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October 5, 2023

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New insights from studying keloid scars could provide novel treatments for fibrosis

by King's College London

New research, published in Matrix Biology , has revealed a potential therapeutic target within keloid cells, which could provide new treatments for a range of skin diseases and fibrosis, including keloid scars.

Keloid scars are thick, raised scars that are formed from flesh wounds and are typically found on earlobes, shoulders, cheeks, or the chest. Treatment options are limited to removal via surgery, but the scars often regrow.

Using keloid scars as a model of fibrosis , the authors set to find new therapeutic targets by closely studying the extracellular matrix (ECM)—a fibrous network deposited by the cells that connects them to each other and provides a supporting scaffold. Keloid cells lay an ECM with altered structure and properties compared to healthy cells , specifically with a striking alignment of its fibers.

Led by Dr. Tanya Shaw, keloid tissue obtained from surgeries was used in the laboratory to exploit a "scar-in-a-dish" approach. After confirming growth and maintenance of their scar-like properties, the researchers were able to analyze keloid cells and their ECM to find new targets for therapies.

The results identified a role for a molecule called interleukin-6 (IL-6), typically associated with inflammation. In fact, targeting IL-6 with a drug already used in clinics to treat arthritis and COVID-19 was found to reduce the ability of keloid cells to generate aligned and bundled ECMs, suggesting it could be utilized as a therapy for keloid scars.

As well as revealing a new therapeutic target for keloid scars, the authors believe that this scar -in-a-dish approach could be used to screen for new inhibitors for a range of other forms of scarring and fibrosis, as bundled ECMs is a hallmark of many types of scarring found in tissues around the body.

In addition to these therapeutic implications, the results highlight how the structural support cells of the skin have the potential to cooperatively affect the physical properties of the tissue. This insight could have many applications within cellular biology , which the authors also hope to explore in further research. Moreover, they also report novel computational approaches to analyze alignment in bioimages open for use to the community.

"Research about scarring and fibrosis has historically been very focused on the over-abundance of ECM, with the highly aligned organization of the tissue largely ignored. We are excited to be highlighting this widely observed feature of scarring and to have discovered a strategy to potentially correct it," says Dr. Tanya Shaw.

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• Systematic review update
• Open access
• Published: 14 March 2023

Keloid treatments: an evidence-based systematic review of recent advances

• Laura A. Walsh 1 , 2 ,
• Ellen Wu 1 ,
• David Pontes 1 ,
• Kevin R. Kwan 1 ,
• Sneha Poondru 2 ,
• Corinne H. Miller 1 &
• Roopal V. Kundu 1 , 2  

Systematic Reviews volume  12 , Article number:  42 ( 2023 ) Cite this article

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Keloids are pathologic scars that pose a significant functional and cosmetic burden. They are challenging to treat, despite the multitude of treatment modalities currently available.

The aim of this study was to conduct an evidence-based review of all prospective data regarding keloid treatments published between 2010 and 2020.

A systematic literature search of PubMed (National Library of Medicine), Embase (Elsevier), and Cochrane Library (Wiley) was performed in November of 2020. Search strategies with the keywords “keloid” and “treatment” were performed by a medical librarian. The search was limited to prospective studies that were peer-reviewed, reported on clinical outcomes of keloid therapies, and were published in the English language between January 1, 2010, and November 24, 2020.

A total of 3462 unique citations were identified, of which 108 studies met inclusion criteria. Current literature supports silicone gel or sheeting with corticosteroid injections as first-line therapy for keloids. Adjuvant intralesional 5-fluorouracil (5-FU), bleomycin, or verapamil can be considered, although mixed results have been reported with each. Laser therapy can be used in combination with intralesional corticosteroids or topical steroids with occlusion to improve drug penetration. Excision of keloids with immediate post-excision radiation therapy is an effective option for recalcitrant lesions. Finally, silicone sheeting and pressure therapy have evidence for reducing keloid recurrence.

Conclusions

This review was limited by heterogeneity of subject characteristics and study outcome measures, small sample sizes, and inconsistent study designs. Larger and more robust controlled studies are necessary to further understand the variety of existing and emerging keloid treatments, including corticosteroids, cryotherapy, intralesional injections, lasers, photodynamic therapy, excision and radiation, pressure dressings, and others.

Peer Review reports

Introduction

Keloids are dermal proliferations of fibrous tissue that most often arise at sites of cutaneous injury and have significant impact on quality of life. Although keloids are seen in all populations, the highest prevalence is in people of color with an estimated incidence of 4–16% [ 1 , 2 ]. These growths represent the most robust form of abnormal wound healing, presenting as raised, firm lesions that extend beyond the margins of original injury [ 2 ]. Several etiological factors have been proposed, including genetic and hormonal influences [ 3 ]. Increased wound tension has also been associated with keloid formation, although body locations with limited tension such as the earlobe are similarly affected [ 4 ].

Multiple hypotheses have been proposed for keloid formation. Though the pathogenesis of keloids is not fully understood, it likely involves the dysregulation of complex inflammatory pathways [ 5 ]. Proinflammatory cytokines IL-6 and -8 have been shown to increase scarring, while similarly, a decrease anti-inflammatory IL-10 increases scarring [ 6 ]. Keloidal fibroblasts and inflammatory cells may drive keloid formation by dysregulation of normal collagen turnover. Keloids are characterized by an increased ratio of type 1 to type 3 collagen deposition in a haphazard pattern with increased fibroblast proliferation rates and increased sensitivity to growth factors [ 6 , 7 ]. Differences in growth factor production could be due to epithelial-mesenchymal interactions, retention of fetal proliferative pathways, or the hypoxic keloidal tissue environment. Tissue tension has also been implicated as mechanical tension is a driver of fibroblast activity and formation of collagen. Certain inherited human leukocyte antigen subtypes have been associated with keloids, suggesting an abnormal immune response to dermal injury as a cause of keloids. Lastly, dermal injury causing an immune response to sebum, leading to cytokine release stimulating mast cell infiltration and fibroblast activity, has been suggested given the predilection for keloids to form in sites of increased density of pilosebaceous units [ 7 ].

Keloids pose a significant functional and cosmetic burden. They are often pruritic or painful [ 8 ]. Additionally, they can introduce tension in adjacent tissue and cause restrictions in normal movement. The psychosocial effects of developing disfiguring scars have also been repeatedly demonstrated [ 9 , 10 ]. Unfortunately, keloids do not regress spontaneously and are often refractory to treatment.

Current treatment options include intralesional and topical therapies, surgical interventions, radiation, and laser-based therapies [ 11 , 12 , 13 ]. Intralesional corticosteroids are a mainstay of treatment, although other injectables include bleomycin, 5-flourouracil, botulinum toxin type A, verapamil, avotermin, IL-10, mannose-6-phosphate, and insulin. Topical therapies include imiquimod and mitomycin C. Surgical excisions are often paired with a combination of these adjuvant pharmacotherapies, and there is ongoing innovation in keloid excision and wound closure technique. Radiation therapies include external-beam radiation and interstitial brachytherapy administered at low- or high-dose rates [ 13 ]. Pulsed dye laser (PDL), cryotherapy, and pressure dressings are often utilized, as well as over-the-counter silicone sheets and topical vitamin E creams. Despite the myriad of proposed treatment options, keloids continue to pose a therapeutic challenge, and an updated body of evidence-based recommendations to guide disease management is lacking.

The objectives of this systematic review were to examine the evidence from the past decade for the treatment of keloids, determine the efficacy and limitations, and recommend areas for improvement.

This systematic review of the relevant literature on keloid treatments was conducted according to methods outlined in the Cochrane Handbook and reported according to the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Search strategy

A medical librarian (C. M.) created the search strategy to investigate therapies for keloid treatment published in English between the years 2010 and 2020. On November 24, 2020, searches were conducted on PubMed (National Library of Medicine), Embase (Elsevier), and Cochrane Library (Wiley) using keywords and subject headings related to “keloid” and “treatment.” The full search strategy is available at https://doi.org/10.18131/g3-b39v-s030 .

Inclusion criteria

Articles were included if they were peer-reviewed, had a prospective study design (including non-randomized interventional studies and randomized controlled trials), reported on clinical outcomes of keloid treatments, and were published in English between January 1, 2010, and the day searches were conducted (November 24, 2020).

Screening and study selection

Studies from the search result were downloaded into an EndNote database. Two reviewers independently screened titles and abstracts of all obtained studies, ensuring studies met the inclusion criteria. Any disagreements were then consulted with a third independent reviewer. Full texts of studies that were included by title and abstract screening were further reviewed, again independently by the two reviewers. Any disagreements were also consulted with a third independent reviewer as needed.

Risk-of-bias assessment

Risk of bias for studies that were classified as randomized controlled trials was evaluated with the RoB 2: a revised Cochrane risk-of-bias tool for randomized trials [ 14 ]. Five categories of bias — randomization process, deviations from intended interventions, missing outcome data, measurement of the outcomes, and the selection of reported outcomes — were assessed using the RoB 2 algorithm and classified as low risk, some concerns, high risk, or no information.

For studies that were non-randomized interventional trials, the risk of bias in non-randomized studies of interventions (ROBINS-I) assessment tool was used to evaluate the risk of bias in seven categories: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, outcome measurement, and selective reporting [ 15 ]. The ROBINS-I guide was used to grade each category as low risk, moderate risk, serious risk, or no information.

Figures of the risk-of-bias results were created using the risk-of-bias VISualization (robvis) online tool [ 16 ].

Data extraction

Two reviewers independently extracted data from the studies in the EndNote database. The following data were extracted as follows:

Publication details: Authors and date of publication

Study design: I.e., randomized control trial, single- or double-blind, split-scar study

Participants: Number of participants and demographics

Type of treatment or intervention

Outcomes including subject- and physician-reported responses to treatment, objective measures of treatment, recurrence rates, follow-up time, and adverse events.

Data synthesis

We were not able to pool data from multiple studies given the heterogeneity of measurements used for quantifying outcomes. Data extracted from eligible studies were analyzed using a narrative approach. This synthesis aimed to provide an evidence-based review of all prospective data regarding keloid treatments and outcomes in the last decade.

There were 3462 articles included in the literature search. Screening of titles and abstracts yielded 440 articles for full-text evaluation, of which 108 were included, 305 were excluded, and 27 did not have full texts available to obtain (Fig. 1 ). Exclusion reasons included retrospective study design (80), wrong publication type (50), wrong study design (45), nonclinical outcome (14), wrong population (14), hypertrophic scar (96), and foreign language (6).

Flow diagram

The total sample size was 4552 subjects (range of 6–240). The follow-up times varied from 4 weeks to 10 years. There were 37 randomized studies, 4 split scar studies, and 1 placebo-controlled studies.

Risk of bias in the 37 randomized controlled trials was low overall throughout the domains assessed in RoB 2 (Fig. 2 ). The measurement of outcomes domain had the highest proportion of studies with some concerns of bias, mainly due to lack of evaluator blinding and differences in timeframe of follow-up amongst the interventions (see Additional file 1 for the RoB 2 assessment for each study). Similarly, majority of non-randomized interventional studies were rated as low or moderate risk of bias with the ROBINS-I algorithm (Fig. 3 ). Only 4 out of the 71 non-randomized interventional studies had some components of serious risk of bias (see Additional file 2 for the ROBINS-I assessment for each study).

Risk-of-bias summary for randomized controlled trials assessed with RoB 2

Risk-of-bias summary for non-randomized interventional studies assessed with ROBINS-I

Corticosteroids

Intralesional corticosteroids are the most commonly used nonsurgical treatment for keloids (Table 1 ). Intralesional triamcinolone acetonide (IL TAC) 10–40 mg/ml is most ubiquitous and induces keloid regression through a variety of proposed mechanisms including suppression of dermal inflammation, reduction of oxygen delivery to the wound bed via vasoconstriction, and antimitotic activity in keratinocytes and fibroblasts [ 17 ]. In review of 19 articles, there was unanimous clinical improvement in keloids with intralesional corticosteroid treatment. However, the degree of improvement and its relationship with treatment characteristics such as dosage, frequency, and timing of injections were variable [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].

In terms of dosing, 20–40 mg/ml of triamcinolone acetonide was most commonly investigated (8 of16 studies). Notably, a study by Huu et al. compared IL TAC 7.5 and 14 mg/cm 2 and found a larger proportion of “good” and “quite good” results in the smaller dosage group; however, the size and characteristics of the studied keloids were not specified [ 28 ]. Frequency of treatments ranged from single injections to weekly and monthly injections. Aluko-Okun et al. (2016) studied optimal TAC dosing and observed the greatest reduction in keloid volume with 2-week treatment intervals [ 21 ].

Intralesional TAC was combined with surgical excisions in several studies with mixed results. Tripoli et al. reported no recurrences in subjects treated with two dosages of TAC after radial excision at their 2-year follow-up [ 35 ]. This is compared to the 9 controls who were excised without TAC and demonstrated a 67% recurrence rate. However, Dos Santos et al. compared excision +/− 3 weeks of preoperative 20-mg triamcinolone hexacetonide and found no significant difference in keloid dimensions at 6-month follow-up [ 26 ]. Bashir studied intraoperative TAC vs. intraoperative and postoperative TAC in 70 subjects and found no significant difference between the two groups [ 23 ]. Finally, when IL TAC 20 mg/ml was combined with intralesional radiofrequency in a cohort of 60 subjects, Kaushal et al. reported fewer recurrences at 6 months compared to IL TAC alone [ 29 ].

In addition to treatment parameters, keloid response is likely influenced by lesion characteristics. Aluko-Olokun et al. (2014) compared response of sessile vs. pedunculated lesions to TAC 10 mg and found a lack of response by pedunculated lesions compared to flattening of 23 of the 26 treated sessile lesions [ 19 ].

While topical steroids are less commonly used in the treatment of keloids, Nor et al. compared IL TAC 40 mg/ml monthly for 3 sessions to daily topical clobetasol propionate 0.05% cream under occlusion with silicone dressing [ 30 ]. There was no significant difference in reduction in keloid size; however, topical treatment resulted in significantly fewer adverse effects.

Finally, there is innovation in TAC drug delivery modalities, including a metal syringe and drug embedded microneedles. The metal syringe was proposed by Aluko-Olokun et al. as a new delivery system to address the issues of syringe failure and inadequate drug delivery to firm lesions [ 20 ]. Dissolving microneedles are self-administered once a month, empowering patients in their own care and reducing the inconvenience of frequent office visits. Initial studies suggest that these alternate delivery methods yield superior results compared to traditional plastic syringes. However, for TAC embedded microneedle arrays (MNAs), the volume decrease seems to be transient and not a durable response [ 33 , 34 ].

Cryotherapy

Cryotherapy or cryosurgery is a long-standing technique which relies on the reduction of temperature to cause irreversible cellular damage (Table 2 ). For treatment of keloids, studies have shown that cryotherapy transitions the keloidal fibroblasts towards a normal fibroblastic phenotype, increasing the ratio of type 3 to type 1 collagen in vitro [ 37 , 38 ]. An additional advantage is that the decellularized matrix is left as a scaffold, possibly preventing recurrence. Cryosurgery alone has been shown to flatten keloids [ 39 ]. Intralesional verapamil, cryosurgery alone, or cryosurgery with intralesional TAC or verapamil all showed significant ( p < 0.001) improvement in all VSS variables with no difference from cryosurgery with IL TAC [ 40 ]. Similarly, Fraccalvieri showed that cryosurgery alone or in combination with shave removal led to a majority of subjects (83% of 76 subjects) experiencing a 75–82% decrease in keloid height [ 41 ]. A smaller study of 12 subjects showed that a combination of shave removal, cryosurgery, and IL TAC had only 1 recurrence with 75% of subjects seeing a significant reduction in thickness [ 42 ]. Additionally, a combination of surgical excision, cryosurgery, and platelet-rich plasma (PRP) led to 70% of the 50 subjects observing improvement in keloid height and a recurrence 6 lesions after 7 months of follow-up [ 43 ].

Intralesional cryotherapy was first introduced in 1993 [ 50 ]. Patni et al. showed that with up to three sessions of intralesional cryotherapy, subjects saw a significant improvement of POSAS, and 50% of subjects saw a scar surface reduction of about 92% [ 48 ]. Additional recent investigation in the field of keloid treatment has compared intralesional cryotherapy to open spray cryotherapy. Mourad et al. and Abdel-Meguid et al. both showed that intralesional cryotherapy improved clinical appearance of keloids [ 44 , 47 ]. However, a randomized trial by Bijlard et al. was terminated prematurely due to intralesional cryotherapy having inferior results to excision and IL TAC for primary keloids and excision and RT for resistant keloids [ 46 ]. A new innovation to intralesional cryotherapy is the use of argon in place of liquid nitrogen. The benefit is more controlled and accurate freezing and has a well-established history of use within the field of oncology. Van Leeuwen et al. showed a volume reduction of 62% [ 49 ]. However, further comparative studies will likely be required for such a technique to become more widely adopted.

Intralesional injection

Many non-corticosteroid intralesional injections and combination treatments have been studied for keloid treatment including verapamil hydrochloride, 5-fluorouracil (5-FU), bleomycin, botulinum toxin A (BTA), hyaluronidase, and platelet-rich plasma (PRP) (Table 3 ). In many cases, TAC was used as the control group treatment when investigating these other agents.

Verapamil is a calcium channel blocker that suppresses extracellular matrix molecules formation and promotes collagen breakdown. It is commonly used in the concentration of 2.5 mg/ml when treating keloids. In several noncontrolled studies, verapamil treatment alone or in combination with keloidectomy or pulse dye laser (PDL) resulted in decreased VSS scores and positive clinical response [ 51 , 55 , 61 ]. However, intralesional verapamil was inferior when compared to IL TAC. In a double-blinded controlled trial comparing 4 monthly doses of verapamil to identically scheduled TAC 5 mg/ml in 14 keloid lesions, there was significantly higher recurrence rates at 12-month follow-up with a hazard ratio for recurrence of 8.44 ( 95% CI 1.62–44.05) [ 54 ]. In their intraindividual study, Saki et al. compared verapamil + cryotherapy to TAC 20 mg/ml + cryotherapy in opposite ends of the same lesion (a split scar study); results showed statistically greater reduction in height and improved pliability in the TAC group [ 68 ].

Bleomycin is an antineoplastic agent that causes necrosis of fibroblasts. Two studies investigated bleomycin and demonstrated its utility in keloid treatment [ 59 , 74 ]. Khan et al. most robustly showed this effect in 164 keloids: 6 doses of monthly 1.5 IU/m was more effective than identically scheduled TAC 40 mg/ml, achieving 50% reduction in the POSAS score from baseline. This difference was independent of age, gender, Fitzpatrick skin type, the duration of keloids, or baseline POSAS score [ 59 ].

The antimetabolite 5-FU inhibits fibroblast proliferation through disruption of DNA replication. 5-FU is used independently and in combination with other treatments, most commonly IL TAC. Saha et al. compared 5-FU with TAC in 44 subjects and showed both were equally effective [ 67 ]. Ali et al., in a randomized controlled trial comparing 50 mg/ml 5-FU alone with combination 5-FU 50 mg/ml (0.9 ml) + 40 mg/ml TAC (0.1 ml), showed that reduction of mean keloid height after treatment was significantly greater in the combination group ( p = 0.0008) [ 53 ]. Saleem et al. similarly showed a combination of TAC+5-FU had significantly greater improvement in VSS than TAC alone in 100 subjects [ 69 ]. Sagheer et al. demonstrated similar superiority of combination TAC 40 mg/dl (0.1 ml) and 5-FU 50 mg/ml compared to 5-FU alone [ 66 ]. Notably, adverse effects were not reported in either study; however, in another noncontrolled study, Reinholz et al. demonstrated local adverse effects in > 90% of their subjects, including hyperpigmentation, telangiectasia, and ulceration [ 64 ]. Srivastava et al. compared TAC vs. 5-FU vs. TAC + 5-FU and showed all improved VSS scores compared to baseline in 60 subjects [ 75 ]. Finally, Sadeghinia et al. compared intralesional TAC 40 mg/ml to 5-FU applied by a unique tattoo method [ 65 ]. In the latter group, 5-FU 50 mg/ml solution was dripped on each 1 cm 2 of the lesions. Subsequently, 40 punctures per 5 mm 2 were made followed by a second round of 5-FU drip application. This methodology theoretically allows for deeper and more even penetration of the drug and resulted in significantly decreased induration and pruritus and improved observer assessment by a blinded dermatologist with respect to overall improvement on a 5-point scale.

Botulinum toxin A (BTA) is a neurotoxin known for its paralytic effects. Its utility in keloid treatment may be related to reduction of muscular tension at wound sites and direct fibroblast regulation. No significant difference was found in 2 double-blinded controlled trials comparing 5 IU/cm 3 to TAC 10 mg/ml and BTA 20 μ/ml to TAC 20mg/ml, respectively [ 63 , 70 ]. Interestingly, in a head-to-head comparison between 5-FU 50 mg/ml and BTA 2.5 U/cm 3 , Ismail et al. showed significantly greater flattening by BTA ( p = 0.04) [ 58 ]. As a combination therapy, Gamil et al. showed significantly ( p = 0.0001) reduced keloid surface area in 24 keloids treated with intralesional BTA and TAC compared to 26 subjects treated with TAC or BTA alone [ 56 ].

The enzyme hyaluronidase catalyzes the breakdown of the mucopolysaccharide hyaluronic acid. Although it has been studied in the treatment of keloids, its mechanism of action is not clearly understood. Aggarwal et al. showed that TAC + 1500 IU/ml hyaluronidase had similar clinical efficacy compared to triamcinolone alone but fewer side effects (18.75% subjects developed atrophy with combination in comparison with 31.25% subjects with triamcinolone alone, p < 0.001, chi-square test) [ 52 ]. The author highlights that in the combination group, the TAC dosage was effectively halved, suggesting a synergistic effect of TAC and hyaluronidase combination treatment. Velurethu et al. showed a combination of intralesional 5-FU, TAC, and hyaluronidase every 4 weeks for 50 subjects with 60 keloids led to flattening in 65% and > 90% reduction in scar volume in 35% of keloids after 4 sessions [ 72 ]. Only two recurrences were observed at follow-up after 6 months.

PRP is autologous platelet concentrate that is used in a variety of conditions to promote wound healing, decrease pain, and combat inflammation. In an RCT comparing gold standard IL TAC 20 mg/ml every 3 weeks for 4 sessions to identically scheduled IL TAC followed by 1 injection of PRP, the latter was shown to have superior keloid response and fewer adverse effects [ 57 ].

In combination with keloid excision, intralesional treatment with the previous therapeutics is used to decrease recurrence rates. Khare et al. treated the wound bed and margin with 5-FU after excision for 28 subjects [ 60 ]. They observed a recurrence rate of 3.57% in the 28 treated subjects compared with a 21.9% recurrence rate over 1 year in the 32 control subjects treated with IL TAC. Similarly, Wilson et al. treated 80 subjects with excision followed by IL 5-FU and BTA 9 days post surgery and observed a recurrence rate of 3.75% [ 73 ]. Pruksapong et al. randomized 25 subjects with 50 keloids to keloid excision and then IL TAC or IL BTA [ 62 ]. Subjects receiving IL BTA had significantly ( p < 0.010) decreased VSS.

Light-based therapy

Both ablative and non-ablative lasers have been proposed for the treatment of keloids (Table 4 ). Ablative lasers include the erbium (Er:YAG) laser and CO2 laser, and they cause local tissue destruction by targeting the water chromophore. Non-ablative lasers such as ND:YAG, diode lasers, and pulsed dye lasers (PDL) target melanin and/or hemoglobin. The mechanism by which lasers treat keloids is less clear and may include local damage to lesional blood vessels or direct fibroblast suppression. While lasers can be used as independent therapy for keloids, they are also being investigated in combination with therapeutics to assist in drug delivery and penetration. In our cohort of prospective studies, CO 2 lasers were the most frequently investigated, followed by erbium ablative lasers, ND:YAG, diode lasers, and finally PDL.

In their RCT of 60 subjects, Behera et al. found no significant difference in therapeutic response by keloids treated with 5 sessions of CO 2 laser compared to cryotherapy, both in conjunction with IL TAC 40 mg/ml [ 78 ]. However, CO 2 laser therapy yielded more frequent early adverse effects. A prospective study of 41 keloids treated with CO 2 followed by topical TAC 40 mg/ml Q4 weeks for 8 sessions showed a recurrence rate of 10.5% at 24 months [ 83 ]. Garg et al. similarly showed a recurrence rate of 11.7% in subjects treated with CO 2 with regular follow-up of IL TAC in 35 treated keloids [ 80 ]. Unfortunately, there were no studies of CO 2 laser + IL TAC compared to IL TAC alone, precluding the direct evaluation of CO 2 laser treatment. Srivastava et al. compared CO 2 ablative laser alone compared to IL TAC 40 mg/ml alone and found no significant differences between keloid response but faster improvement in the IL TAC group [ 71 ].

In a split-side controlled study, Abd El-Deyem et al. demonstrated the superiority of fractional ablative 2940 nm Er:YAG laser-assisted delivery of betamethasone vs IL TAC 10 mg/ml alone [ 76 ]. The difference in steroid used between groups is a significant confounding variable. Conflicting results were reported in another study where no difference in clinical improvement was appreciated between keloids treated with Er:YAG laser and IL TAC 10 mg/ml versus topical desoximetasone 0.25% ointment with 3-h occlusion [ 84 ].

A prospective study of 62 subjects showed that the addition of 1064-nm Nd:YAG to IL disprospan and IL 5-FU resulted in superior results compared to either drug alone or the two combined (78% excellent responses vs. 58% and 20%) [ 79 ]. These results make a compelling case for Nd:YAG-assisted drug delivery. Annabathula et al. combined Nd:YAG, CO 2 , and PDL Q4 weeks for 5 sessions. In their 11 subjects whom completed the study, 5 showed minimal to no improvement, 4 moderate (26–50%), improvement, and 2 > 50% improvement based on size, color, and aesthetic impression by three blinded dermatologists [ 77 ].

Kassab et al. followed clinical improvement of earlobe keloids treated with 980 nm diode followed by IL TAC 40 mg/mL Q3 weeks for a variable 2–5 sessions [ 81 ]. While 7% of lesions shrunk at least 75% in size, the sample size was small ( n = 16).

Photodynamic therapy

There is sparse but emerging evidence on the utilization of photodynamic therapy (PDT) in treating keloids and hypertrophic scars (Table 5 ). PDT is typically administered following the application of a photosensitizing agent such as 5-aminolaevulinic acid (ALA). While the mechanisms underlying the response of keloids to PDT are still under investigation, PDT is emerging as a potential adjunct therapeutic option for keloid treatment.

Basdew et al. conducted one of the first large-scale studies investigating the clinical use of PDT for keloid treatment, comparing surgical excision with either adjunctive interstitial brachytherapy or ALA applied to the wound bed followed by postoperative interstitial PDT using an inserted transparent catheter with a cylindrical diode laser diffuser [ 86 ]. Subjects and observers were more satisfied with results after brachytherapy than PDT; however, subjects had a positive general impression after PDT. Adverse effects of burning were present for all subjects during interstitial illumination treatments necessitating intravenous opioids. Topical PDT sessions were better tolerated. Bu et al. preformed a prospective trial comparing surgery and superficial X-ray radiation therapy vs. surgery, superficial X-ray radiation therapy, and PDT in the split scar study in 10 subjects [ 85 ]. Both treatments noted significant symptom reduction. Only 1 keloid was painful at baseline which was relieved in both treatment groups by 6-month follow-up but reappeared in the treatment of postoperative radiation alone at 20-month follow-up. One of the ten subjects experienced keloid recurrence at 20 months on both sides of the scar. Adverse effects of mild pain were noted with PDT as well as one blister developing after PDT. Mild hyperpigmentation was observed in 6 subjects at 6-month follow-up of both treatment groups with gradual relief by the 20-month follow-up. These studies highlighted that although PDT carries the adverse effect of pain, it can potentially be a beneficial adjunct therapy.

Radiotherapy

Surgical excision of keloids is a potential treatment for mature keloids after failure of first-line therapies. However, as a monotherapy, it is associated with a recurrence rate of up to 100% [ 87 ]. To reduce the risk of recurrence, combination treatment modalities have been used. Surgical excision followed by radiation therapy has been showed to be highly effective at reducing recurrence (Table 6 ). Reduction in fibroblast proliferation and suppression of collagen synthesis by downregulation of TGF-beta and histamine release from mast cells is thought to be the underlying mechanism of action. Typical side effects include dyschromia and telangiectasia.

Direct comparisons of methods of keloid treatment are lacking. Aluko-Olokun et al. showed that IL TAC was superior to excision + RT in flattening facial keloids [ 88 ]. Similarly, Khalid et al. showed keloids treated with excision followed by IL TAC and 5-FU recurred in 8 of 30 subjects compared to 17 of 30 keloids treated with excision + RT at 6 months [ 110 ]. In contrast, Emad et al. found lower treatment failure and higher patient satisfaction with excision + RT than IL TAC and cryotherapy [ 90 ].

The majority of studies of excision + RT show administration of radiation within 24 h. Lee et al. compared timing of RT after excision. Of 37 keloids treated, 7 recurred with 1 being treated within 24 h and the other 6 treated after 72 h [ 99 ]. There have been a range of radiation doses and schedules investigated in the treatment of keloidal scars with no clear consensus on optimal dose and schedule. Recent evidence examining outcomes of keloids treated with excision and radiation therapy has recurrence rates ranging from no recurrence of the 26 and 16 treated keloids [ 104 , 105 ] to 56.6% recurrence in 30 treated keloids [ 110 ]. Jiang et al. (2015 and 2018) showed low recurrence rates of 2 of 32 treated keloids (6%) and 3 of 37 keloids (8.1% )[ 95 , 96 ], and Dunst et al. (2013) showed no recurrence with excision followed by 18 Gy of RT in 3 fractions over 36 h [ 89 ]. With the same total dose of radiation, Jones et al. showed a recurrence rate of 19% with RT divided over 4 days [ 97 ]. In another more extended schedule of radiation, Mohammadi et al. showed no recurrence over a minimum follow-up of 11 months for keloids treated with excision followed by 3 Gy of radiation daily for 5 days [ 104 ]. Vila Capel et al. demonstrated a higher 24% recurrence for excision followed by 15 Gy of radiation over 5 fractions given over 1 week using an electron beam with a novel aluminum spoiler [ 108 ].

Van Leeuwen et al. found a recurrence rate of 3.1% with excision followed by 12 Gy of RT in two fractions within 24 h [ 106 ]. In contrast, 12–15 Gy of radiation divided into three fractions started within 24 h of excision for repeat C-section keloids showed a recurrence rate of 23% (Kim 2012) [ 98 ]. A single 13-Gy dose of brachytherapy within 2 h of excision from an implanted catheter also showed a similar rate of recurrence of 24% (Hafkamp 2017) [ 94 ]. Vera et al. showed a recurrence rate of 4.9% with excision followed by 12 Gy of brachytherapy in 4 fractions every 12 h (Vera, 2019) [ 105 ]. Song et al. also investigated a single radiation dose, showing no recurrence with excision followed by one dose of 10 Gy of radiation within 72 h and continued pressure therapy and oral tranilast (no dose specified, approved in Japan and South Korea) for greater than 3 months [ 105 ]. Combination of therapies showed a recurrence rate within the range seen for either excision or RT. Using a combination of excision, intraoperative intralesional triamcinolone, one dose of 10 Gy of radiation within 20 h of excision, and 12 weeks of silicone sheeting with pressure therapy if VSS was > 5 was shown to have a recurrence rate of 12.5% for auricular keloids (Masoodi 2014) [ 103 ].

Examining specifically chest wall keloids, studies have focused on precut and pre- and post-RT methods. Zeng et al. showed only one subject with mild hypertrophic scaring after a protocol of precutting for excision, two doses of pre-radiation, excision with flap repair, and post-op RT [ 109 ]. Li et al. compared a similar precut method to more conventional excision + radiation for treatment of chest wall keloids [ 100 ]. The pre-cut, pre-RT method was superior with a 16.7% recurrence rate compared to 55.2% with only post-excision radiation. In a larger study of this technique, Li et al. demonstrated a recurrence rate of 12.79% over 24 months of follow-up using the precut, pre-radiation method [ 101 ].

Liu et al. demonstrated a novel surgical technique of dissecting the keloid tissue from the overlying skin for use as a flap during repair [ 102 ]. Excision was followed by RT at days 1 and 7 post-op and hyperbaric oxygen at day 2. Continued silicone and pressure bandaging was used for 6–12 months. Over 18 months of follow-up, the recurrence rate was 11.1%.

Radiation as a monotherapy has also been investigated in the form of personalized patches containing either rhenium-188 or phosphorus-32. Subjects have generally shown flattening of their treated keloids with 59–77% showing > 50% flattening, with the highest percentages in those treated with a P-32 patch [ 91 , 92 , 93 ]. The side effects of treatment were radiation dermatitis, which was no different between the P-32 and Re-188 patches.

Silicone and pressure

Alteration of mechanical forces such as application of pressure or reduction of wound tension has been a long-standing treatment for keloids (Table 7 ). There has been sparse research examining the use of pressure as a monotherapy for keloids. One such study was a prospective noninvasive intervention study examining the daily application of traditionally worn tight clothing for 2 years conducted by Aluko-Olokun et al. [ 111 ] A mean volume reduction of 66.8% was seen in keloids with pedunculated lesions and 100% in keloids in sessile lesions. This study highlights the possible effectiveness of tight clothing as a noninvasive therapy for keloids, especially those with sessile morphology.

Wound tension has been implicated in the pathogenesis of keloid formation. Chen et al. examined the use of a tension offloading device (TOD) applied for 6 months immediately after surgical excision [ 115 ]. After 2 years of follow-up, 35 of 38 subjects achieved healing with no recurrence. The use of the TOD requires high patient compliance. According to the authors, the 3 subjects that experienced recurrence in the study were noncompliant with recommended guidelines for TOD use.

A prospective observational study by Tanaydin et al. followed 28 subjects that underwent surgical excision followed by application of a custom molded adjustable pressure clip to be worn 12 to 16 h per day for an average of 12–15 months [ 118 ]. In the group that reported nonrecurrence (71%), subjects were more compliant with therapy compared to the recurrence group. Another method of applying adjustable pressure is through magnets as studied by Park et al. where the outcomes of 40 subjects undergoing surgical excision of pure helical rim keloids followed by silicone gel sheets sandwiched between magnets for 12 h a day for 4 months were recorded [ 82 ]. At 18-month follow-up, there was a recurrence-free rate of 95% alongside a significant reduction in pain, itch, stiffness, thickness relief, and pliability on POSAS; no adverse events were reported.

The use of adjuvant therapy following surgical excision and application of pressure dressings has also been studied. Hatamipour et al. preformed a double-blinded randomized control trial comparing surgical excision with topical silicone vs adjuvant treatment with 5-FU [ 117 ]. At 1-year follow-up, 75% of subjects receiving all three therapies were keloid-free. Similarly, there have been studies examining adjuvant TAC injection with pressure therapy. De Sousa et al. performed a study examining surgical excision with intraoperative and postoperative TAC injection every 3 weeks for 12 weeks as well as silicone pressure dressing applied postoperatively for 48 h [ 116 ]. Keloid recurrence of 9.1% was seen at the end of follow-up at 16 months. Carvalhaes et al. also examined the use of intralesional TAC given before excision, perioperatively, and postoperatively [ 114 ]. Pressure earrings were used following excision in all groups. IL TAC at 20 mg/ml and 40 mg/ml were effective with no difference between groups. In a study by Bran et al., 7 subjects that underwent surgical excision of auricular keloids with corticosteroid injection followed by application of a custom-made pressure device had complete resolution with no recurrence at 2-years follow-up [ 113 ]. Bae-Harboe et al. examined injection of collagenase Clostridium histolyticum to earlobe keloids followed by use of compression earrings [ 112 ]. An average of 50% reduction was seen in all keloids.

Other treatments

Recent prospective studies have focused on novel treatment methods (Table 8 ). Extracorporeal shockwave therapy (ESWT) as a monotherapy for keloids showed a reduction in volume, height, and appearance that was not significantly different compared to intralesional triamcinolone [ 119 ]. When ESWT was combined with IL TAC, Kim et al. noted a significant improvement in VSS compared to IL TAC alone, with no significant difference in side effects [ 120 ]. Further long-term studies of the effect of ESWT would be interesting as an additional treatment modality prior to excision. Application of a drug-free solid microneedle array found that after 4 weeks of treatment, there was a transient decrease in volume without a difference in VSS compared to an untreated control [ 121 ]. The treatment modality was well tolerated, but given that the volume improvement was lost, it is unclear what, if any, therapy duration would be needed for a durable clinical response. Finally, a custom radiotherapy patch led to durable symptomatic improvement and reduction in size in elevation [ 122 ]. Further studies will be needed to show how well these patches perform compared to standards of care such as IL TAC. Radiofrequency, most often used in cosmetic procedures such as micro-needling as well as ablative procedures for malignancy, was combined with IL TAC for the treatment of keloids. Weshay et al. treated 21 subjects with 3 to 4 sessions of radiofrequency and then IL TAC, and of the 18 subjects who completed the study, there was a 95.4% reduction in mean volume [ 123 ].

Many new treatment modalities were investigated as adjunctive therapy with excision. Oral colchicine taken 1 month prior to excision until 1 year after impressively found no recurrence during the follow-up period, though only 10 subjects were treated (Sigler 2010) [ 128 ]. Excision with IL-TAC until scar flattening was compared to post-excision 5% topical imiquimod every other night for 12 weeks, showing a reduction in recurrence from 50 to 21.43% [ 126 ]. Berman et al. found a very promising recurrence rate of 7.7% for keloids treated with excision and then placement of a porcine hydrogel scaffold [ 124 ]. Similarly, Garakaparthi et al. showed a 19.2% recurrence rate with excision and then administration of a hydrogel scaffold for treatment of ear lobe keloids [ 125 ]. To improve upon the low recurrence rates of excision followed by RT, Song et al. investigated the addition of hyperbaric oxygen therapy daily for 2 weeks in addition to excision and RT and found it reduced the recurrence rate to 5.9% compared to 14.15% with excision and RT alone [ 129 ]. Lastly, Salunke et al. showed that a ligation with cauterization method reduced the recurrence rate from 70% with ligation alone to 10% [ 127 ].

Discussion and recommendations

Pressure and silicone-based therapies have long-standing data behind their efficacy and safety when used both as prevention after surgery and treatment of established keloids, as has been noted by multiple recent consensus guidelines [ 130 ]. Recent evidence contributes similar results to the collective literature, showing silicone dressings decreased recurrence while being both safe and well tolerated. Only one recent study examined pressure therapy without excision. Bae-Harboe showed a 50% improvement with pressure earring applied after intralesional collagenase administration. Flatter lesions would likely respond better in combination with corticosteroid impregnated tape and silicone dressings [ 131 ]; however, no recent studies have compared these modalities. Overall, these studies highlighted that the key to effectiveness of compression therapy may lie in compliance as well as providing adequate levels of pressure. Limitations to pressure therapy include conspicuous nature of devices, keloid morphology, and patient comfort. Pressure therapy may provide some effect for those looking for conservative treatment for keloids, but effectiveness is increased with combination therapy and with adjustable pressure devices worn for at least periods of 12 h. As ways to manipulate mechanical pressure to treat keloids are explored, the reduction of tension utilizing special tension offloading devices shows promise.

For established keloids, intralesional corticosteroids are the first-line treatment with or without additional therapeutics topically or intralesionally, as is recommended by many consensus guidelines [ 131 , 132 , 133 , 134 ]. Recent studies have focused on how best to administer IL TAC. Optimal interval timing between injections was suggested to be 2 weeks, though standard of care is typically 4–6 weeks, so further studies confirming this will be needed to change clinical practice. As clinically suspected, sessile lesions were found to respond better to IL TAC compared to pedunculated keloids. The role of IL TAC as an adjuvant to surgical excision continues to have conflicting results in the literature, and some studies lack a control group, making it difficult to recommend compared to methods such as excision with adjunctive RT, which has consistently low recurrence rates.

Other intralesional injections including botulinun toxin A (BTA), bleomycin, mitomycin C, PRP, and collagenase have been recently investigated. The success of treatment with verapamil is mixed and treatment both as an intralesional therapy or as an adjuvant to cryotherapy or excision; verapamil has not consistently outperformed IL TAC. However, verapamil is well-tolerated, so likely lower risk of adverse events. 5-FU has been extensively studied, and recent literature has confirmed synergy in treatment with IL TAC, outperforming either treatment alone in multiple comparative studies, though does have an increased risk of ulceration. 5-FU tattooing has shown promising results, outperforming IL-TAC in a randomized double-blinded study. In recent studies, bleomycin did not outperform IL TAC and had an increased risk of bulla and ulceration. Interestingly, BTA outperformed 5-FU alone and was found to have no difference compared to IL TAC in a double-blinded study, with a low risk of hypopigmentation. Surgical excision with adjuvant cryotherapy and PRP showed a recurrence rate of 16.21%, though since the study had no control group, further study is needed to recommend PRP.

Intralesional cryotherapy is recommended for smaller lesions [ 131 ]. Recent comparative studies have shown that intralesional cryotherapy was less effective than excision + IL TAC or excision + RT for resistant keloids, leading to early termination of the trial. Intralesional cryotherapy was shown to have better clinical improvement in two recent studies. Intralesional cryotherapy is a better option for keloids with greater thickness and are not optimal candidates for excision.

Light-based treatment, most commonly PDL or ablative laser therapy, has been recommended as a second-line therapy prior to excision [ 132 ]. Fractional CO2 showed no difference in improvement compared to IL verapamil or TAC, and efficacy of CO2 laser with IL TAC compared to cryotherapy with IL TAC was not significantly different. Given the cost and access barriers, laser is likely best in combination with IL or topical CS therapy for the best clinical outcomes shown by multiple recent studies showing improvement with laser treatment followed by IL TAC and/or 5-FU [ 79 , 80 , 81 ]. Laser-assisted delivery of corticosteroids and combination of different lasers for treatment of keloids are emerging treatments. Recent studies have shown comparable or slightly improved results with Er:YAG or CO2 followed by topical corticosteroid and occlusion as compared with IL TAC alone or IL TACwith laser. PDT is another emerging application in the field of keloid treatment, though excision followed by PDT has not been found to be more effective than RT.

Excision followed by radiation therapy has been shown to consistently reduce the risk of recurrence. Comparison showed a higher response rate and lower adverse effects compared to cryotherapy with IL TAC. Brachytherapy and externally applied radiation have both shown success with no head-to-head trials. Most successful RT protocols deliver 12–18 Gy over 3–5 days with the optimal timing of radiation beginning within 24 h of excision. For pre-ternal keloids, a specialized method of pre-cut for excision followed by pre-radiation and post-radiation after excision showed a significantly reduced recurrence rate compared to excision with post-radiation only. Radiation therapy alone has shown symptomatic improvement and some success in flattening lesions, but recent studies have not compared it to other first-line therapies such as IL TAC.

Recent investigations of novel treatments have had some promising results. Application of a hydrogel scaffold after excision had low recurrence rates, though have not yet been compared in randomized comparative trials. Both drug-loaded and drug-free microneedle arrays have been tried as a less invasive and painful option, but the clinical improvement has not been shown to be durable as a monotherapy. ESWT with and without IL TAC has been shown to have similar results to IL TAC, which shows promise and warrants further investigation. Topical imiquimod after excision was shown to have reduced recurrence compared to excision with IL TAC, which is a good option for accessible lesions such as ear keloids. Colchicine as an oral therapy started 1 month prior to excision showed no recurrence and was well tolerated, which is a promising systemic therapy option.

Limitations

Although potential treatments for keloids range from topical and injectable therapeutics to surgical interventions and light therapies, there is no one consistent method of treatment that can guarantee response to therapy and prevent recurrence. Evidence for therapies lack consistent controls, and outcomes are heterogeneous, making it difficult to compare outcomes across studies. Heterogeneity of subject characteristics such as family history, keloid location, skin tension, size, and number, as well as gender and Fitzpatrick skin type, could all play a role in keloid response. There are many novel and effective treatments not included in this review, as non-English language studies, databases from other fields (such as nursing), case studies, case series, and retrospective studies and reviews were excluded from this review of the past decade of investigation. The field of keloid treatment would benefit from consistent, validated outcomes. There are multiple standardized tools for the assessment of keloids including the Patient and Observer Scare Assessment Scale, the Vancouver Scar Scale, and the JSW Scar Scale, and objective measurements of dimensions, color, pliability, and perfusion can be compared [ 135 ]. Both subject-controlled and split scar studies are successful controls, and randomization with at least evaluator blinding will improve the quality of evidence. Patient satisfaction and quality of life can also be assessed with the Dermatology Life Quality Index.

Keloids are a pathologic scarring response to dermal injury that progress to involve normal tissue outside the original injury and have a significant impact on quality of life. With multiple treatment modalities available, first-line therapy is silicone gel or sheeting with corticosteroid injections for more tumoral lesions or tape for flatter keloids. Providers can consider adjuvant intralesional 5-FU, bleomycin, or verapamil depending on patient preference and side effect profile. Laser therapy can be considered in combination with intralesional injection of corticosteroids or topical steroids with occlusion. For keloids that inadequately respond, excision with RT of 16–20 Gy over a maximum of 5 days started within 24 h can be considered. Additional treatment with silicone sheeting and pressure therapy is reasonable with possible oral colchicine to prevent recurrence. As the field continues to progress in the understanding of keloid etiology, the promise of new therapeutic targets and more specialized treatment regimens emerges.

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Walsh, L.A., Wu, E., Pontes, D. et al. Keloid treatments: an evidence-based systematic review of recent advances. Syst Rev 12 , 42 (2023). https://doi.org/10.1186/s13643-023-02192-7

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Review article, progress in the clinical treatment of keloids.

• Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Keloid is a pathological scar that is higher than the skin surface following skin damage. Its lesion range often extends beyond the original damage boundary and does not naturally subside over time. Its pathogenesis is very complex, currently the main causes include fibroblast excessive proliferation, collagen and extracellular matrix (Extracellular matrix, ECM) excessive deposition, excessive angiogenesis, and so on. The traditional treatment method primarily involves surgical intervention, but it is associated with a high recurrence rate post-surgery. Consequently, many treatment methods are derived according to the different clinical characteristics of keloid. This paper will review the therapeutic progress in recent years from surgical treatment, physiotherapy, drug therapy, and biological therapy, with the goal of offering valuable insights for the clinical treatment of keloids.

1. Introduction

Figure 1 shows the main treatment methods for keloid nowadays, which can be categorized into: physical therapy, drug therapy, biological therapy and surgical therapy, corresponding to serial numbers I, II, III, and IV in the figure, respectively. Physical therapy mainly includes phototherapy (①), cryotherapy (②), radiation therapy (③) and photodynamic therapy (④), which mainly inhibit or improve the formation of scar through the influence of physical factors on fibroblasts, blood vessels and collagen; drugs used in drug therapy (⑤) include hormones, antitumor, botulinum toxin type A, vitamins, and natural plant organics and so on, which mainly regulate the cellular function of the skin by local injection or topical application of drugs; biologic therapies (⑥), including RNA-based therapies, cytokine therapies, enzyme inhibitor therapies, constitutive fat grafting, and platelet-rich plasma therapies, etc., which are mainly used to regulate the repair process of the skin by utilizing biomolecules or cells to inhibit or improve the fibrosis; while surgical treatment (⑦) is suitable for medium to large and mature keloids, and the therapeutic effect is achieved by removing the scar tissue. Of course, according to different clinical characteristics, the above different treatment methods can be reasonably combined to achieve the best therapeutic effect.

Figure 1 . Schematic diagram of keloid treatment methods.

Keloid is a pathological scar with an appearance higher than the skin surface and a tough texture, which occurs on the skin surface with high tension, such as facial jaw, ear, chest and back ( 1 ). The extent of the lesion will continuously expand into the surrounding normal skin tissue and go beyond the boundary of the original injury, and it will not subside spontaneously over time. There are many factors affecting keloids, most of which come from external factors, such as surgery, trauma, skin infections, burns, acne, herpes zoster, mosquito bites, etc. Additionally, some internal factors caused by personal differences, such as gender, age, bad living habits, formation site, hypertension and other basic diseases and genetic factors will lead to the production of keloids ( 2 ). Due to the serious impact on beauty, and may appear itching and exercise limitations and other symptoms, the physical and mental health of patients are greatly affected.

The pathogenesis of keloid is after skin damage will repair any link in the process of abnormal, such as excessive angiogenesis, inflammatory reaction, aggravation of fibroblasts excessive proliferation, can cause ECM excessive production, collagen proportion disorder and collagen disorder, eventually manifested as excessive fibrosis form keloid ( 3 ).

In recent years, the keloid treatment method has emerged in an endless stream. However, due to the keloid treatment method with tumor-like characteristics, high recurrence rate and strong personal differences, finding a set of effective treatment plans has also become an important task for clinicians and researchers ( 4 ). This paper reviews the clinical treatment status and progress of keloid to provide a reference for clinicians ( Figure 1 ).

2. Surgical treatment

Surgical therapy is usually suitable for medium and large keloids and already mature keloids, but postoperative recurrence rates are extremely high, reaching 45–100% ( 5 ). It is generally used in combination with postoperative adjuvant therapy, thus reducing the recurrence rate ( 6 ).

Excessive skin tension is the main cause of postoperative recurrence ( 7 ). After keloid removal, the tension-reduction suture is generally used to prevent recurrence; if the keloid area is too large to be directly stitched, it will be solved by skin dilator and adjacent flap transplantation. In recent years, the more common sutures include: distal buried dermal suture ( 8 ), Buried vertical mattress type suture ( 9 ), Zhang sutures ( 10 ) wait a minute. Under the action of reducing tension and suture, the production of keloid can be greatly reduced, and other auxiliary treatment after surgery can effectively inhibit the recurrence of keloid. Surgical treatment has also become the cornerstone of keloid treatment.

The treatment of keloids is closely related to their size and location and can be specifically divided into preoperative, intraoperative, and postoperative.

2.1. Preoperative

The preoperative surgical approach is established and an adequate surgical plan may effectively prevent keloid development. The outer layer is a dense layer of collagen, the middle is a rich vascular network, and the inner layer is a core made up of fibroblasts, with a clear demarcation layer between the superficial skin layer and the papillary layer of the dermi ( 11 ). If the keloid is large because direct excision and suturing will lead to an excessive amount of tension on the surface skin, the superficial skin, as well as the subcutaneous vascular network of the keloid, is usually preserved [The skin of the keloid and the subcutaneous vascular network (i.e., the keloid flap)] are typically preserved, with only the nuclear portion of the inner keloid layer excised, which is more common clinically: earlobe keloid ( 12 ) and chest keloid ( 13 ). Particularly noteworthy is the blood supply to the flap which separates the few penetrating vessels beneath the flap during the process of dissection; direct sectioning of the entire layer will result in the flap becoming a fully layered composite tissue with no vascular supply. The wound will not heal, or the possibility of infection will increase. Proper blood supply allows for better survival of the flap on the one hand and less scar growth on the other ( 14 ).

2.2. Intraoperatively

Watson et al. suggested that the most important aspect of surgical treatment of keloid is a reasonable incision design and good suturing technique ( 15 ).

The design of the surgical incision is a critical factor that significantly influences the wound tension during the proliferative and remodeling phases of scarring, and is closely related to scar prevention. The incision must follow the Relaxed skin tension (RSTL) line. Despite the Lange line and RSTL running in the same direction in several regions of the body, these lines differ significantly in mechanically complex regions (e.g., the corners of the mouth, the external canthus, and the temples), and if there are no such lines in regions of high surface tension, such lines are present, the patient must be told in advance.

Traditional interrupted sutures do not provide prevention of keloids and there is a risk of scar enlargement and spread due to increased wound strain due to motion, body position, or tissue loss (after excision of the lesion). Different sutures can be used intraoperatively to prevent keloids by reducing tension, such as intradermal sutures, hypotonic sutures, super hypotonic sutures, etc. Subcutaneous closure with polypropylene sutures, in conjunction with appropriate compression therapy treatment of the tissue, is the currently more clinically utilized technique. A permanent transparent nylon suture placed deep into the dermis is also effective.

2.3. Postoperatively

Silicone scar patches or silicone oil-based creams are effective in limiting the growth of scar tissue by increasing the humidity and local skin temperature of the scar epidermis ( 16 – 18 ). The application of silicone scar patches should be made as soon as the surgical wound has healed (2 weeks postoperatively). Cut the patch of scar slightly larger than the scar, and when the wound surface is fully epithelialized, a silicone gel may be used instead ( 19 ).

Compression therapy may prevent keloid elevation but is not as effective in keloid treatment compared with proliferative keloid therapy. One exception to this is the application of magnetic pressure ear clips following the excision of the keloid from the earlobe, which may inhibit keloid proliferation to some extent ( 2 ).

More recently, there has also been a growing amount of basic research devoted to the prevention of scar formation by exploiting the special properties of certain materials to fabricate hypotonic sutures, hypotonic dressings, and so on. Liquid-crystal elastomers (LCEs) are a class of soft active materials that are receiving increasing attention due to their excellent conductive and optical properties. Low-temperature synthesis methods using optimized composition ratios allow the LCE metamaterials to provide a reasonably high actuation stress/strain at substantially lower actuation temperatures (46°C). By combining this biocompatible LCE metamaterial with a medical dressing, a breathable, shrinkable, hemostatic patch can be developed and animal study species have demonstrated the benefits of this hemostatic patch and suture compared to conventional strategies (e.g., medical dressings and sutures) to speed up skin regeneration while avoiding the keloids ( 20 ).

In conclusion, surgical treatment remains the cornerstone of the treatment of hyperplastic scars, and in order to achieve optimal therapeutic results, it usually requires preoperative consideration of appropriate surgical options, intraoperative rational incision design, fine suturing, and postoperative combination with adjunctive therapies such as silicone scar patches or silicone ointments and compression therapy. Recent studies have also shown promise in the development of new materials for the prevention of scar formation. If the scar never improves, or if it is in an intimal location and the patient has fertility needs (e.g., perineum), it may be treated with injections of scar softening (e.g., tretinoin, a steroid inhibitor for scar reduction) or laser treatments (e.g., Nd: YAG 1064, fractional laser, pulsed dye laser, IPL, Q switched laser) as described below.

3. Physiotherapy

Physical therapy is a method of treating disease by utilizing various physical energies such as heat, light, and radiation, and it has many applications in the treatment of keloids. Physical therapy for keloids includes cryotherapy, photoelectric therapy, radiation therapy and photodynamic therapy. Cryotherapy can be used alone or in combination with surgery and local injections to reduce recurrence rates and improve esthetics and symptoms. Photoelectric therapy, which includes non-exfoliative photoelectric therapy and exfoliative photoelectric therapy, prevents and treats keloids by selectively acting at different depths of the skin. Radiation therapy prevents and treats keloids by inhibiting angiogenesis and fibroblast production. Photodynamic therapy treats keloids through the use of laser-activated photosensitizing drugs and is favored for its low toxicity and high selectivity. These physical therapies can be used either alone or in combination with other treatments to improve efficacy and minimize adverse effects.

3.1. Cryotherapy therapy

Cryotherapy is an effective treatment for keloids with a low rate of recurrence and may be applied alone or in combination with surgery and Intralesional injections to decrease recurrence rates and improve esthetics and symptoms ( 21 ). The mechanism of action is primarily vascular quiescence and the direct physical effect of cell freezing, where the direct physical effect of freezing cells refers to intracellular freezing, leading to disruption of cellular membranes and cell death; vascular quiescence refers to the process of freezing and thawing of cells, which results in tissue hypoxia and malnutrition, leading to focal cell death. Current methods of cryotherapy fall into two categories, contact cryotherapy ( 22 ) and Intralesional cryosurgery ( 23 ). Contact cryotherapy is typically used for hyperplastic keloids and keloids that are too small for a cryo-needle to be inserted, but multiple treatments are needed to flatten the keloids and can even lead to depigment of the patient’s superficial skin. In contrast, intralesional cryosurgery is a relatively new and safe treatment that can be used for any type and form of hyperplastic scars and keloids, particularly bulky keloids, and typically requires only a single treatment to flatten the patient’s keloids ( 23 ). Compared to Intralesional injections of tretinoin, 5-fluorouracil, and classical contact cryotherapy, intralesional cryosurgery causes minimal damage to the superficial skin and minimal pigmentation changes ( 24 , 25 ), and its adverse effects primarily include depigmentation, recurrence, and pain, but in clinical trials pain and recurrence were uncommon and depigmentation was only of a temporary nature ( 26 ).

Cryotherapy may also be used in conjunction with surgery and Intralesional injections to further decrease recurrence rates and improve esthetics and symptoms ( 27 – 29 ). For example, combining cryotherapy with Intralesional steroid injections results in superior outcomes compared to both alone and is more effective in reducing keloid size; Litrowski has shown that the combination of surgery and cryotherapy is a valuable treatment for keloids that is effective, convenient, well-tolerated, and does not have any significant side effects beyond local pain and hyperalgesia ( 30 ); Azzam added platelet rich plasma (PRP) injections to combine all three, using cryotherapy during surgery, and showed that triple therapy could achieve improved efficacy, a lower rate of recurrence, good cosmetic outcomes, and the absence of significant side effects ( 31 ); Stromps combined the method of cryotherapy with silicone gel sheets and found that it had the potential to significantly reduce the size of the keloid and improve its hardness, pain, and discomfort ( 32 ).

3.2. Photoelectric therapy

At present, photoelectric treatment has been widely used in the prevention and treatment of scar. According to the depth and principle of its action on the skin, it is generally divided into non-exfoliative photoelectric treatment and exfoliative photoelectric treatment clinically.

3.2.1. Non-exfoliative photoelectric therapy

Pulsed dye laser (PDL) is one of the first lasers used in the treatment of keloids, with the major application wavelengths of 585 nm and 595 nm. By selecting the blood vessels acting on the epidermis and the superficial dermis, PDL can destroy hemoglobin, reduce tissue capillaries, and inhibit the proliferation of fibroblasts ( 33 ). The Alster team first used 585 nm PDL to treat scars in the area of the sternum, with significant improvements in the height, elasticity, flexibility, and erythema of the keloid size by comparing the treated and untreated groups ( 34 ). The Manuskiatti team then had an in-depth discussion on the precision of the PDL treatment and found that there was no significant difference in the treatment results obtained with different energies, and that multiple effects in a short period of time could enhance the treatment effect ( 35 ).

Neodymium: yttrium aluminum garnet laser (Nd: YAG laser) wavelength is 1,064 nm. Compared with PDL, Nd: YAG is more suitable to solve the vascularization problem of keloids, which can also damage hair follicles and reduce hair follicle inflammation ( 36 ). The Chi Xu team used 585 nm PDL and 1,064 nm Nd: YAG to treat keloids between 4 and 6 weeks, and found that the flow perfusion of keloids could be significantly reduced, and the Nd: YAG laser combined with PDL was better ( 37 ).

The intense pulse laser IPL (Intense pulsed light) emits incoherent broadband wavelength pulse light and targets pigmentation and vasculature ( 38 ). The effect alone is not good, more combined with drugs, can relieve the thickness, erythema and pigmentation of keloids ( 39 ).

3.2.2. Exfoliative photoelectric treatment

CO 2 laser damages blood vessels and gasfies scar tissue while inhibiting fibroblast proliferation and inducing collagen remodeling ( 40 ), However, the recurrence rate within 2 years of treatment alone is extremely high, so it is mostly clinical combination therapy, such as TAC ( 41 ).

Compared with CO 2 laser and Nd: YAG laser (Er: YAG laser), Er: YAG laser is also relatively effective, but skin scab and erythema are less time and less painful ( 42 ).

Keloid tissue is hard, and therefore drug injection is difficult. Radio frequency plasma (plasma) can dissociate the nitrogen molecules in the air into high-energy plasma states, and act on the dermis through heat energy to promote the rearrangement of collagen tissue rearrangement in the scar ( 43 ). It has a remarkable effect on the treatment of auricular keloid ( 44 ). RF is often used in combination with steroid drug injections to make the drug more easily absorbed ( 45 ). Compared with conventional intralesional RF, the Taneja team innovatively proposed to use the holes under the surface of the customized venous intubation to deliver energy during the RF process. Compared with conventional spot radiation energy, the energy can be dissipated in all directions, thus reducing the damage to the epidermis ( 46 ).

Regardless of the photoelectric treatment modality, it is important to reduce the inflammatory response after photoelectric therapy and prevent pigment changes. Therefore, it is often combined with auxiliary drugs that anti-inflammation and inhibit melanin formation, such as asiabside ointment ( 47 ).

3.3. Radiation therapy

Radiotherapy (RT) has been used to treat keloids for more than 100 years, mainly in preventing and treating keloids by inhibiting angiogenesis and fibroblast proliferation ( 48 ). RT is more suitable as postoperative adjuvant therapy than treatment alone. In a meta-analysis, postoperative RT was combined, but allowed reducing the recurrence rate after the surgery alone from 45–100% to less than 20% ( 49 ). In terms of treatment effect, the control of RT treatment dose and irradiation time is particularly important. The total recommended dose for treating keloids ranges from 12 to 20Gy, with the maximum biologically effective dose is 30Gy, but the degree of damage to visceral organs remains to be determined ( 50 , 51 ). In addition to treatment modality, anatomical location is a key factor affecting the recurrence rate, the highest in the chest and lowest in the ear ( 49 ).

Radio therapy for keloids was first introduced in 1906 but 107 years later an optimal protocol has not been established. X-rays, beta rays, or gamma rays have been used in most studies. Heavy particle radiotherapy has been used in the clinical management of refractory and radiation-insensitive tumors in recent years, but its use in keloids has been infrequently reported. Chen’s team ( 52 ) carried out the first end-to-end particle radiotherapy after keloid surgery, and 16 patients were administered a total dose of 8Gy throughout the study, with an average follow-up of 29.7 months and a cure rate of 95%, and no patients experienced any complications. Heavy particle lineage therapy has been shown to have a precise killing effect on tumor cells by destroying the DNA double-strand of tumor cells, which can significantly reduce damage to normal tissues and organs with high efficacy and safety as well as achieve the ideal dose distribution and biologic effect. Thus, heavy particle lineage therapy could be a potential clinical treatment modality for keloids.

3.4. Photodynamic therapy

Because of the characteristics of Photodynamic therapy (PDT) low toxicity and high selectivity, is widely popular in clinical treatment, mainly through the use of laser activated photosensitive drugs, make heme bioconversion into protoporphyrin IX, the endogenous molecular oxygen into cytotoxic reactive oxygen species, direct damage to monocytes and macrophages, inhibit the inflammatory response to treat keloids ( 53 ). Clinically more used photosensitive drug is Zhuthemtin ointment ( 54 ). Several clinical trials have demonstrated that PDT is an important alternative to patients after ineffective steroid hormone therapy, but further evidence is needed due to the small number of clinical studies ( 55 ) ( Table 1 ).

Table 1 . Classification of keloid physical methods.

Overall, physical therapy offers a promising approach to the prevention and treatment of scars. However, the use of these physical therapies is still subject to some limitations, such as the efficacy of physical therapies may be limited by factors such as the type, size and depth of scars, as well as the possible adverse effects such as pain, itching, and hyperpigmentation that may occur during the treatment process. Therefore, future studies should further refine these physical therapies and explore new treatment methods to improve the efficacy and reliability of scar treatment.

4. Drug treatment

4.1. glucocorticoid drugs.

Triamcinolone (TAC) is the most commonly used hormone drug, mainly treating keloids with obvious “inflammatory” characteristics, which can effectively reduce the thickness of keloids, and relieve itching and pain ( 56 ). TAC as a monotherapy recurrence rate is as high as 50%, and up to 63% of patients will have postinjection side effects, such as telangiectasia, subcutaneous fat atrophy, pigmentation, Cushing’s syndrome ( 53 ), Combination therapy reduces side effects, such as RT ( 45 ), CO 2 laser ( 41 ), 5-FU ( 57 ). In order to avoid the pain caused by glucocorticoid injection, steroid dressing is becoming more and more popular, Jinrong Li team also use electrospinning polymer microfiber dressing to treat keloids, which embedded with dexamethasone and antibacterial anti-inflammatory tea polyphenols, after 3 months of treatment, the size of keloid and erythema have improved, but also further reduce the risk of inflammation and infection ( 58 ).

4.2. Antitumor drugs

Keloids have the characteristics of tumor, so antitumor drugs also have a certain effect in the treatment of keloids. 5-Fluouracil (5-Fluorouracil, 5-FU) has direct cytotoxic effects that inhibit fibroblast proliferation, G2/M cell cycle arrest and apoptosis ( 59 ). In Tamoxifen (TAM), a selective estrogen receptor modulator used to treat breast cancer, it has been found that the average number of fibroblasts in keloids was significantly reduced after TAM treatment ( 60 ). Mitomycin C has antitumor activity and thus inhibits scarring by inhibiting DNA, RNA synthesis in fibroblasts ( 61 ).

4.3. Botulinum toxin type A

Botulinum toxin type A (BTX-A) is a potent neurotoxin that can cause rhabdomyolplegia. It plays a therapeutic effect in fibroblasts by inhibiting the proliferation of fibroblasts and TGF- β 1 expression ( 62 ). However, the Gauglitz team obtained different results, with the intratumoral injection of BTX-A lasting once every 1 month, and found that BTX-A had no effect on the proliferation and metabolism of fibroblasts, and could not improve the scarring. Although the treatment effect of the action alone is general, the preoperative injection can play a role in preventing the recurrence, and the adverse effects of the post-injection are relatively mild, and it can be self-recovered in a short time ( 63 ).

4.4. Immunomodulators

Tacrolimus as an mTOR receptor inhibitor can reduce histamine release, and effectively relieve itching, along with less skin absorption and a high safety profile ( 64 ). 5% Imiquimod ointment enhances cellular immune activity and suppresses keloid production by inhibiting collagen and glycosaminoglycan production ( 65 ). However, the effect is short and it will relapse completely after 4 weeks ( 66 ). Interferon (IFN) is an immunomodulator of glycoproteins that produces antifibrotic effects by interfering with collagen synthesis and fibroblast proliferation ( 5 ). In a clinical randomized controlled experiment, some scholars found that IFN can reduce the height of keloid, but due to the small clinical sample size, it is necessary to further explore the appropriate drug dose and action time of IFN ( 67 ).

4.5. Antihypertensive drugs

Angiotensin-converting enzyme inhibitors play an important role in collagen biosynthesis and wound healing ( 68 ). The formation of keloids involves the activation of the RAS system. Therefore, hypertensive drugs that antagonize the RAS system are an emerging treatment for keloid scars. They mainly include angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB). They inhibit excessive collagen formation in keloids and hypertrophic scars by antagonizing the RAS system. Ardekan’s team used 5% captopril cream for 6 weeks in a burn patient and found that it reduced the height of the keloid and improved redness and itching ( 69 ). In contrast to these results, Johanneke did not find that captopril improved scar formation in his experiments and only resulted in delayed wound closure ( 70 ). Chen found that the combination of captopril 10–2 mol/L and 5-FU 1 mg/mL reduced fibroblast proliferation and collagen deposition in keloid cultures, which was superior to captopril or 5-FU as a single therapeutic agent ( 71 ). Mohammadi et al. found that 1% enalapril significantly improved pruritus ( 72 ). Verapamil is a calcium channel antagonist that induces collagen degradation by inhibiting the inflammatory response and reducing ECM and collagen production ( 73 ). Verapamil was first given by Lawrence’s team for 7–14 days postoperatively and 52% of these patients recovered ( 74 ). Compared to TAC, side effects such as skin atrophy, capillary dilation, and hyperpigmentation were significantly lower with verapamil than with tretinoin, but weaker in terms of both flexibility and angiogenesis, and it can be seen that tretinoin is better than verapamil, while verapamil is safer ( 75 ). Hedayatyanfard found that losartan potassium ointment (5%) could treat keloid and hyperplastic scars through antifibrotic effects, with significant improvements in keloid scars on four indicators of vascular status, pigmentation, flexibility, and scar height ( 76 ). Zhao’s study found that a complex losartan cream (containing chitosan, cumene, and losartan) was effective in inhibiting scar formation by inhibiting the TGF-β/Smad pathway ( 77 ).

4.6. Other new organics therapy

4.6.1. vitamin a.

The potential role of vitamin A and its derived forms in the treatment of keloids has been explored in numerous studies over the past several years. Retinoic acid and 9-cis-retinoic acid are two of these compounds that have received a great deal of attention. Retinoic acid is capable of ameliorating chronic inflammation in keloids by reversing the action of matrix metalloproteinases (MMP) and by preventing the expansion of keloid tissue in normal annular skin ( 78 ). Studies have also shown that silicone and retinoic acid creams can prevent and ameliorate hypertrophic scarring ( 79 ). Retinoic acid 9-cis is another compound that has received a great deal of attention as a potential treatment for pathological scarring. 9-cis retinoic acid has been found to increase HOXA5 expression, promote activation of the p53 signaling pathway, and inhibit proliferation, migration, and collagen synthesis in fibroblasts from pathological scar tissue while increasing apoptosis. 9-cis-retinoic acid may thus be a potential treatment strategy for pathologic scarring ( 80 ).

4.6.2. Vitamin D

Vitamin D is a lipid-soluble vitamin that is widely found in nature and has been shown to play a significant role in human health. Keloid is a common skin disorder that is challenging to treat. A growing body of research in recent years has demonstrated that vitamin D is closely associated with keloid development and progression. For example, vitamin D deficiency could contribute to keloid development, and injection therapy with vitamin D can significantly decrease keloid thickness ( 81 ); vitamin D plays an important role in the inhibition of inflammation and fibrosis, which are two inevitable steps in keloid development and progression ( 82 , 83 ); vitamin D plays an important role in the inhibition of inflammation and fibrosis, which are two inevitable steps in keloid development and progression. Some studies have also found lower levels of the vitamin D receptor (VDR) in keloids compared to normal skin, suggesting that VDR may play a role in keloid pathology ( 84 ). Several other studies have found that low serum concentrations of 25-hydroxyvitamin D and Koebnerisin can be used as potential markers to predict keloid tendencies ( 85 ).

4.6.3. Natural plant organics therapy

Available studies have shown that some of the numerous natural compounds have the potential to inhibit the development of keloids, and unlike synthetic compounds, these natural compounds can avoid potential adverse effects when treating keloids, although, at the same time, they may act by affecting multiple signaling pathways. For example, quercetin is capable of attenuating keloid drug resistance to radiotherapy, with the primary mechanism of action being via inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway negatively regulating hypoxia inducible factor 1 (HIF-1) ( 86 ); asiaticoside is capable of modulating extracellular matrix protein production and hindering invasive keloid fibroblast growth, in the former by downregulating TGF-β receptor expression at the mRNA level to upregulate Smad7 expression in a dose dependent manner ( 87 ), and the latter through the approach of inhibition of the GDF-9/MAPK/Smad signaling pathway ( 88 ); salvia extract inhibits fibroblast proliferation and invasion and reduces collagen synthesis, which is achieved through up-regulation of Smad7 expression, down-regulation of Smad2/3 phosphorylation level, and down-regulation of surviving protein in keloid processing ( 89 , 90 ); and methoxycinnamine inhibits the deposition of collagen by limiting the induction of fibroblast collagen synthesis by TGF-β ( 91 ) ( Table 2 ).

Table 2 . Classification of keloid drugs and methods.

In summary, a variety of drug therapies have been developed for the prevention and treatment of this disease; however, these therapies are associated with varying degrees of side effects. Combination therapies and novel organic therapies are expected to improve therapeutic efficacy while reducing adverse effects. Future research should focus on exploring the mechanism of action and therapeutic efficacy of novel organic therapies and developing effective combination therapies to improve the treatment of scar hypertrophy.

5. Biological therapy

5.1. rna-based therapy.

Current studies have shown that dysregulated noncoding RNAs (ncRNAs) have a significant role in the formation of keloids. Of these, three main types of ncRNAs, i.e., miRNA, lncRNA, and circRNA, have been reported to control fibroblast proliferation, migration, invasion, apoptosis, and collagen synthesis through different pathways ( 92 ), thereby participating in the keloidogenesis and developmental process. Some researchers consider miR-29a-3p to be a core miRNA that may play an important role in keloid development and progression and may therefore be an effective target for keloid therapy ( 93 ). Key processes involved in keloid regulation by lncRNA include the proliferation of fibroblasts, deposition of ECM ( 94 ), Wnt signaling ( 95 ), Hh signaling ( 96 ) and TGF-β signaling ( 97 ). CircRNAs in post-transcriptional biological functions, the differentially expressed circRNAs are primarily involved in apoptosis, adhesion to adherents patches, PI3K-Akt, and metabolic pathways ( 98 ). These include lncRNAs, circRNAs, which contain multiple miRNA binding sites, and adsorb miRNAs such as sponges, which act as competing endogenous RNAs (ceRNAs) and competitively bind miRNAs to regulate gene expression ( 99 , 100 ).

We anticipate that ncRNAs will be potential diagnostic and therapeutic targets in the treatment of keloids, and additional studies are required to identify more effective strategies for keloid prevention and clinical treatment. Even though ncRNA-based therapeutic approaches offer some advantages over traditional small-molecule drugs, such as easier access to the target, the method of ncRNA drug delivery, and the issue of immune-related toxicity and other adverse effects must still be considered and addressed.

5.2. Cytokine-based therapy

5.2.1. tgf-β.

TGF-β is a naturally occurring multifunctional peptide that regulates gene expression through activation of the SMAD signaling pathway, thus affecting all stages of keloid wound healing. TGF-β receptor and ligand expression levels are significantly higher in keloid fibroblasts (KFs) compared to normal conditions and therefore TGF-β1 has been suggested to be one of the key players in the formation of keloids. At present, several drugs and compounds have been found to inhibit the TGF-β1 signaling pathway as well as to treat keloids. One of these, tacrolimus (FK506), a drug that inhibits TGF-β1-induced proliferation, migration, and collagen synthesis in keloid KFs, can effectively block the TGF-β/Smad signaling pathway through the downregulation of the TGF-β receptor ( 101 ). Furthermore, a lipocalin (ADP355) -based peptide is also capable of inhibiting TGF-β1-induced fibrosis in keloids and can potentially treat keloids through modulation of signaling pathways such as AMPK, SMAD3, and ERK. In xenograft mice, ADP355 has also been shown to significantly reduce total mouse keloid tissue weight, as well as the expression of pre collagen ( 102 ). Hederagonic inhibited the proliferation of KFs at a concentration of 50 nM, reduced the expression of TGF-β1-induced α-SMA and the production of type I procollagen, and decreased the migration of KF cells ( 103 ); compounds such as oleanolic acid ( 104 ), glycyrrhiza glabra ( 105 ), and loureirin A ( 106 ) were also found to regulate the proliferation and extracellular matrix deposition of keloid KFs by mediating the TGF-β1/Smad1 signaling pathway, with therapeutic potential for keloids. Based on the results of these drugs and compounds, inhibition of the TGF-β1 signaling pathway appears to be an effective approach to the treatment of keloids. However, further studies are still required to determine the safety and efficacy of these drugs and compounds to translate them into practical applications for the treatment of these diseases.

5.2.2. Epidermal growth factor

Epidermal growth factor (EGF) has been shown to affect skin homeostasis and wound healing by regulating a variety of cellular functions of dermal fibroblasts. Fibroblasts isolated from keloids have been shown to produce 2 to 3 times the amount of collagen as fibroblasts from normal skin ( 107 ), so EGF could be one of the potential treatment options for keloids. Hyunbum found that exogenous EGF was able to increase the level of matrix metalloproteinase MMP-1, which induces collagen breakdown, and decrease lysyl oxidase (LOX) and 4 lysyl oxidase-like (LOXL), which synthesize collagen, thereby altering the remodeling process of ECM, which in turn improved the fibrotic phenotype of keloid dermal fibroblasts, as evidenced by the process of significant FSP-1, α-SMA, vimentin gene expression and vimentin protein expression decreased. Based on this, LOX and LOX-like family members could be seen as potential therapeutic targets for skin fibrosis and keloid tissue formation ( 108 ). In addition, Le found that silencing metalloproteinase protein 17 (ADAM17) may limit ECM deposition in keloid fibroblasts by inhibiting the activity of the EGFR/ERK pathway, thereby reducing proliferation, invasion, and migration ( 109 ).

5.3. Enzyme inhibitor

5.3.1. tyrosinase inhibitors.

Tyrosinase inhibitors can inhibit the formation of keloids by targeting the Akt/PI3K/mTOR pathway, the MAPK/ ERK pathway. Thus, sunitinib may effectively inhibit keloid development through inhibition of the Akt/PI3K/mTOR pathway. Doses of 6 μM of this drug have been shown to significantly inhibit keloid fibroblast (KFs) proliferation, and doses in the range of 2.0 to 6.0 μM induce apoptosis in over 60% of keloid fibroblasts with no cytotoxicity to normal cell lines. In addition, sunitinib inhibited the migration and invasion of KFs and significantly reduced the levels of KFs collagen I and III at the mRNA and protein levels ( 110 ). Wang found that sorafenib was able to exert targeted inhibitory effects on the TGF-β/SMAD and MAPK/ERK signaling pathways, and may not only inhibit ECM proliferation, invasion, and production of KFs in vitro , but also exert inhibitory effects on KFs migration, angiogenesis, and collagen accumulation in keloid explants grown in vitro ( 111 ). Nintedanib is a receptor tyrosine kinase inhibitor targeting VEGF, PDGF, FGF, and TGF-β receptors, and it has been shown that when nintedanib is administered at doses between 1 and 4 μM, it inhibits cell proliferation, induces GO/G1 phase block, inhibits migration and invasion of keloid fibroblasts, and significantly inhibits the expression of type I and type III collagen in keloid fibroblasts ( 112 ). This study demonstrates the feasibility of tyrosinase inhibitors as one of the therapeutic options for the treatment of keloids.

5.3.2. Heat shock protein

Heat shock protein (HSP) has been shown to promote wound healing by acting as a molecular chaperone and regulating the combined inflammatory and stress response during the wound healing process. Excessive levels of HSP, on the other hand, can enhance the inflammatory response and lead to an uncontrolled synthesis process. HSP plays a key role in keloid tissue. Studies have shown that the levels of hsp27, hsp47, hsp60, hsp70, and hsp90 are increased in keloid tissue compared to normal tissue ( 113 ). 17-AAG, an hsp90 inhibitor, inhibits the expression of Akt in fibroblasts, thereby suppressing their proliferation and reducing their migratory capacity, in addition to downregulating type I collagen mRNA and protein expression and inhibiting the TGF-β1/SMAD pathway, which has potential value for keloid therapy ( 114 , 115 ).

5.4. Composition fat transplantation

Adipose-derived Mesenchymal Stem Cells (ADSCs) are cells with multi-directional differentiation potential and stem cell immune phenotype isolated from adipose tissue. They have become the research focus of keloid treatment because they can inhibit fibroblast proliferation and collagen synthesis, with convenient material source and little trauma ( 116 ). The extraction and culture process of ADSC is relatively complex, and the relevant research is still in the basic research stage and needs further clinical verification. Nano-fat grafting is a purely physical method of destroying mature adipocytes in adipose tissue and obtaining a celiac-like adipose tissue that preserves ADSCs and contains stromal vascular component cells, ECM, oil droplets, and swelling fluid. In recent years, many studies have reported that the internal scar injection of nano-fat can improve the scar hyperpigmentation, thickness, softness, and reduce the pain sensation ( 117 ). It has also shown that the therapeutic effect is not ideal, probably because of the relatively small ADSC content in the mixture during extraction ( 118 ). The stromal vascular component of fat is rich in stem cells and various growth factors, which has special regenerative potential, which mainly can treat keloids through growth factors that can promote wound healing, reduce inflammatory response and induce collagen remodeling ( 119 , 120 ).

5.5. Platelet-rich plasma

Platelet-rich plasma (PRP) contains growth factors that can be involved in the different stages of wound healing ( 121 ). Some scholars did not respond to 17 patients with keloid resection after 4 TAC or RT injections, so PRP was injected every other month. After 3 injections, vascular hyperplasia, inflammation, pigmentation and flexibility were greatly improved, especially the pruritus condition improved significantly ( 122 ). Overall, PRP injection is a safe and effective adjuvant therapy ( Table 3 ).

Table 3 . Classification of keloid biological methods.

In conclusion, keloids are a common and difficult to treat skin disease. Biologic therapies have made some progress as an emerging therapeutic approach. RNA-based therapies, cytokine therapies, enzyme inhibitors, constitutive fat grafts, and PRP have all been shown to be potentially valuable in the treatment of keloids. However, the safety and efficacy of these approaches need to be further investigated, especially in clinical applications. We hope that these biologic therapies will be studied and applied more intensively in future studies to provide more effective methods and strategies for the treatment of keloids.

6. Combined treatment

The recurrence rate of keloids is extremely high with monotherapy, and many local complications can occur. Therefore, the combination of multiple treatments is needed to reduce the recurrence rate, while improving the adverse effects caused by monotherapy approaches. According to the type of combination, it can be divided into double line therapy and triple line therapy.

6.1. Binary therapy

Intralesional injection of TAC is the most widely used treatment after kelkelectomy. There are clinical studies that show that after TAC + 5-FU for 12 months, the height, texture and congestion of keloid can be significantly improved ( 123 ). Meanwhile, TAC + verapamil was also shown to be effective and reduced the occurrence of telangiectasia and skin atrophy, which was statistically significant for the overall improvement of keloids ( 124 , 125 ). In a reticular meta-analysis, The Sha Yang team compared cure rates across different treatment modalities, The results found that the highest treatment rate of TAC + BTX-A, TAC + BTX-A (82.2%) > TAC + 5-FU (69.8%) > BTX-A (67.3%) > 5-FU + A silicone (59.4%) > TAC + A silicone (58.3%) > 5-FU (49.8%) “bleamycin (42.0%) > TAC (26.7%)” Verapamil (26.2%) “Silicone (18.3%) ( 126 ). Meanwhile, the Hend D Gamil team also proved that the combination treatment of TAC and BTX-A was more effective than that of T AC and BTX-A, compared with the treatment alone ( 127 ). This shows that TAC is more effective than verapamil in monotherapy, and better tolerated than 5-FU and bleomycin, and results in maximizing cure rates when combined with other drugs.

In addition to combining drugs, there are many combinations of bitherapies. Drug and Laser Combination: Postoperative TAC + radiation/laser therapy (PDL, Nd: YAG, CO 2 ) Ablation can prevent the hyperpigmentation due to the inflammatory response after the laser treatment ( 128 – 130 ). Combination of drugs and pressure treatment: In the treatment of auricular keloid, the Carvalhaes team injected TAC into the lesion once every month before surgery, and applied pressure earrings to the ear scar after surgical resection. The patient was well tolerated, and the recurrence rate was significantly reduced ( 131 ). Laser combined with laser: Ouyang explores PDL + CO 2 . The effect of laser treatment showed that the combination treatment was better than PDL treatment alone ( 132 ).

6.2. Triple therapy

Studies have been tried with two drugs + laser TAC + 5-FU + PDL ( 133 ) Or one drug plus two laser CO 2  + PDL + TAC and other triple therapy to treat keloids ( 134 ). 5-FU + TAC + sodium hyaluronate was combined ( 135 ), Sodium hyaluronate can significantly reduce hyperpigmentation. Zeng et al. proposed “sandwich therapy,” namely preoperative radiotherapy, perforator flap transplantation of superficial iliac artery, postoperative radiotherapy for keloids, all flap survives well and has no serious complications ( 136 ). Triple therapy provides a multifaceted approach to the treatment of keloid, but it is difficult to determine the individual contribution of each treatment modality to the final outcome, and further clinical trials are validation ( Table 4 ).

In general, the combination therapy idea mainly based on drug therapy has been widely adopted in clinical practice in recent years. By exploring the action characteristics of each therapy method and making up for the possible side effects of each therapy, it is possible so as to build a relatively complete treatment combination.

Table 4 . Summary of keloid combination therapy.

7. Discussion

At present, for diagnosed keloids, intralesional corticosteroid injections are used as a first-line treatment either as monotherapy or in combination with other modalities. Primarily devoted to adjuvant therapy following surgical excision, TAC is also a good conservative treatment when the patient is unsuitable for postoperative excisional radiation therapy, e. g. in the perineum. It is recommended that the optimal interval between injections be 2 weeks. In a systematic review published in Laura A. Walsh, other methods of intralesional injection are compared, including botulinum toxin A (BTA), bleomycin, mitomycin C, PRP, and collagenase. Verapamil may be treated both as an intra-focal injection and as an adjunctive treatment to cryotherapy or resection, and while its therapeutic efficacy may not always be superior to TAC, the drug is well tolerated and the potential for adverse effects may be lower. It has been shown that 5-FU can be used in conjunction with TAC therapy to prolong synergy but also increases the risk of ulcer development. Bleomycin is not as effective as TAC and has an increased risk of macrosomia and ulceration. BTA is superior to 5-FU alone and is no different from TAC in a double-blind study with a lower risk of hypopigmentation. BTA is a potent antihypertensive agent. Surgical excision combined with adjuvant cryotherapy and PRP resulted in a recurrence rate of 16.21%, but as there was no control group in this study, further clinical studies are required to further confirm the therapeutic role of PRP. Phototherapy (most commonly PDL or ablative laser therapy) has been advocated as a second-line treatment after surgical excision, and laser-assisted corticosteroid administration and the combined use of different lasers for keloid scarring are emerging treatments.

Treatment of keloids ranges from pre-surgical prophylaxis to post-surgical treatment and from pharmacologic therapy to physiotherapy, which are all currently clinically covered, but none appear to guarantee treatment response and prevent relapse. This is mainly due to the lack of a consistent control group across the many studies, which makes it difficult to compare results across studies. Heterogeneity in subject characteristics such as family history, keloid location, skin tone, size, and number as well as sex and skin type may also play a role in keloid formation. Recent research into new therapies has shown some promising results such as heavy particle therapy, antihypertensives, vitamins, biologic agents, etc. Again, however, the number of studies that have been confirmed in clinical research is relatively low, and most of them are in the basic experimental phase, so comparisons are difficult. There is a need to systematize the treatment of keloid scars, with the accurate diagnosis of keloid scars before treatment, all-around prevention before, during, and after surgery, management of patients’ habits, and exploration of the mechanism of keloid scar formation.

In recent years, new treatment methods of keloid have emerged in an endless stream, and surgical therapy, physiotherapy and hormone, anti-tumor and other drug therapies have been widely used in clinical practice. Other new drug therapies cover a wide range of mechanistic pathways and have good clinical research prospects. However, many experiments have been limited to animal experiments or randomized controlled experiments with small sample sizes, making it necessary to conduct more diverse clinical studies need to further determine the optimal time and dose of treatment. Since the onset of keloid is also closely related to the patient’s individual constitution, personalized, comprehensive treatment is the key to achieving the optimal results.

Author contributions

WQ: Writing – original draft, Writing – review & editing. XX: Writing – original draft, Writing – review & editing. JT: Writing – review & editing. NG: Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Hubei Province Knowledge Innovation Project (2019CFB561).

Acknowledgments

The authors thank NG and JT for their constructive comments during the preparation of this manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: keloids, surgical therapy, physical therapy, drug therapy, biological therapy

Citation: Qi W, Xiao X, Tong J and Guo N (2023) Progress in the clinical treatment of keloids. Front. Med . 10:1284109. doi: 10.3389/fmed.2023.1284109

Received: 30 August 2023; Accepted: 03 November 2023; Published: 16 November 2023.

Reviewed by:

Copyright © 2023 Qi, Xiao, Tong and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jing Tong, [email protected] ; Nengqiang Guo, [email protected]

† These authors have contributed equally to this work

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• Published: 01 August 2023

Establishment of a humanized mouse model of keloid diseases following the migration of patient immune cells to the lesion: Patient-derived keloid xenograft (PDKX) model

• A Ram Lee 1 , 2 , 3   na1 ,
• Seon-Yeong Lee 1 , 3   na1 ,
• Jeong Won Choi 1 , 3 ,
• In Gyu Um 1 , 2 , 3 ,
• Hyun Sik Na 1 , 2 , 3 ,
• Jung Ho Lee 4   na2 &
• Mi-La Cho   ORCID: orcid.org/0000-0001-5715-3989 1 , 2 , 3 , 5   na2  

Experimental & Molecular Medicine volume  55 ,  pages 1713–1719 ( 2023 ) Cite this article

2443 Accesses

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Metrics details

• Experimental models of disease
• Lymphocyte activation

Keloid disorder is an abnormal fibroproliferative reaction that can occur on any area of skin, and it can impair the quality of life of affected individuals. To investigate the pathogenesis and develop a treatment strategy, a preclinical animal model of keloid disorder is needed. However, keloid disorder is unique to humans, and the development of an animal model of keloid disorder is highly problematic. We developed the patient-derived keloid xenograft (PDKX), which is a humanized mouse model, and compared it to the traditional mouse xenograft model (transplantation of only keloid lesions). To establish the PDKX model, peripheral mononuclear cells (PBMCs) from ten keloid patients or five healthy control subjects were injected into NOD/SCID/IL-2Rγnull mice, and their keloid lesions were grafted onto the back after the engraftment of immune cells (transplantation of keloid lesions and KP PBMCs or HC PBMCs). Four weeks after surgery, the grafted keloid lesion was subjected to histologic evaluation. Compared to the traditional model, neotissue formed along the margin of the grafted skin, and lymphocyte infiltration and collagen synthesis were significantly elevated in the PDKX model. The neotissue sites resembled the margin areas of keloids in several respects. In detail, the levels of human Th17 cells, IL-17, HIF-1a, and chemokines were significantly elevated in the neotissue of the PDKX model. Furthermore, the weight of the keloid lesion was increased significantly in the PDKX model, which was due to the proinflammatory microenvironment of the keloid lesion. We confirmed that our patient-derived keloid xenograft (PDKX) model mimicked keloid disorder by recapitulating the in vivo microenvironment. This model will contribute to the investigation of cellular mechanisms and therapeutic treatments for keloid disorders.

Introduction

Although keloid lesions are benign, they display aggressive and uncontrolled growth and a high rate of recurrence. These lesions can occur on any area of skin; the most commonly affected sites are the anterior chest, shoulders, back, and earlobe 1 . In most cases, the affected sites are accompanied by pain, disfigurements, and pruritis, which can cause emotional distress and other psychosocial symptoms 2 .

The pathophysiology of keloid disorder is unclear, and effective treatments that do not induce recurrence are not available. The etiology may encompass both genetic and environmental factors. Cytokines such as transforming growth factor (TGF), insulin-like growth factor, and vascular endothelial growth factor are highly expressed in keloid tissue 3 . In addition, proinflammatory cytokines generated by chronic inflammation are associated with pathologic fibroproliferative responses in keloid tissue 4 , 5 .

To investigate the pathogenesis of keloid disorder and develop a treatment strategy, a preclinical animal model is needed. However, keloid lesions develop only in humans, and the development of animal models is problematic. To overcome this difficulty, the keloid xenograft model, in which keloid lesions are grafted onto the skin or in a subcutaneous pocket of an immune-deficient mouse, was developed 6 . In this model, the grafted keloid lesion remained viable for several weeks to months with evidence of angiogenesis and fibrosis 7 , 8 ; this model has been applied extensively in keloid research 9 , 10 , 11 . However, because keloids lack T and B cells, the microenvironment may not reflect the inflammatory process of keloid disorder.

We developed a new humanized mouse model known as the patient-derived keloid xenograft (PDKX) model and compared it to the mouse xenograft model. To establish the PDKX model, peripheral blood mononuclear cells (PBMCs) from a keloid patient were injected into NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice and keloid tissue were grafted onto the back 4 weeks after immune cell transplantation. Four weeks after surgery, the grafted keloid tissue was subjected to histologic analysis.

Materials and methods

Keloid lesions and peripheral blood of patients.

This study was approved by the Institutional Review Board of Bucheon St. Mary’s Hospital (HC18TESI0013). Keloid lesions ( n  = 10) and PBMCs ( n  = 10) were obtained from 10 keloid patients who underwent surgery for ear keloid lesions. Healthy PBMCs ( n  = 5) were obtained from five healthy controls in this study. Informed consent was obtained from all patients according to the principles of the Declaration of Helsinki.

Eight-week-old NSG male mice were purchased from Jackson Laboratories (Bar Harbor, ME). All experimental procedures were approved by the Department of Laboratory Animals, Institutional Animal Care and Use Committee (IACUC) of the School of Medicine, Catholic University of Korea, and conformed with the guidelines of the United States National Institutes of Health (Permit Number: 2021-0027-02).

Animal experimental modeling

PBMCs were obtained from the blood of five healthy controls and ten keloid patients and intraperitoneally injected into NSG mice at a dose of 3 × 10 6 /mouse. Two weeks after transplantation, a keloid lesion (0.5 cm 3 , 130–150 mg) was transplanted into the back under the panniculus carnosus muscle. In the control group, keloid lesions were transplanted without preoperative PBMC transplantation. Four weeks after tissue transplantation, the mice were euthanized, and the transplanted human keloid skin lesion was removed for histologic evaluation (Fig. 1a ).

a Schematic representation of the humanized mouse model of keloid disorder. PBMCs isolated from the blood of keloid patients (KF, n  = 10) and healthy controls (HC, n  = 5) were injected intraperitoneally into NSG mice (3 × 10 6 cells per mouse). Two weeks later, the keloid lesion was transplanted into the back of the NSG mouse and observed for 4 weeks. b Peripheral blood samples of the mice have analyzed for human CD4+ T-cell engraftment by flow cytometry. c and d Four weeks after xenograft, the transplanted tissues were harvested, and the size and weight were measured. The bar graphs are from three independent experiments; means ± SDs. ** p  < 0.01.

Measurement of keloid lesions

Before transplantation and 4 weeks after skin tissue transplantation, the transplanted grafts were excised and subjected to morphologic analysis, as well as weight and size measurement using an electronic microbalance and ruler.

Flow cytometry

To confirm the engraftment of human immune cells in mouse blood, flow cytometry was performed. To confirm the engraftment of human CD4 T cells, mononuclear cells in mouse blood were stained with human anti-CD4-PeCy7 (Cat. no. 300511; Biolegend, San Diego, CA). Four weeks after tissue transplantation, IL-17-expressing human CD4 + T cells (Th17) were analyzed in the whole blood of mice. Mononuclear cells in mouse blood were stained with human anti-CD4 and IL-17-PE (12-7179-42; eBioscience, San Diego, CA). Before intracellular staining, the cells were stimulated for 4 h with phorbol myristate acetate (25 ng/mL) and ionomycin (250 ng/mL) in the presence of GolgiStop (554715; BD Biosciences, San Jose, CA). Intracellular staining was performed using a BD Cytofix/Cytoperm Plus Fixation/Permeabilization Kit and BD Golgistop Kit (554715; BD Biosciences). Flow cytometry was performed using a cytoFLEX flow cytometer (Beckman Coulter, Brea, CA), and the data was analyzed using FlowJo software (Tree Star, Ashland, OR).

Histological analysis

Explanted tissue was subjected to histological analyses to evaluate inflammation and collagen density.

The grafted tissues were excised and fixed in 4% neutral buffered formalin for 24 h, embedded in paraffin, and sectioned at a thickness of 5-µm. The tissue slides were deparaffinized and stained with hematoxylin and eosin (H&E). Masson’s trichrome (MT) staining was performed to examine collagen deposition using a Masson’s trichrome staining kit (PolySciences, Inc., Warrington, PA) 12 , 13 . Inflammation in H&E-stained tissue sections was assigned an ordinal score from 0 to 3 for mononuclear cell infiltration (grade 0: none; grade 1: mild; grade 2: moderate; and grade 3: severe). Collagen in Masson’s trichrome-stained sections was quantified using ImageJ software.

Immunohistochemistry (IHC)

The tissue sections were incubated at 4 °C with the following primary monoclonal antibodies: anti-HIF-1α (MA1-516; Thermo Fisher Scientific, Waltham, MA), anti-IL-17 (MAB3171-100; R&D Systems, Minneapolis, MN), anti-CD4 (ab133616; Abcam, Cambridge, UK), anti-IL-4 (PA5-25165; Thermo Fisher Scientific), anti-SDF-1 (ab9797; Abcam), anti-CCL2 (ab9669; Abcam), anti-CCL3 (PA5-47000; Thermo Fisher Scientific), anti-CXCL9 (ab9720; Abcam), anti-TGFβ (ab170874; Abcam), and anti-COL1A1 (PA5-50938; Thermo Fisher Scientific). Subsequently, the sections were exposed to horseradish peroxidase-coupled goat secondary antibodies conjugated to dextran (Dako, Glostrup, Denmark). The neotissue of sections was visualized using DAB + chromogen. Three slides were stained per sample of skin tissue; samples were taken at ≥500 µm intervals. The immunostained sections were examined using a photomicroscope (Olympus, Tokyo, Japan). The DAB-positive area was analyzed by color deconvolution with NIH ImageJ software.

Confocal microscopy

CD4, IL-17, IL-4, pSTAT3 (y705), CXCR3, and procollagen levels were analyzed by confocal microscopy. Paraffin-embedded sections were incubated with 10% normal goat serum for 30 min and stained with anti-CD4 (AF-379-NA; R&D Systems), anti-IL-17 (MAB3171-100; R&D Systems), anti-IL-4 (PA5-25165; Thermo Fisher Scientific), anti-pSTAT3 (y705) (ab76315; Abcam), anti-CXCR3 (SC-133087; Santa Cruz Biotechnology, Dallas, TX), and anti-procollagen (ab64409; Abcam) antibodies. Next, the samples were reacted with anti-goat IgG-FITC (SC-2024; Santa Cruz Biotechnology), anti-mouse-IgG1-Alexa Fluor 555 (A21127; Invitrogen, Waltham, MA), anti-rabbit-IgG-PE (4050-09; Southern Biotech, Birmingham, AL), anti-rabbit-IgG APC (A-10931; Invitrogen), anti-mouse-IgG-Alexa Fluor 647 (1031-31; Southern Biotech), and anti-rat IgG-Alexa Fluor 488 (A-11006; Invitrogen)-conjugated secondary antibodies. Nuclei were stained with DAPI (D3571; Thermo Fisher Scientific). The sections were visualized using a confocal microscope (LSM 700; Carl Zeiss, Oberkochen, Germany); the colocalization area and intensity were analyzed using ZEN 2009 software (Carl Zeiss).

Statistical analysis

The results are presented as the means ± standard deviations (SD). Data were analyzed using Student’s t -test or the Mann‒Whitney U test with Prism 5 software (GraphPad, La Jolla, CA); p < 0.05 (two-tailed) was considered indicative of significance.

Development of the PDKX model through the transplantation of human keloid PBMCs and tissue

We generated a patient-derived PDKX model as described in the “Materials and methods” section (Fig. 1a ). Two weeks after the injection of immune cells from keloid patients or healthy controls into NSG mice, we evaluated the engraftment levels of human CD4 T cells. Human-derived CD4 + T cells were identified in the blood of recipient mice. In both PDKX model models that were injected with keloid patient (KP) and healthy control (HC) PBMCs, CD4 + T cells were engrafted well. However, the level of engrafted CD4+ T cells was different in the KP PBMC and HC PBMC groups (Fig. 1b ). Four weeks after tissue transplantation, the size, and weight of the transplanted tissue were analyzed, and the transplanted tissues were significantly larger in the KP PBMC (9.5 ± 5 mg)-injected group than in the HC PBMC (3.3 ± 2.3 mg)-injected group (Fig. 1c and d ).

Verification of keloid KP PBMCs and the keloid lesion-derived PDKX model by comparison with HC PBMCs and keloid lesions

We found neotissue formation along the margin of the grafted skin tissue in the KP PBMC and HC PBMC groups. Interestingly, the neotissue of grafted skin showed the most abundant inflammatory cell infiltration and fibrosis in the KP PBMC group. The transplanted tissues in the KP PBMC PDKX model group had an increased collagen density and collagen bundle sizes (Fig. 2a ). The number of CD4 + IL-17 + T cells was significantly increased in KP PBMCs and keloid lesion-transplanted mice (Fig. 2b ). We confirmed that neotissue formation along the margin of grafted skin and collagen synthesis was significantly elevated in our PDKX model.

a Representative images of transplanted keloid lesions stained with H&E and MT. Inflammation scores and integrated densities are shown. b Mononuclear cells from humanized mouse blood stained with human CD4-PeCy7 and human IL-17-PE. The frequency of human CD4 + IL-17 + T cells is shown. The bar graphs are from three independent experiments; means ± SDs. * p  < 0.05; ** p  < 0.01; *** p  < 0.001.

Evaluation of cytokine expression by cell subtypes in the transplanted keloid tissue of the KP and HC PBMC PDKX models

IL-17 expression in T cells is increased in keloid patients and the transitional region of keloid lesions. The IL-17-STAT3-HIF-1α axis is involved in defective homeostasis and increased fibrosis in dermal fibroblasts, implicating IL-17/Th17 cells in keloid disease 14 . IL-4 and IL-17 promote inflammation and fibrosis in systemic sclerosis, pulmonary disease, and liver cirrhosis 15 , 16 , 17 . Therefore, we evaluated cytokine-expressing immune cells in keloid lesions transplanted with KP PBMCs. The numbers of cells expressing human IL-4, IL-17, and HIF1-α were increased in the perigraft area (Fig. 3a ). The number of CD4 + IL-17 + T cells was significantly increased in KP PBMCs and keloid lesion-transplanted mice. The numbers of p STAT3 705 -positive CD4 T cells and CXCR3-positive CD4 T cells were significantly increased in the perigraft area in the KP PBMC group compared to the HC PBMC and control groups (Fig. 3b ). Therefore, Th17 cell infiltration was significantly elevated in our PDKX model.

a Six weeks after the induction of humanized mice, the transplanted keloid lesions were harvested and analyzed by IHC using antibodies against human HIF-1α, CD4, IL-4, and IL-17. Representative IHC images (upper panels) and graphs (lower panels). b Harvested tissues were stained for CD4 (FITC), IL-17 (PE), p STAT3y705 (PE), CXCR3 (white), or DAPI (blue). Representative confocal images (upper panels) and graphs (lower panels). Original magnification, ×400; scale bars, 100 μm. Bars represent positive cell numbers per high-power field (HPF); means ± SDs. * p  < 0.05; ** p  < 0.01; *** p  < 0.001.

T-cell migration was enhanced by CC chemokines in transferred keloid tissue

SDF-1 expression is significantly elevated in the keloid margin area, enhancing the recruitment of Th17 cells 5 . We found that SDF-1, CCL2, CCL3, and CXCL9 expression was significantly increased in the perigraft area in the KP PBMC group (Fig. 4a and b ). Chemokines promote inflammation and fibrosis in keloid disorders 18 . Activated fibroblasts and endothelial cells release CCL2, thereby recruiting monocytes and inducing the production of extracellular matrix. The CCL3 level is increased in the plasma of keloid patients 19 . Recruited monocytes also produce other chemokines, such as CXCL9, promoting the infiltration of CXCR3-expressing Th17 cells 20 . Therefore, increased levels of SDF-1 and CC chemokines contribute to the integrity of keloid lesions and promote fibrosis.

a and b Six weeks after the induction of humanized mice, the transplanted tissues were harvested and analyzed by IHC using antibodies against human SDF-1 CCL2, CCL3, and CXCL9. Representative IHC images and graphs. Original magnification, ×400; scale bars, 100 μm. Bars are positive cell numbers per HPF; means ± SDs. * p  < 0.05; ** p  < 0.01; *** p  < 0.001.

Exacerbation of skin fibrosis in the KP PBMC transplant group by increased procollagen and TGF-β expression

Procollagen is synthesized by fibroblasts and assembled into collagen fibrils 21 . TGF-β and collagen type I alpha 1 (COL1A1) are mediators of fibrosis in keloid patients 22 , 23 . Procollagen, TGF-β, and COL1A1 expression were significantly increased in the KP PBMC group (Fig. 5a and b ). Therefore, our PDKX model accurately reflects chronic inflammation and allows in vivo growth of keloid tissue.

Six weeks after the induction of humanized mice, the transplanted tissues were harvested and analyzed by confocal microscopy and IHC. a The tissues were stained for procollagen (FITC) and DAPI (blue). Representative confocal images (upper panels) and graphs of areas of procollagen and DAPI colocalization (lower panels) are shown. b TGF-β and COL1A1 levels were evaluated by IHC. Representative IHC images (upper panels) and graphs (lower panels). Original magnification, ×400; scale bars, 100 μm. Bars are positive cell numbers per HPF; mean ± SD. * p  < 0.05; ** p  < 0.01.

There is no single unifying hypothesis that adequately explains keloid formation; therefore, currently, available treatments include surgical excision and intralesional steroid treatment, but these treatments often induce recurrence 24 . To develop new treatments, greater insight into the molecular pathogenesis of keloid disorder is needed. However, keloid lesions only develop in humans, and so prior studies have used excised keloid lesions or fibroblasts 25 .

In in vivo transplantation-based models, immunodeficient animals (e.g., athymic mice) or an immune-privileged site (e.g., the cheek pouch of a hamster) are used because of the risk of rejection 6 , 24 . Shetlar 6 , 7 described the implantation of keloid lesions into the subcutaneous tissue of athymic mice, and the implanted tissue maintained its integrity for >240 days without rejection. Subsequent keloid research was performed using similar animal models 8 , 10 , 26 .

However, these models do not recapitulate the disease microenvironment. The degree of inflammation and characteristics of fibroblasts can be different according to the lesion. For example, lymphocyte infiltration and proinflammatory cytokine (IL-17, IL-1β, IL-6, and tumor necrosis factor-α) expression are increased in the keloid margin area (growing margin) compared to the intralesional or extralesional areas (surrounding normal skin) 5 . Keloid fibroblasts from keloid margin sites show higher collagen I and III expression in vitro than those from intralesional or extralesional sites, and the paracrine effects of inflammatory cells on keloid fibroblasts contribute to disease progression 27 , 28 . Therefore, to reflect chronic inflammation in keloid disease, the keloid fibroblast–immune cell interaction needs to be modeled.

In this study, we injected T cells into NSG mice 2 weeks prior to the implantation of keloid lesions. Because human T cells were injected into immunocompromised mice, lethal xenogenic graft-versus-host disease (GVHD) could develop within 4–8 weeks 29 . The NSG mouse lacks major histocompatibility complex (MHC) classes I and II, extending the experimental period 30 . In a preliminary experiment, the mice survived for up to 12 weeks without GVHD, and fluorescence-activated cell sorting analysis showed successful engraftment of T cells in 4 weeks. We observed that the level of engrafted CD4 + T cells was significantly increased in the KP PBMC group. It has been reported that chimeric human T cells exhibit the phenotype of mature memory cells in a humanized SKID model 31 . In addition, memory T cell infiltration is abnormally present in the scar tissue of keloid patients 32 .

In our PDKX model, neotissue formed along the margin of the grafted skin, and lymphocyte infiltration and collagen synthesis were significantly elevated. The neotissue resembled the keloid margin area of keloids in several respects. First, SDF-1 and IL-17 expression was significantly elevated. Shin et al. 33 reported high infiltration of SDF-1α + myofibroblasts into keloid margins, which was associated with increased recruitment of CXCR4-expressing immune cells and CXCR4-expressing fibrocytes. Additionally, IL-17 and SDF-1 expression was significantly elevated in the keloid margin area, upregulating SDF-1 and further increasing Th17-cell recruitment, creating a positive feedback loop and excessive fibrosis 5 .

Recently, it was reported that type 3 immunity (IL-17/Th17) is associated with progressive keloid disorder and that IL-17/Th17 induces inflammation and fibrosis in keloid fibroblasts through STAT3/HIF-1α 5 , 34 , 35 .

Furthermore, the inflammatory niche-driven IL-17/IL-6 axis is associated with the acquisition by keloid-derived precursor cells of a tumor-like stem cell phenotype 36 . Therefore, IL-17 is important in the pathogenesis of keloids. However, SDF-1 and IL-17 expression was low in the perigraft area in the control group, whereas Th17 cell infiltration and SDF-1 expression were significantly elevated in our PDKX model.

Second, the expression of CC chemokines was significantly elevated in neotissue in the PDKX model. CCL2 stimulates the expression of collagen by fibroblasts and is implicated in renal fibrosis, ischemic cardiomyopathy, atherosclerosis, and pancreatitis 37 , 38 , 39 . CCL2 and CCR2 expression is reportedly enhanced in keloid tissue, increasing fibroblast proliferation 18 . Additionally, CCL3, CCL4, G-CSF, and GM-CSF levels were significantly elevated in the plasma of keloid patients compared to healthy controls, implicating inflammatory cytokines in the formation of keloid lesions 19 . In this study, CCL2 and CCL3 expression was significantly elevated in the perigraft and intragraft areas, contributing to keloid-lesion integrity and augmenting fibrosis. Monocyte chemokines such as CXCL9 promote the infiltration of CXCR3-expressing Th17 cells 20 .

Because keloid disorder is a chronic fibroproliferative disorder, the maintenance or growth of scar tissue in vivo is important. However, Kischer et al. 8 , 40 showed that the size of keloid lesions decreased (slope −0.736) after implantation on the back of an athymic nude mouse, and the volume of keloid lesions decreased by half after 67 days. Waki et al. 9 reported that grafts grew rapidly for 4 weeks after implantation and decreased in size thereafter. In this study, the weight of keloid lesions did not change significantly but increased significantly (~1.5-fold) in the keloid + KP PBMC group. This proinflammatory microenvironment is likely responsible for the increase in graft weight. Additionally, the allogeneic immune response was not seen as a concern because the inflammatory response was not found to be significantly higher in the normal PBMC (peripheral blood mononuclear cell) group than in the patient PBMC group.

In conclusion, our PDKX model reflects chronic inflammation in keloid lesions and enables their growth in vivo. This model will contribute to keloid research by recapitulating the in vivo microenvironment.

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Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2020R1F1A1075541), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HV22C0069) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI20C1496).

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These authors contributed equally: A Ram Lee, Seon-Yeong Lee.

These authors jointly supervised this work: Jung Ho Lee, Mi-La Cho.

Authors and Affiliations

Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea

A Ram Lee, Seon-Yeong Lee, Jeong Won Choi, In Gyu Um, Hyun Sik Na & Mi-La Cho

Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea

A Ram Lee, In Gyu Um, Hyun Sik Na & Mi-La Cho

The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea

Department of Plastic and Reconstructive Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea

Jung Ho Lee

Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, South Korea

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A.R.M., J.W.C., J.H.L., and M.-L.C. designed the experiments and analyzed the data. A.R.M., S.-Y.L., J.H.L., and M.-L.C. wrote the manuscript. The in vitro experiments were performed by A.R.M., J.W.C., and I.G.U. J.W.C., H.S.N., and I.G.U. conducted the IHC experiments. All authors critically reviewed and approved the final version of the manuscript.

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Correspondence to Jung Ho Lee or Mi-La Cho .

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Lee, A.R., Lee, SY., Choi, J.W. et al. Establishment of a humanized mouse model of keloid diseases following the migration of patient immune cells to the lesion: Patient-derived keloid xenograft (PDKX) model. Exp Mol Med 55 , 1713–1719 (2023). https://doi.org/10.1038/s12276-023-01045-6

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New Keloid Research Raises Hope for Future Treatments

by Jennifer L.W. Fink • September 7, 2014

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Keloids are incredibly common in some patient populations. These abnormal scars, which grow well beyond the border of the original injury site, are typically unsightly, inconvenient, and often uncomfortable. Keloids cause pain, pruritis, and even hyperesthesia, as well as social discomfort and embarrassment.

Until recently, very little was known about the etiology of keloids, and even less was known about how to effectively treat and manage these growths. Surgical excision is frequently inadequate, because many, if not most, keloids recur after excision. Other treatment measures, including corticosteroid injection and the use of pressure dressings, were based on medical intuition and anecdotal evidence more than on scientific research.

Not surprisingly, keloids remain a challenge for patients and practitioners alike. Fortunately, new research is beginning to reveal more about the etiology of keloids. Innovative treatments continue to hit the market, with more anticipated in the future. Experts predict that biologic therapies may eventually be used to treat—and even prevent—keloids. There’s even hope that an increasing understanding of keloid formation and treatment will lead to innovations within the field of plastic surgery.

“When you look at facial plastics, our nemesis is scar formation,” said Lamont R. Jones, MD, vice chair of the department of otolaryngology–head and neck surgery at Henry Ford Hospital in Detroit. “What is exciting about studying keloids is that if we understand what’s going on in keloids, we can exploit that knowledge for other uses in facial plastics.”

Epigenetic Link

Because keloids are most commonly seen in people of African, Hispanic, and Asian descent, researchers have long suspected a genetic component to keloid formation. The observation that more than half of all patients with keloids report a family history of keloid scarring has strengthened that suspicion (Mol Med. 2011;17:113-125).

By 2008, researchers had identified at least one autosomal dominant inheritance pattern of keloids and some genes (most notably HLA-DRB1*15 and DQB1*0503) associated with an increased risk of keloid scarring (Mol Med. 2011;17:113-125). But keloids have also been associated with immune response and blood type, leading researchers to believe that keloid formation is much more complex than the presence, absence, or mutation of any one gene.

“Most disease conditions are complex. A lot of times, there is not just one gene that’s involved but a pathway. There may be multiple genes that come together to help produce whatever the end result may be,” Dr. Jones said. “So, identifying a gene and pathways may key you into the bigger picture of what’s going on with that process, and identifying that gives you the opportunity to look at other relationships, which may be more important than a particular gene alone.”

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Keloid research: current status and future directions

Affiliations.

• 1 Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Keelung & Chang Gung University College of Medicine, Taoyuan.
• 2 Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan.
• PMID: 31452957
• PMCID: PMC6700880
• DOI: 10.1177/2059513119868659

Introduction: Keloids and hypertrophic scars are fibroproliferative disorders of the skin that result from abnormal healing of injured or irritated skin. Multiple studies suggest that genetic, systemic and local factors may contribute to the development and/or growth of keloids and hypertrophic scars. A key local factor may be mechanical stimuli. Here, we provide an up-to-date review of the studies on the roles that genetic variation, epigenetic modifications and mechanotransduction play in keloidogenesis.

Methods: An English literature review was performed by searching the PubMed, Embase and Web of Science databases with the following keywords: genome-wide association study; epigenetics; non-coding RNA; microRNA; long non-coding RNA (lncRNA); DNA methylation; mechanobiology; and keloid. The searches targeted the time period between the date of database inception and July 2018.

Results: Genetic studies identified several single-nucleotide polymorphisms and gene linkages that may contribute to keloid pathogenesis. Epigenetic modifications caused by non-coding RNAs (e.g. microRNAs and lncRNAs) and DNA methylation may also play important roles by inducing the persistent activation of keloidal fibroblasts. Mechanical forces and the ensuing cellular mechanotransduction may also influence the degree of scar formation, scar contracture and the formation/progression of keloids and hypertrophic scars.

Conclusions: Recent research indicates that the formation/growth of keloids and hypertrophic scars associate clearly with genetic, epigenetic, systemic and local risk factors, particularly skin tension around scars. Further research into scar-related genetics, epigenetics and mechanobiology may reveal molecular, cellular or tissue-level targets that could lead to the development of more effective prophylactic and therapeutic strategies for wounds/scars in the future.

Keywords: DNA methylation; Keloid; epigenetics; genetics; long non-coding RNA; mechanobiology; microRNA; non-coding RNA.

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Modelling Keloids Dynamics: A Brief Review and New Mathematical Perspectives

• Published: 19 October 2023
• Volume 85 , article number  117 , ( 2023 )

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• R. Eftimie   ORCID: orcid.org/0000-0002-9726-1498 1 ,
• G. Rolin 2 , 3 ,
• O. E. Adebayo 1 ,
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Keloids are fibroproliferative disorders described by excessive growth of fibrotic tissue, which also invades adjacent areas (beyond the original wound borders). Since these disorders are specific to humans (no other animal species naturally develop keloid-like tissue), experimental in vivo/in vitro research has not led to significant advances in this field. One possible approach could be to combine in vitro human models with calibrated in silico mathematical approaches (i.e., models and simulations) to generate new testable biological hypotheses related to biological mechanisms and improved treatments. Because these combined approaches do not really exist for keloid disorders, in this brief review we start by summarising the biology of these disorders, then present various types of mathematical and computational approaches used for related disorders (i.e., wound healing and solid tumours), followed by a discussion of the very few mathematical and computational models published so far to study various inflammatory and mechanical aspects of keloids. We conclude this review by discussing some open problems and mathematical opportunities offered in the context of keloid disorders by such combined in vitro/in silico approaches, and the need for multi-disciplinary research to enable clinical progress.

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Acknowledgements

RE and OA acknowledge funding from a French Agence Nationale de Recherche (ANR) Grant Number ANR-21-CE45-0025-01; SPAB and SU acknowledge funding from a Luxembourg National Research Fund (FNR) Grant Number INTER/ANR/21/16399490; G.R. acknowledges funding from an ANR Grant Number ANR-21-CE45-0025-03; FC’s work is partially supported by the I-Site BFC project NAANoD, the EIPHI Graduate School (contract ANR-17-EURE-0002) and the ANR project S-KELOID (ANR-21-CE45-0025-04). FC is also grateful to the Center for Mathematical Modelling Grant FB20005.

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Laboratoire de Mathématiques de Besançon, Université de Franche-Comté, 25000, Besançon, France

R. Eftimie & O. E. Adebayo

INSERM CIC-1431, CHU Besançon, F-25000, Besançon, France

EFS, INSERM, UMR 1098 RIGHT, Université de Franche-Comté, F-25000, Besançon, France

Institut de Mathématiques de Bourgogne, Université de Franche-Comté, 21078, Dijon, France

Institute for Computational Engineering, Faculty of Science, Technology and Communication, University of Luxembourg, Esch-sur-Alzette, Luxembourg

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Eftimie, R., Rolin, G., Adebayo, O.E. et al. Modelling Keloids Dynamics: A Brief Review and New Mathematical Perspectives. Bull Math Biol 85 , 117 (2023). https://doi.org/10.1007/s11538-023-01222-8

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What’s New in Keloids?

Hilary Baldwin, MD, presents on keloids in light skin patients, hypopigmentation after treatment, to stitch or not to stitch, and more.

In a presentation at the Skin of Color Update 2021, held virtually September 10-12, Hilary Baldwin, MD, dermatologist, medical director at the Acne Treatment and Research Center in Brooklyn, New York, and assistant professor at Rutgers Robert Wood Johnson Center in New Brunswick, New Jersey, explained that as keloids pharmacogenetics are not well known, it can cause keloids to not respond to corticosteroid (CS) treatment. 1 Other reasons for this can be attributed to poor technique, insufficient dosing/concentration, and reduced genetic sensitivity to glucocorticoids (GC). 

She quoted a study in which 19 patients were evaluated, 12 of the patients had CS responses in the past and 7 patients did not. The study found that GC receptors were less sensitive in those who did not respond in treatment and continued to be downregulated as time moved on. They also found at week 4 that melanin decreased in patients, and it might be related to treatment success. Baldwin summed up the results by stating that if a patient is not responding, then it is time to try another treatment.

Baldwin said that she does not believe hypopigmentation is a worry for darker skinned patients, as it is a sign that treatment is working and usually ends up going away. She explains to her patients that the hypopigmentation is from the treatment.

“I have never had a patient say to me, ‘You know, I hate this whiteness. I don’t want you to do this anymore,” Baldwin said, “Not one person ever has said [to me] they would rather have the keloid than the hypopigmentation.”

Baldwin commented that lighter skinned patients are harder for her to treat than patients with darker skin and she believes this may be because of the melanin in the skin. 

For keloids, according to Baldwin, size does not matter, but patients tend to be more impressed when larger keloids are removed versus smaller ones. This relates to the residual scarring left behind. A patient with a smaller keloid may be more unhappy with the residual scarring, but a patient with a larger keloid will be less critical. She warned to watch for large blood vessels as they can be hidden inside cuboidal material. 

Baldwin also recommends being careful when deciding to stitch or not to stitch after removing a keloid. She said she avoids it when she can, but in some cases it is unavoidable, and in those cases to keep in mind that every place the suture was put is a potential keloid to the patient. 

For post-surgical therapy, Baldwin uses:

• CS 40 mg/cc every 2 weeks until fully healed
• Interferon 1.5 mg/linear cm day 1 and day 7
• Radiation therapy day 1 and days 4-10
• Pressure dressings

When deciding on which one to use, she advises to look at the location of removal, and from there chooses the appropriate method. If possible, she will use all 4.

In some cases, keloids will occur after acne develops. If this happens, Baldwin will first treat the acne, to prevent more keloids from forming, and thereafter treat the keloids.

She then brought up the question of pods, an occurrence of keloid edges after injecting the middle portion of an existing keloid. Baldwin started to inject from the outer edges of a keloid to prevent this phenomenon.

The issue of distinguishing between a keloid and a piercing bump was discussed. With growing amount of ear piercings, Baldwin explained, it can be hard to know the difference between the two.

“Well, the piercing bumps occur early, and they are slightly tender,” Baldwin said. “They are often pus filled and they usually resolve spontaneously with warm soaks.” She went on to explain that CS can speed the resolution of piercing bumps, so she will inject the bump as this way if it is a keloid, it will be the start of treatment and if not, the piercing bump is still being treated.

This also brings up the issue with hypertrophic scars (HS) and keloids. Often, it is hard to spot the difference between these, according to Baldwin, and the papers on them often do not distinguish the results of treatment for HS vs keloids. She believes this needs more investigation. 

Lastly, she brought up dupilumab. There was a case of a 53-year-old male patient with both atopic dermatitis (AD) and keloids (2 of them) who was treated with dupilumab for his AD and spontaneously, according to Baldwin, the keloids improved after 7 months. She thinks that may this needs to be investigated as a treatment for keloids.

Disclosures:

Hilary E. Baldwin, MD, had no relevant disclosures.

1. Baldwin H. What’s New in Keloids. Presented at the: Skin of Color Update; September 10, 2021; Virtual.

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• Patient Care & Health Information
• Diseases & Conditions
• Keloid scar

Your doctor usually can tell whether you have a keloid by looking at the affected skin. You might need a skin biopsy to rule out skin cancer.

More Information

• Skin biopsy

Keloid scar treatments include the following. One or a combination of approaches might be best for your situation. Even after successful flattening or removal, keloids can grow back, sometimes bigger than before. Or you may develop new ones.

• Wound care. For newer keloids, the first treatment option might be compression dressings made from stretchy fabric or other materials. This method is also used after surgery to remove keloids. The goal is to reduce or prevent a scar by putting pressure on the wound as it heals. Such dressings need to be worn for 12 to 24 hours a day for 4 to 6 months to be effective. This method can be very uncomfortable.
• Corticosteroid cream. Applying a prescription strength corticosteroid cream can help ease itchiness.
• Injected medicine. If you have a smaller keloid, your doctor might try reducing its thickness by injecting it with cortisone or other steroids. You'll likely need monthly injections for up to six months before seeing the scar flatten. Possible side effects of corticosteroid injections are skin thinning, spider veins and a permanent change in skin color (hypopigmentation or hyperpigmentation).
• Freezing the scar. Small keloids might be reduced or removed by freezing them with liquid nitrogen (cryotherapy). Repeat treatments might be needed. Possible side effects of cryotherapy are blistering, pain and loss of skin color (hypopigmentation).
• Laser treatment. Larger keloids can be flattened by pulsed-dye laser sessions. This method has also been useful in easing itchiness and causing keloids to fade. Pulsed-dye laser therapy is delivered over several sessions with 4 to 8 weeks between sessions. Your doctor might recommend combining laser therapy with cortisone injections. Possible side effects, which are more common in people with darker skin, include hypopigmentation or hyperpigmentation, blistering and crusting.
• Radiation therapy. Low-level X-ray radiation alone or after surgical removal of a keloid can help shrink or minimize the scar tissue. Repeat treatments might be needed. Possible side effects of radiation therapy are skin complications and, in the long term, cancer.
• Surgical removal. If your keloid hasn't responded to other therapies, your doctor might recommend removing it with surgery in combination with other methods. Surgery alone has a recurrence rate of 45% to 100%.
• Radiation therapy

Alternative medicine

There are no proven methods of removing keloid scars naturally. Some clinical studies have shown that onion extract used orally or on the skin might possibly be effective in improving the appearance of keloid scars and reducing itchiness and discomfort.

Potential future treatments

Research into wound-healing issues, including keloid formation, shows promise. For example, studies include:

• Experimental topical creams and injectables to reduce and stop the growth of keloids
• Botulinum toxin type A (Botox) to improve wound healing
• Identifying genetic markers in keloid tissue
• Stem cell therapy

Lifestyle and home remedies

Try these keloid self-care tips:

• Care for your wound as directed. Wound care can be time-consuming, and compression dressings can be uncomfortable. Try to stick with the routine recommended by your doctor, as these steps are important to keloid prevention.
• Apply a corticosteroid cream. This type of nonprescription cream can help ease itchiness.
• Apply silicone gel. Applying nonprescription silicone gel can help ease itchiness.
• Protect the area from re-injury. Avoid irritating the keloid with clothing or other types of friction or injury.
• Protect your skin from the sun. Sun exposure might change the color of your keloid, making it more noticeable. That change might be permanent. Before going outside, protect your skin by covering the keloid or by liberally applying sunscreen.

Preparing for your appointment

Call your doctor if you notice a change in your skin that might indicate a keloid is forming or if you've been living with a keloid for a while and want to seek treatment. After your initial appointment, your doctor may refer you to a doctor who specializes in the diagnosis and treatment of skin conditions (dermatologist).

You might want to ask a trusted family member or friend to come to your appointment, if possible. Someone close to you may provide additional insight about your condition and can help you remember what's discussed during your appointment.

What you can do

Before your appointment, make a list of:

• Any symptoms you've been experiencing, and for how long
• Your medical information, including other injuries or surgeries you've had and whether your family has a history of keloids
• Questions to ask your doctor to make the most of your time together

Questions may include:

• Am I at risk of developing keloids?
• How can I reduce the risk of developing a keloid?
• What if I want to get a tattoo or body piercing?
• What if I need surgery?
• How soon after beginning treatment might my symptoms start to improve?
• When will you see me again to evaluate whether my treatment is working?
• What are the chances of the keloid coming back?
• What are possible side effects of the treatment you're suggesting?
• I'm scheduled for surgery. What can I do to minimize the risk of a keloid developing from the scar?
• What's your advice on wound care after surgery?
• Can my keloid turn into cancer?
• What self-care steps might prevent a keloid from coming back?
• Do you recommend any changes to the products I'm using on my skin, including soaps, lotions, sunscreens and cosmetics?

Don't hesitate to ask any other questions.

What to expect from your doctor

Your doctor or mental health provider may ask:

• When did you first develop this problem?
• Have your symptoms been getting better or worse over time?
• Have any of your relatives had similar symptoms?
• How is your skin condition affecting your self-esteem and your confidence in social situations?
• What treatments and self-care steps have you tried so far? Have any been effective?
• Have you ever been injured?
• Have you ever had surgery?
• AskMayoExpert. Keloid and hypertrophic scar. Mayo Clinic; 2020.
• Betarbet U, et al. Keloids: A review of etiology, prevention, and treatment. Journal of Clinical Aesthetic Dermatology. 2020;13:33.
• Kelly AP, et al. Keloids. In: Taylor and Kelly's Dermatology for Skin of Color. 2nd ed. McGraw-Hill Education; 2016. https://accessmedicine.mhmedical.com. Accessed May 27, 2021.
• High WA, et al., eds. Special considerations in skin of color. In: Dermatology Secrets. 6th ed. Elsevier; 2021. https://clinicalkey.com. Accessed June 1, 2021.
• Ekstein SF, et al. Keloids: A review of therapeutic management. International Journal of Dermatology. 2021; doi.10.111/ijd.15159.
• Avram M, et al. Ear piercing and ear lobe repairs. In: Procedural Dermatology. McGraw-Hill Education; 2015. https://accessmedicine.mhmedical.com. Accessed May 27, 2021.
• Keloids. American Academy of Dermatology. https://www.aad.org/public/diseases/a-z/keloids-overview. Accessed May 27, 2021.
• Ojeh N, et al. Keloids: Current and emerging therapies. Scars, Burns and Healing. 2020; doi.10.1177/2059513120940499.
• Mascharak S, et al. Preventing engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science. 2021; doi.10.1126/science.aba2374.
• Onion. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed June 7, 2021.

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5th International Keloid Symposium

• Seoul, South Korea, May 10-12, 2024

Clinical Science Guiding Laboratory Research

• Fostering Scientific Research in Keloid Disorder, Promoting Education, Advocacy, and Service to all Keloid Patients.

Welcome to the Keloid Research Foundation

Established in 2011 by Dr. Michael H. Tirgan, the KRF is a 501 (C)(3), non for profit medical research and educational organization. The mission of KRF is to foster scientific research in keloid disorder and to promote education, advocacy, and service to those who suffer from this disorder. Donors can deduct contributions they make to KRF under IRC Section 170.

Keloid is a genetic skin disorder which results in excessive growth and formation of tumor-like areas in an otherwise healthy skin. Despite their benign nature, keloids may constitute severe aesthetic as well as functional problems that can negatively impact patients' quality of life.

Keloids are mostly observed between ages of 10 and 30 years. There is no consensus on the best method of treatment for this condition; neither do we have any form of wholly satisfactory therapy. Keloids do not regress and are characterized by a high rate of recurrence after surgery or other forms of treatment. Indeed, surgical treatment often gives rise to even larger lesions. In addition, being a uniquely human condition, no animal study models are available.

Although a common medical condition, keloid disorder has been neglected by the research community. There are no statistics as to its incidence and prevalence, neither in the United States, nor elsewhere in the world. This disorder, although quite common and although at times very disabling, has not captured the interest of the research community and remains an area of unmet medical need. It behaves quite similar to cancer, yet it does not metastasize to tissues outside skin (or maybe it does and we simply do not know about it).

KRF was formed to foster scientific research in this disease. To accomplish its goals, KRF will raise funds, increase awareness and bolster interest in this disease. We will not make any progress in this disease unless we dedicate the same kind of interest, effort and energy that we have dedicated to cancer research.

Keloid Research is an online, open access scientific publication of the Keloid Research Foundation. Until now, keloid manuscripts have been published in a variety of journals. Our goal is to create a centralized publishing platform for all researchers who are passionate about this disorder, so that relevant clinical and laboratory research can be published in one place and under one umbrella. The journal is aiming to provide an international forum for the publication of original work, describing basic science, translational and clinical investigations in keloid disorder. Click on the image below to be directed to the journal's website.

KRF is also the sponsor of the annual International Keloid Symposium . Our last meeting, the 3rd International Keloid Symposium was held in April 2019 in Beijing. The 2020 and 2021 annual meetings were cancelled due to COVID-19 pandemic.

We are now pleased to announce that our next meeting, the 4th International Keloid Symposium will be a three-day meeting and will be held on October 7-9 2022 in Montpellier, France. Click on the image below to be directed to the symposium website.

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Clinical effect of dermatologic trephination combined with radiotherapy in the treatment of keloids.

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Liang Chen, Xiao Ming Qin, Lin Qi Wang, Qiu Yu Wang, Kong Chao Yang, Clinical Effect of Dermatologic Trephination Combined With Radiotherapy in the Treatment of Keloids, Aesthetic Surgery Journal , 2024;, sjae119, https://doi.org/10.1093/asj/sjae119

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Keloids are excessive formations of scar tissue that develop at the site of a skin injury. Due to their invasive nature, they have a negative impact on the skin's appearance and are prone to recurrence, making them a challenging condition to treat in terms of skin aesthetics.

The objective of this article is to compare the long-term effects of dermatologic trephination with non-surgical treatments in scar repair and evaluate their clinical value.

A retrospective analysis was conducted on 48 patients who received keloids treatment in the Department of Dermatology and Thoracic Surgery of our hospital from January 2021 to October 2023, of which 24 patients received dermatologic trephination and 24 patients received non-surgical treatment. Outcome measures included scar appearance, scar healing time, pain and itching levels, and patient satisfaction.

In the comparison of scar healing time, the healing time of patients using dermatologic trephination was significantly shorter than that of patients in the non-surgical group. In the evaluation of the degree of itching, the degree of itching in patients undergoing dermatologic trephination was significantly lower than that of patients in the non-surgical group. In the evaluation of satisfaction, the satisfaction of patients using dermatologic trephination was significantly higher than that of patients in the non-surgical group.

This study demonstrates that trephination achieves more significant long-term results in keloid revision, including improved keloid appearance, itching and patient satisfaction.

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Keloid Treatment Market Expected to Reach US$5.6 Billion by 2033, Driven by Growing Demand for Effective Solutions

The Keloid Treatment Market solutions has reached a significant landmark, valued at US$3.8 billion in 2023 according to a new report by Future Market Insights (FMI). This leading market research firm also forecasts a promising future for the industry, predicting a steady growth trajectory with a Compound Annual Growth Rate (CAGR) of 3.8% over the next decade (2023-2033).

This upward trend is projected to propel the market to a remarkable US$5.6 billion by 2033. The increasing demand for effective keloid treatment options is a key driver of this market expansion.

Keloids, characterized by the abnormal growth of scar tissue, have become a widespread concern globally. The escalating incidence of keloids has generated an increasing demand for effective treatment solutions. This surge is not only attributed to the rising prevalence of keloids but also to the continuous advancements in medical technologies and increased awareness among individuals seeking optimal solutions for scar management.

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Global Keloid Treatment Industry: Dynamics

The Global Keloid Treatment Industry growth is substantially driven by the rising prevalence of keloid scars as well as the development of multiple keloids. A growing consciousness among patients regarding their appearance is also driving the market of keloid treatment as keloid scars on the exposed body parts lead to ugly appearances. Other factors that are driving the growth in the keloid treatment market include increasing reimbursement for keloid therapies, formalization of standard treatment guidelines for keloid and increasing use of combination therapies. Clinics and hospitals are focussing on the adoption of advanced therapy options. CryoShape is used to reduce the impact of keloid scar and recurrence rate. Sensus Healthcare has developed an advanced superficial radiation therapy device to impart better treatment with limited adverse reactions.

Keloid Treatment Market: Segmental Forecast

The Global Keloid Treatment Industry is segmented based on treatment type, end user and region. The market has been segmented based on treatment type into occlusive dressing, compression therapy, cryosurgery, excision, radiation therapy, laser therapy, interferon therapy, intralesional corticosteroid injection, and others. Other treatment options include  dermal fillers , topical creams, 5-fluorouracil, retinoic acid and imiquimod. The intralesional corticosteroid injection treatment segment dominates the Global Keloid Treatment Industry as this procedure is considered the gold standard and is being used in combination with other therapies. Intralesional corticosteroid injection is expected to be the second most lucrative segment by treatment type, with a market attractiveness index of 2.1 during the forecast period.

Based on end users, the Global Keloid Treatment Industry is segmented into hospitals,  dermatology  clinics, ambulatory surgical centres and others. The hospital segment is expected to remain dominant, as most of the radiation therapies and excision procedures are performed in hospitals. Hospitals are the largest segment by the end-user, which is estimated to represent  US$ 1,164.7 Mn , or  37.0%  share of the total market in 2017 and is projected to reach a market valuation of US$ 1,643.8 Mn , or 37.2% share of the total market by the end of 2027, expanding at a  CAGR of 3.5%  in terms of value.

Keloid Treatment Industry: Regional Analysis

Based on region, the Global Keloid Treatment Industry is segmented into North America, Latin America, Western Europe, Eastern Europe, Asia Pacific excluding Japan, Japan and the Middle East & Africa.

North America dominated the Global Keloid Treatment Industry in 2016 and is expected to continue to dominate the global market throughout the forecast period. North America is the largest region in the keloid treatment market, which is estimated to represent  US$ 1,105.6 Mn , or  35.1%  share of the total market in 2017 and is projected to reach a market valuation of  US$ 1,549.6 Mn , or  35.1%  of the total market by the end of 2027, expanding at CAGR of  3.4%  in terms of value. Clinics in North America are opting for advanced treatment therapies that can aid in reducing the risk of recurrence.

Keloid Treatment Market: Vendor Analysis

Leading players in the Global Keloid Treatment Industry are launching new portable and mobile radiation therapy devices and offering patients better treatment options. Companies are targeting dermatology clinics to market their devices, where patients are provided the first line of treatment for keloid. Some of the players operating in the Global Keloid Treatment Industry who have been profiled in the report include Novartis AG, Sensus Healthcare, RXi Pharmaceuticals, Inc., Sonoma Pharmaceuticals, Inc., Perrigo Company plc, Bristol-Myers Squibb Company, Pacific World Corporation, Valeant Pharmaceuticals International, Inc., Revitol Corporation and Avita Medical Limited.

Segmentation The Keloid Treatment Market is segmented as follows:

• Keloid treatment industry, by treatment type
• Keloid treatment industry, by end-user
• Keloid treatment industry, by region

The keloid treatment industry report begins with an overview of keloid treatment and key market definitions. This section also underlines factors influencing revenue growth of the Global Keloid Treatment Industry along with a detailing of the key trends, drivers, restraints, and opportunities. The next section of the report analyses the market based on treatment type and presents the forecast in terms of value for the next 10 years.

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Treatment types covered in the report include:

• Occlusive Dressing
• Compression Therapy
• Cryosurgery
• Radiation Therapy
• Laser Therapy
• Interferon Therapy
• Intralesional Corticosteroid Injection

The subsequent section covers the market analysis based on end-users and presents the forecast in terms of value for the next 10 years. End users considered in the report include:

• Dermatology Clinics
• Ambulatory Surgical Centres

Sabyasachi Ghosh  (Associate Vice President at Future Market Insights, Inc.) holds over 12 years of experience in the Healthcare, Medical Devices, and Pharmaceutical industries. His curious and analytical nature helped him shape his career as a researcher.

Identifying key challenges clients face and devising robust, hypothesis-based solutions to empower them with strategic decision-making capabilities come naturally to him. His primary expertise lies in Market Entry and Expansion Strategy, Feasibility Studies, Competitive Intelligence, and Strategic Transformation.

Holding a degree in Microbiology, Sabyasachi has authored numerous publications and has been cited in journals, including The Journal of mHealth, ITN Online, and Spinal Surgery News.

About Future Market Insights (FMI)

Future Market Insights, Inc. (ESOMAR certified, recipient of the Stevie Award, and a member of the Greater New York Chamber of Commerce) offers profound insights into the driving factors that are boosting demand in the market. FMI is the leading global provider of market intelligence, advisory services, consulting, and events for the Packaging, Food and Beverage, Consumer Technology, Healthcare, Industrial, and Chemicals markets. With a vast team of over 400 analysts worldwide, FMI provides global, regional, and local expertise on diverse domains and industry trends across more than 110 countries.

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Leading Change in Cancer Clinical Research, Because Our Patients Can’t Wait

May 31, 2024 , by W. Kimryn Rathmell, M.D., Ph.D., and Shaalan Beg, M.D.

Greater use of technologies that can increase participation in cancer clinical trials is just one of the innovations that can help overcome some of the bottlenecks holding up progress in clinical research. 

Thanks to advances in technology, data science, and infrastructure, the pace of discovery and innovation in cancer research has accelerated, producing an impressive range of potential new treatments and other interventions that are being tested in clinical studies . The extent of the innovative ideas that might help people live longer, improve our ability to detect cancer early, or otherwise transform care is staggering. 

Our understanding of tumor biology is also evolving, and those gains in knowledge are being translated into the continued discovery of targets for potential interventions  and the development of novel types of treatments. Some of these therapies are producing unprecedented clinical responses  in studies, including in traditionally difficult-to-treat cancers. 

These advances have contributed to a record number of Food and Drug Administration (FDA) approvals in recent years with, arguably, the most notable approvals being those for drugs that can be used for any cancer, regardless of where it is in the body . 

In some instances, the activity of new agents has been so profound that clinical investigators are having to rethink their criteria for implementation in patient care and their definitions of treatment response. 

For example, although HER2 has been a known therapeutic target in breast cancer for many decades, the new antibody-drug conjugates  (ADCs) that target HER2 have proven to be vastly more effective than the original HER2-targeted therapies. This has forced researchers to rethink fundamental questions about how these ADCs are used in patient care: Can they be effective in people whose tumors have lower expression of HER2 than we previously thought was needed ? And, if so, do we need to redefine how we classify HER2-positive cancer? 

As more innovative therapies like ADCs hit the clinic at a far more rapid cadence than ever before, the research community is being inundated with such fundamentally important questions.

However, the remarkable progress we're experiencing with novel new therapies is tempered by a critical bottleneck: the clinical research infrastructure can’t be expected to keep pace in this new landscape. 

Currently, many studies struggle to enroll enough participants. At the same time, there are patients who don’t have ready access to studies from which they might benefit. Furthermore, ideas researchers have today for studies of innovative new interventions might not come to fruition for 2 or 3 years, or even longer—years that people with cancer don’t have. 

The key to overcoming this bottleneck is to invite innovation to help reshape our clinical trials infrastructure. And here’s how we plan to accomplish that.

Testing Innovation in Cancer Clinical Trials

A transformation in cancer clinical research is already underway. That transformation has been led in part by the success of novel precision oncology approaches, such as those tested in the NCI-MATCH trial .

This innovative study ushered in novel ways of recruiting participants and involving oncologists at centers big and small. And NCI-MATCH has spawned several successor studies that are incorporating and building on its innovations and achievements.

An innovation that emerged from the COVID pandemic was the increase of remote work, even in the clinical trials domain. Indeed, staffing shortages have caused participation in NCI-funded trials to decline. In response, NCI is piloting a Virtual Clinical Trials Office to offer remote support staff to participating study sites. This support staff includes research nurses, clinical research associates, and data specialists, all of whom will help NCI-Designated Cancer Centers and community practices engaged in clinical research activities.

Such technology-enabled services can allow us to reimagine how clinical trials are designed and run. This includes developing technologies and processes for remotely identifying clinical trial participants, shipping medications to participants at home, having imaging performed in the health care settings where our patients live, and empowering local physicians to participate in clinical trials.

We also need mechanisms to test and implement innovations in designing and conducting clinical studies. 

For example, NCI recently established the Clinical Trials Innovation Unit (CTIU) to pressure test a variety of innovations. One of the first trials to emerge from the CTIU’s initial efforts was the Pragmatica-Lung Cancer Treatment Trial , a phase 3 study designed to be easy to launch, enroll, and interpret its results. 

The CTIU, which includes leadership from FDA and NCI’s National Clinical Trials Network , is already working on future innovations, including those that will streamline data collection and apply innovative approaches for other cancers, all with the goal of making cancer clinical studies less burdensome to run and easier for patients to participate.

Data-Driven Solutions

The era of data-driven health care is here, providing still more opportunities to transform cancer clinical research. 

The emergence of artificial intelligence (AI) solutions, large language models, and informatics brings real potential for wholesale changes in how we match patients to clinical studies, assess side effects, and monitor events like disease progression. 

Recognizing this potential, NCI is offering funding opportunities and other resources that will fuel the development of AI tools for clinical research, allow us to carefully test their usefulness, and ultimately deploy them across the oncology community. 

Creating Partnerships and Expanding Health Equity

To be sure, none of this will be, or can be, done by NCI alone. All these innovations require partnerships. We will increase our engagement with partners in the public- and private-sectors, including other government agencies and nonprofits. 

That includes high-level engagement with the Office of the National Coordinator for Health Information Technology (ONC), with input from FDA, Centers for Medicare & Medicaid Services, and Centers for Disease Control and Prevention.

Dr. W. Kimryn Rathmell, M.D., Ph.D.

NCI Director

One example of such a partnership is the USCDI+ Cancer program . Conducted under the auspices of the ONC, this program will further the aims of the White House's reignited Cancer Moonshot SM by encouraging the adoption and utilization of interoperable cancer health IT standards, providing resources to support cancer-specific use cases, and promoting alignment between federal partners. 

And just as importantly, the new partnerships we create must include those with patients, advocates, and communities in ways we have never considered before.

A central feature of this community engagement must involve intentional efforts to expand health equity, to create study designs that are inclusive and culturally appropriate. Far too many marginalized communities and populations today are further harmed by studies that fail to provide findings that apply to their unique situations and needs.

Very importantly, the future will require educating our next generation of clinical investigators and empowering them with the tools that enable new ways of managing clinical studies. By supporting initiatives spearheaded by FDA and professional groups like the American Society of Clinical Oncology, NCI is making it easier for community oncologists to participate in clinical trials and helping clarify previously misunderstood regulatory requirements. 

These efforts must also ensure that we have a clinical research workforce that is representative of the people it is intended to serve. Far too many structural barriers have prevented this from taking place in the past, and it’s time for that to change. 

Expanding our capacity doesn’t mean doing more of the same, it means challenging ourselves to work differently. This will let us move forward to a new state, one in which clinical research is integrated in everyday practice. It is only with more strategic partnerships and increased inclusivity that we can open the doors to seeing clinical investigation in new ways, with new standards for success.

A Collaborative Effort

Shaalan Beg, M.D.

Senior Advisor for Clinical Research

To make the kind of progress we all desire, we have to recognize that our clinical studies system needs to evolve.

There was a time when taking years to design, launch, and complete a clinical trial was acceptable. It isn’t acceptable anymore. We are in an era where we have the tools and the research talent to make far more rapid progress than we have in the past. 

And we can do that by engaging with many different communities and stakeholders in unique and dynamic ways—making them partners in our effort to end cancer as we know it.

Together, our task is to capitalize on this work so we can move faster and enable cutting-edge research that benefits as many people as possible. 

We also know that there are more good ideas in this space, and part of this transformation includes grass roots efforts to drive systemic change. So, we encourage you to share your ideas on how we can transform clinical research. Because achieving this goal can’t be done by any one group alone. We are all in this together. 

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Keloids: what do we know and what do we do next?

It is believed that the knowledge of excessive scarring and keloids as a pathologic consequence of cutaneous injury was first described in approximately 1700 BCE as outlined in the Edwin Smith Papyrus. 1 Keloids represent a pathologic response to dermal injuries resulting in firm, rubbery tumors with a shiny surface appearance that grow beyond initial wound boundaries. Keloid scarring is unique to human beings, and it occurs predominantly on the chest, back, shoulders, and earlobes, whereas it rarely occurs on the soles or palms. One plausible explanation stems from the fact that humans have different sebaceous glands than other mammals and that these higher risk areas of the human body may have higher concentrations of sebaceous glands. The so-called “sebum hypothesis” proposes that the sebum released by the sebaceous glands onto the skin surface may come into contact with T-cells after cutaneous injury and cause an inflammatory reaction that leads to keloid progression, 2 but more in-depth studies to prove this hypothesis are warranted.

Fibroblasts derived from keloids are marked by an overproduction of fibronectin and type I procollagen, a high expression of transforming growth factor (TGF)- β 1, TGF- β 2, vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor-1, and an upregulation of platelet derived growth factor receptors. 3 The genetic basis for these alterations in fibroblast response remain unanswered, but several studies examining differential gene expression in keloid fibroblasts have observed an upregulation of antiapoptotic genes such as p53, 4 bcl-2, 4 and PEA-15. 5 Other studies have demonstrated differential apoptotic gene expression according to the area of the keloid with antiapoptotic AVEN upregulation at the keloid leading edge and proapoptotic ADAM-12 gene upregulation in the central core of the keloid. 6 These findings suggest an important role for apoptosis in the progression of the disease and a genetic variability depending on the location of the sample acquisition. Moreover, certain ethnic groups such as Blacks, Hispanics, and Asians have been shown to be more predisposed to keloids, 7 and a family history of keloids has also been associated with a higher probability of keloid formation after cutaneous injury. 8 These observations suggest a genetic predisposition that may give us further insight into the pathophysiology of the disease. Interestingly, studies involving entire genome scans of families whom are susceptible to keloid formation have pointed to specific genes, 8 but unequivocal proof of a gene responsible for keloid propensity has yet to be determined.

As stated, this fibroproliferative disorder can occur as a consequence of cutaneous injuries such as surgery, burns, and other trauma, but there is also evidence of spontaneous keloid formation in the absence of injury. It has also been reported that keloids can develop several years after a minor injury, which undermines evidence of their potential for spontaneous formation. Further-more, the delayed keloid response also make the investigation of its early stage pathologic mechanism, as well as diagnosis, that much more difficult to assess. 9

We need to face the fact that we do not know much about keloids, their pathologic mechanisms, their genetic footprint, or even effective therapies to treat them; only then can we begin to ask ourselves the right questions. One important hurdle is the lack of a well-characterized diagnosis of keloids and its clear distinction from hypertrophic scarring, a problem that still remains widespread in the medical community. 10 Research into effective therapies for the treatment of keloids has been confounded by this lack of a proper characterization of keloids and their differentiation from hypertrophic events. This point is well highlighted by Durani and Bayat 11 in a meta-analysis review of 112 different clinical studies, where they reported a lack of confidence in current research on keloid therapeutic outcomes. How, then, can we begin to solve a problem when the problem itself is not well defined? Researchers need to go back to the basics and try to understand the pathologic mechanisms of keloids before any therapeutic treatments can be investigated. In this issue of Translational Research , Mogili et al 12 report on the balance of angiogenic and antiangiogenic factors in the systemic and local environment in patients with keloids. The authors report an upregulation of VEGF and a downregulation of endostatin in the serum and the affected tissue of patients who suffer from keloids. Although the upregulation of VEGF in keloids is not an original finding, the discovery of a downregulation of endostatin is a more interesting finding considering some controversy on this subject in the literature. However, this preliminary study does have its limitations. The low sample size makes it difficult to make accurate claims regarding tissue expression levels of VEGF and endostatin. In addition, the authors fail to demonstrate any evidence for therapeutic potential from the observed findings by not delving deeper into the underlying pathobiologic mechanisms of the VEGF/endostatin changes. Regardless, the findings from this study add one more piece to solving the complex puzzle of keloid characterization, and more studies are warranted to provide additional insight into keloid pathology.

Once keloids have been better characterized and better differentiated from other fibroproliferative skin pathologies, a more in-depth analysis of well-designed, randomized control studies of keloid therapeutic strategies will be required. However, research into novel experimental therapies is also warranted. One such approach stems from the similarities between keloids and cancerous tumors. Currently, treatments such as surgical excision, radiotherapy, and laser therapy have been applied commonly for the treatment of both cancer and keloids. In 1999, Fitzpatrick 13 was the first to demonstrate the use of 5-Fluorouracil, a common chemotherapy agent, to effectively reduce keloid size. This work opens the door for a whole gamut of potential therapies, and it may be worthwhile to look closely at the vast knowledge of cancer therapeutics and borrow certain techniques for the management of keloids. Another promising avenue of research toward effective keloid therapy lies in the use of stem cells. In light of their role in the innate wound healing process, mesenchymal stem cells (MSCs) have been proposed as potential therapeutics to promote scarless wound healing. Mansilla et al 14 demonstrated that treatment of mouse skin defects with human MSCs resulted in scarless healing after 14 days. Moreover, Klinger et al 15 demonstrated the potential use of lipofilling to improve scar quality, presumably mediated by adipose tissue-derived stem cells. However, Akino et al 16 reported that human mesenchymal stem cells may actually play a role in promoting keloid formation. Nevertheless, more studies investigating the use of stem cell technology for the treatment of keloids are warranted.

In conclusion, we do not know a lot about keloids, yet we are making strides to closer understanding the problem, and promising therapies have begun to be generated and will continue to evolve over the years to come.

Acknowledgments

Supported by Grant RO1 GM087285-01 from the National Institutes of Health, Project #25407 from the CFI Leader’s Opportunity Fund, and the Physicians’ Services Incorporated Foundation Health Research Grant Program.