Emerging Surgical Therapies for Vitiligo: Tissue vs Cell-Based Approaches

Introduction

Vitiligo is a common acquired depigmenting disorder caused by the loss of melanocytes. Currently understood as an autoimmune disease associated with skin cell metabolism and oxidative stress,¹ its development involves metabolic, inflammatory, and immune factors. The condition has a global lifetime prevalence of 0.36%² and substantially impairs the quality of life and psychological health of those affected.

Pharmacological and phototherapy approaches primarily target the underlying autoimmune response and are most effective in active, progressive vitiligo. However, their efficacy is limited in stable, completely depigmented lesions where melanocytes have been irreversibly lost. Surgery overcomes this limitation by directly replenishing melanocytes. In recent years, transplantation techniques—which involve transferring normal skin or cells to depigmented areas—have emerged as a safe and effective approach for patients with stable disease lasting more than one year.^1,3–5Following recipient-site preparation using methods such as dermabrasion, laser ablation (eg, CO₂ or Er lasers), suction blistering, cryotherapy, or chemical peeling,^6,7 tissue grafting or cell transplantation is performed to introduce functional melanocytes into vitiliginous patches and facilitate repigmentation.

This review aims to summarize the various surgical and innovative therapies reported in the literature, with the goal of supporting clinical vitiligo management and inspiring further research into surgical treatment strategies.

Methods

Literature Search Strategy

This study followed the PRISMA statement for literature retrieval. A systematic search was conducted in four major medical databases: PubMed, Embase, Web of Science, and the Cochrane Library. The search period covered from the inception of each database to the search date. The language of the retrieved literature was limited to English.

A combination of MeSH terms and free-text words was used. Using PubMed as an example, the search strategy was: (vitiligo[Title/Abstract] AND (surgery[Title/Abstract] OR surgical[Title/Abstract] OR transplantation[Title/Abstract] OR grafting[Title/Abstract])). The search strategies for other databases were adjusted according to their respective syntax requirements. Additionally, supplementary searches were performed by reviewing the reference lists of the included studies.

Inclusion and Exclusion Criteria

The inclusion criteria were: (1) patients with stable vitiligo; (2) studies reporting outcomes of surgical interventions for vitiligo; (3) studies published in English.

The exclusion criteria were: (1) non-English publications; (2) duplicate publications; (3) studies with unavailable full texts and conference abstracts.

Study Screening and Results

The initial search yielded 1245 records. After removing duplicates, the remaining records underwent title and abstract screening, during which 986 records were excluded. The remaining 259 records were assessed for full-text eligibility. After excluding studies with unavailable full texts and conference abstracts, 66 studies were finally included in this review.

Surgical Techniques

Tissue Grafting

Tissue grafting for vitiligo aims to achieve repigmentation via the autologous transfer of pigmented skin. Its use is limited by donor site availability, making it unsuitable for large areas. The main techniques include:

Mini-Punch Grafts

Conventional punch grafting (4 mm) has been used for the treatment of stable vitiligo, with reported excellent repigmentation rates of 50% and cobblestone appearance in 35% of patients.⁸ In contrast, mini-punch grafting (1–2 mm) offers advantages for irregular anatomical sites such as the nipple-areola complex, lips, palms, perineum, and soles, with fewer complications.^9,10

Hair Follicle Transplantation

Follicular transplantation achieves cutaneous repigmentation by transplanting autologous pigmented follicle units from healthy donor sites, such as the occipital scalp, into vitiliginous patches.

Techniques for Harvesting and Implanting Pigmented Follicular Units

This technique implants hair follicle units—primarily anagen-phase follicles from the occipital scalp—into vitiliginous patches. Follicular melanocytes and stem cells contribute to repigmentation.¹¹ The grafts consist mainly of terminal pigmented hair follicles with minimal dermis and epidermis,¹² and even a small number of transplanted melanocytes can produce significant repigmentation.¹³ The subsequent growth of new pigmented hairs also provides visual coverage for areas with leukotrichia.

The method of harvesting these pigmented follicles is critical to their survival. Traditional harvesting methods using large punches or needles can cause significant perifollicular damage and scarring, compromising graft viability. In contrast, minimally invasive harvesting techniques have been developed to reduce tissue trauma. For instance, follicular unit extraction (FUE) with finer instruments and follicular scraping aim to preserve the integrity of the follicle during extraction, thereby improving graft survival and success rates.¹⁴

Management of Leukotrichia (White Hairs) in the Recipient Area

For optimal cosmetic outcomes, persistent white hairs within the vitiligo patch often need to be addressed prior to or in conjunction with surgical repigmentation. The goal here is the selective and permanent destruction of depigmented follicles.

Follicular scraping can be used as an ablative technique directly in the recipient area to remove white hairs. After tumescent anesthesia, a 1–3 cm incision is made down to the subcutaneous layer. Subcutaneous tissue is separated, and curettage is performed until white hairs extract easily. The wound is sutured, with removal after 7–9 days. Pigmented hair transplantation can then be performed into the scarred area 1–3 months later.¹⁴ Electrolysis is another effective method that uses low-current direct current to destroy hair follicles via electrochemical reaction, minimizing peripheral tissue damage compared to older techniques. It effectively achieves permanent white hair removal, which can improve the overall aesthetic result and prevent the visual contrast of white hairs against repigmented skin.¹⁵ A specialized application involves its use in eyelash vitiligo; electrolysis of the depigmented lash follicle can be followed by immediate reimplantation of a pigmented follicle using a triangular needle to secure the root subdermally, achieving a natural, curved appearance.¹⁶

Suction Blister Epidermal Grafting (SBEG)

A commonly used, effective surgical method for small lesions, SBEG involves harvesting the roof of a suction-induced blister from the thigh or abdomen and transplanting it, dermis-side down, onto a dermabraded recipient site. Blister induction time can be reduced by increasing temperature, decreasing blister diameter, or using tumescent anesthesia.¹⁷ Alternatives include cryotherapy or heated suction. Correct orientation is critical; identification methods include fibrin clot presence, epidermal curling tendency, and more pronounced wrinkling on the epidermal side under microscopy.¹⁸ The graft is covered with glycerin gauze for 7–10 days. Advantages include stable repigmentation; drawbacks include peripheral hypopigmented halos and donor-site hyperpigmentation.¹⁹

Thin Skin Grafts

This category includes thin (0.1–0.2 mm) and ultrathin (0.08–0.15 mm) skin grafts harvested at the dermo-epidermal junction using a knife or dermatome.²⁰ Donor skin should be 10%–20% larger than the recipient area,²¹ typically taken from the buttock, thigh, or scalp.²² These grafts provide rapid, uniform repigmentation. Meshing the graft can expand coverage. Before cell transplantation, this was the most effective surgical method,²³ offering superior cosmetic outcomes without cobblestoning compared to SBEG.²⁴

Flip-Top Grafting

After donor skin is harvested and sectioned, 1–5 epidermal flaps (5×5 mm, including minimal papillary dermis) are raised within the vitiligo patch. The grafts are placed under the flaps and sealed with cyanoacrylate. Dressings are removed after one week, with success confirmed by observing pigmentation beneath the flap.²⁵ This method avoids full epidermal removal, reducing scarring and improving survival. Limitations include technical difficulty, small treatment area, and unsuitability for palms/soles.

Smash Grafting

Donor skin is minced into tiny fragments with scissors, mixed with saline, and applied as a semi-solid paste to the recipient site. This simple technique can cover an area up to 10 times larger than the donor site.²⁶ The loss of graft structure allows for even distribution regardless of orientation. Microskin grafting, which employs the same principle, has been successfully used for vitiligo affecting genital areas, achieving nearly complete and uniform repigmentation. However, the overall efficacy of smash grafting requires further validation.²⁷

Epidermal Grafting

Perilesional normal skin serves as the donor site. After applying 2% mupirocin ointment, the site is superficially dermabraded until pinpoint bleeding occurs. The abraded epidermal fragments are collected on a sterile spatula—aided by the ointment—and spread onto the prepared vitiliginous skin. Benefits include single-site surgery, reduced pain, and less dressing use.²⁸ Drawbacks include limited suitability for large areas and possible peripheral hypopigmentation.

An advanced modification involves centrifuging the collected fragments in Ringer’s lactate, mixing the sediment with plasma gel (prepared by combining 0.1 mL autologous serum with 0.9 mL platelet-poor plasma), and applying the mixture to achieve repigmentation comparable to non-cultured melanocyte transplantation.²⁹ Of note, while the traditional method falls under epidermal grafting, the modified version—utilizing centrifugation and plasma gel—processes tissue into a cellular suspension/paste, aligning its mechanism and application more closely with cell transplantation.

A summary table of tissue transplantation for vitiligo is shown in Table 1.

Table 1 Tissue Grafting Techniques for Vitiligo

Cell Transplantation

Cell transplantation techniques for vitiligo include cultured and non-cultured epidermal cell suspensions, as well as non-cultured outer root sheath cell suspensions Potential side effects include hypopigmented halos at the recipient site, and scarring or hyperpigmentation at the donor site.³⁰

Cultured Melanocyte Transplantation (CMT) vs Non-Cultured Epidermal Cell Suspension (NCES)

Cultured Melanocyte Transplantation (CMT)

Melanocytes are expanded in vitro for approximately three weeks before transplantation, achieving a donor-to-recipient area ratio of up to 1:60. The proliferation rate varies by donor site, with facial melanocytes demonstrating the fastest growth and the most sustained proliferation in culture, followed by buttock, abdominal, and limb skin; chest and back skin show the slowest growth.³¹ The requirement for a GMP-certified laboratory, high risk of contamination, and substantial cost limit its use to extensive vitiligo and restrict routine clinical application. Therefore, this review focuses on non-cultured techniques.

Non-Cultured Epidermal Cell Suspension (NCES)

This method involves transplanting a suspension of melanocytes and keratinocytes on the same day (warm trypsinization) or the next day (cold trypsinization) onto a dermabraded recipient area, bypassing the costly and time-consuming cell culture process. It yields repigmentation outcomes comparable to tissue grafting, with a donor-to-recipient ratio of 1:10 to 1:20, and is an effective, durable, and well-tolerated treatment for stable vitiligo.³² One study reported that 67% of patients achieved over 50% repigmentation 24 weeks after a single session.³³ Beyond vitiligo, NCES has been successfully used for repigmenting depigmented areas resulting from burns, herpes zoster, chemical leukoderma, and discoid lupus erythematosus.^33–36A retrospective study of 41 patients with stable vitiligo reported an excellent repigmentation rate (91–100%) of 34.1%, notably with all four pediatric patients (under 14 years of age) achieving >76% repigmentation, suggesting favorable outcomes in children.³⁷

Cell Delivery Methods

The standard method involves applying the cell suspension directly onto the prepared recipient site.^38,39 Adding hyaluronic acid or hydroxypropyl methylcellulose to the suspension increases viscosity and improves adherence.^40,41

Microneedling creates microchannels that facilitate drug or cell delivery. One study reported improved repigmentation after microneedling followed by NCES application, though it may be less effective than dermabrasion.^42–44

Using a tattoo device to inject the suspension intradermally offers advantages such as reduced procedure time, less postoperative pain, and potentially superior repigmentation compared to traditional methods, warranting further investigation.⁴⁵

Trypsinization Protocols

Warm trypsinization (37°C for 45–60 minutes) is widely adopted due to high enzymatic activity and the ability to complete the procedure in one day, enhancing patient convenience. Although cold trypsinization (4°C overnight) may yield higher cell viability and melanin content, clinical repigmentation outcomes between the two methods are comparable.^46–48

Trypsin activity can be halted by:

Washing the cell pellet with phosphate-buffered saline (PBS) or Dulbecco’s Modified Eagle Medium (DMEM) removes trypsin.^39,49,50

Using autologous serum or fetal bovine serum (FBS), which contains protease inhibitors like α1-antitrypsin, effectively neutralizes trypsin.^29,51

Repigmentation on curved or mobile areas (eg, nose, lips) can be uneven due to suspension runoff. Using custom-made elastic impression materials to create well-defined recipient chambers has been shown to improve outcomes by containing the suspension.^52,53

Technical Variations and Adjuncts

Several simplified protocols have been developed to make NCES more accessible. The four-compartment (FC) method uses a specially designed Petri dish divided into four compartments to perform trypsinization, washing, and cell separation in sequence, eliminating the need for a centrifuge and trypsin inhibitors while maintaining high cell viability.⁵⁴ Similarly, the “4-well plate” technique offers another cost-effective, clinic-friendly modification.^55,56

The evidence for adding PRP to NCES is mixed. Some studies suggest it enhances repigmentation, possibly through growth factor stimulation, while others show no significant benefit over standard suspensions, particularly on acral sites.^57–59

Pre-treatment of the recipient site with 5-FU after microneedling has been proposed to improve repigmentation, potentially by modulating local immune responses and promoting melanocyte migration.⁶⁰

These laboratory-grown epidermal sheets, with a near-physiological ratio of melanocytes to keratinocytes, represent an advanced alternative. They are particularly suitable for large areas and difficult-to-treat sites like the hands, offering more uniform repigmentation. Limitations include a longer preparation time (2–4 weeks) and higher technical demands.^19,52,61

Non-Cultured Hair Follicle Cell Suspension (NC-HFCS)

NC-HFCS is prepared from anagen hair follicles obtained via follicular unit extraction. The suspension contains melanocytes, melanocyte stem cells, and keratinocyte stem cells. Approximately 15–25 follicles can treat a 20 cm² area. Studies indicate that NC-HFCS and NCES have comparable efficacy, although NCES is often considered more practical and less time-consuming.⁶² Combining NCES with NC-HFCS may yield better results than NCES alone, possibly due to the immunomodulatory properties and stem cell support provided by follicular cells.⁶³

A summary comparison table of cell transplantation for vitiligo is shown in Table 2.

Table 2 Cell Transplantation Techniques for Vitiligo

Summary and Future Perspectives

Surgical treatments for vitiligo have advanced considerably, demonstrating safe and effective outcomes in patients with stable disease. Tissue transplantation (eg, punch grafting, suction blister, smash grafting) remains a simple, low-cost option with proven efficacy, particularly for localized lesions. Cell transplantation (eg, non-cultured melanocyte suspension, cultured melanocytes) offers superior repigmentation uniformity and can cover larger areas, albeit with higher technical demands and costs. The optimal approach should be selected based on individual patient assessment, including lesion location, size, and skin phototype.¹⁷

A major gap in the current literature is the lack of systematic comparisons of cost-effectiveness and learning curves across different surgical techniques. Future direct comparative studies are urgently needed to establish clear selection parameters. Additionally, the cellular mechanisms underlying surgical repigmentation remain largely unexplored. Emerging evidence suggests that CD8+ T cell count is negatively correlated with post-surgical repigmentation success, serving as a potential biomarker for identifying ideal surgical candidates.⁶⁴ miRNAs in exosomes also regulate melanocyte function, offering promising therapeutic prospects.^65,66

Looking forward, integrating surgical advances with personalized medicine and regenerative dermatology holds great promise. By combining patient-specific biomarkers (eg, CD8+ T cell levels), exosome-based therapies, and engineered cell or tissue products, future surgical approaches can be tailored to individual immune and regenerative profiles, ultimately enhancing repigmentation outcomes and expanding treatment options for refractory vitiligo.