Mesenchymal stromal cells (MSCs) are the most preferred cellular therapeutic agents with the regenerative potential, and fibroblasts are one of the most abundant cell types with the ability to maintain homeostasis. Because of the promising properties of MSCs, they have been well studied and their differentiation potentials, immunomodulatory potentials, gene expression profiles are identified. It has been observed that fibroblasts and mesenchymal stromal cells have similar morphology, gene expression patterns, surface markers, proliferation, differentiation, and immunomodulatory capacities. Thus, it is hard to distinguish these two cell types. Epigenetic signatures, i.e., methylation patterns of cells, are the only usable promising difference between them. Such significant similarities show that these two cells may be related to each other.

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: Partially funded by grants from the Hospital General Universitario de Albacete.

: Conflicts of interest: None declared.

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Original articleHair follicle–containing punch grafts accelerate chronic ulcer healing: A randomized controlled trial

Background

Objective

Methods

Results

Limitations

Conclusion

Section snippets

Study design

Results

Discussion

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Vasc Surg

Lancet

J Invest Dermatol

Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis

Nat Med

Epidermal stem cells arise from the hair follicle after wounding

FASEB J

Exploring the role of stem cells in cutaneous wound healing

Exp Dermatol

Wound healing and skin regeneration

Cold Spring Harb Perspect Med

Dermal papilla cells improve the wound healing process and generate hair bud-like structures in grafted skin substitutes using hair follicle stem cells

Stem Cells Transl Med

Hair follicles and their potential in wound healing

Exp Dermatol

Epigenetic control of skin and hair regeneration after wounding

Exp Dermatol

Regeneration after experimental removal of skin in man

Am J Anat

Reepithelialization of a full-thickness burn from stem cells of hair follicles micrografted into a tissue-engineered dermal template (Integra)

Plast Reconstr Surg

Transplantation of chronic wounds with epidermal sheets derived from autologous hair follicles- the Leipzig experience

Int Wound J

Original article
Hair follicle–containing punch grafts accelerate chronic ulcer healing: A randomized controlled trial