Novel Therapies for Keloids - An Overview

Introduction

Keloids can be described by aggressive dermal growth that extends beyond the initial injury site. Although various treatment modalities have been used to treat them, they have yet to prove entirely effective. These include surgical excision, corticosteroids, laser therapy, cryotherapy, topical silicone gel sheeting, radiotherapy, and photodynamic therapy.

Some promising anti-keloid medicines recently surfaced are anti-hypertensive medications, electrical stimulation, calcineurin inhibitors, physical contact microneedles, ribonucleic acid-based therapies, and mesenchymal stem cell therapy. However, these treatment modalities require further research.

What Are Keloids?

Thick, elevated scars known as keloids result from aberrant wound healing brought on by inflammation or trauma to the skin. They usually appear on skin-injury-prone areas like the chest, cheeks, shoulders, and earlobes. Environmental and genetic factors work together to shape the development of keloids. People with darker skin tones demonstrate a higher prevalence of keloid development. The pathophysiology of keloids includes overactive fibroblasts (cells that aid in developing connective tissue), creating excessive quantities of collagen and growth factors.

Keloid scars, characterized by thick, uneven scarring and typically found on places like the middle chest, cheeks, shoulders, and earlobes, might appear months or years after the initial incident. These scars are elevated, shiny, and hairless and vary in size depending on the extent of the initial injury and the length of the keloid growth. Depending on the person, they might have a soft, hard, or rubbery texture with reddish, brown, or purplish colors. The itching and discomfort that keloids frequently cause exacerbate the physical and mental suffering that those who have them endure.

What Are the Various Novel Treatment Modalities for Keloids?

A wide range of therapeutic modalities have been investigated for the treatment of keloids. These include surgical excision, cryotherapy, radiotherapy, laser therapy, photodynamic therapy, topical mitomycin C, intralesional steroids, silicone gel sheeting, and compressive therapy. However, because of the high keloid recurrence rates and the lack of thorough studies into current treatments, none of these approaches have become the gold standard for success. Novel medication therapies have been developed in the last few decades due to improvements in understanding the molecular mechanisms underlying diseases. The various novel treatment modalities include:

• Anti-Hypertensive Pharmaceuticals:

  • (Angiotensin-Converting Enzyme) ACE Inhibitors - Angiotensin-converting enzyme (ACE) inhibitors like Lisinopril, Ramipril, and Enalapril have demonstrated potential in lessening the production of keloid and enhancing the appearance of scars. These drugs prevent angiotensin I from being converted to angiotensin II, which lowers levels of TGF-β (tumor growth factor) and collagen production, which is linked to the development of keloid formation. Studies have shown that using ACE inhibitors topically or orally can have favorable effects, including increased scar breadth, vascularity, and patient satisfaction.

  • Verapamil - Verapamil is a calcium blocker that belongs to the phenylalkylamine family. It lowers blood pressure by blocking calcium channels. Apart from its impact on the heart, it can potentially manage keloid scars. Studies reveal that Verapamil inhibits the formation of fibrous tissue by inducing the synthesis of pro-collagenase (an enzyme that degrades collagenase). Research indicates that increasing the dosage or frequency of Verapamil injections may enhance therapy results when administered in addition to surgical excision. Promising outcomes have been shown in recent retrospective studies when Verapamil and intralesional TAC (Triamcinolone) are combined. These treatments significantly and durably reduce keloid scars. Verapamil appears to be a promising treatment for keloid scars overall, but the rate of recurrence varies greatly, from 1.4 to 48 percent. More investigation is required to optimize its effectiveness in keloid management.

• Microneedle Physical Contact - Tiny needles called microneedles are used to administer medications via the skin. Since they are smaller than standard needles, there will be less discomfort and harm. According to studies, microneedles have demonstrated encouraging outcomes in treating hypertrophic scars and keloids. For instance, keloids were smaller when drug-containing microneedle patches were dissolved. In a different investigation, microneedles prevented the formation of keloid fibroblasts in both animal models and cell cultures, decreasing the scar thickness and relieving patient complaints. Scar tissue reduction was observed even using non-pharmacological microneedles. Although the precise mechanism is still unclear, microneedles can potentially treat scars and keloids. Further research is necessary to demonstrate the safety and efficacy of microneedles in clinical settings.

• Calcineurin Inhibitors -

  • Tacrolimus (FK-506) is an immunosuppressive drug that is frequently used to treat psoriasis (skin cells accumulate and produce dry, itchy patches as well as scales), keloids, and atopic dermatitis (inflammation of the skin) as well as to prevent organ rejection. It reduces fibroblast activity and collagen formation in keloids by blocking specific cell signaling pathways. According to some research, Tacrolimus may have anti-keloid effects by preventing certain signaling molecules necessary for developing keloid formations. Although topical Tacrolimus ointment has demonstrated potential in preventing hypertrophic scars (a thick, elevated scar resulting from an atypical wound healing reaction) and mitigating symptoms such as itching and redness, further studies are required to validate its efficacy in treating keloids.

  • Anti-inflammatory and antiproliferative effects are also seen in Sirolimus (Rapamycin), another drug. It targets mTOR (mammalian target of Rapamycin), a protein involved in collagen synthesis and cell proliferation. Sirolimus has been demonstrated to downregulate the expression of certain proteins involved in collagen synthesis and fibroblast proliferation in keloids. Furthermore, it can reduce extracellular matrix deposition and stop keloid fibroblasts from producing too much collagen. Sirolimus has promise as a keloid treatment, but further investigation is required to grasp its safety and efficacy in clinical settings completely.

• Interferons - Effective against various carcinomas, interferons are potent cytokines with anti-viral, anti-fibrotic, and anti-proliferative qualities. It has been discovered that interferon isoforms, specifically INF-α2b (alpha 2b) and INF-γ (gamma), decrease collagen production and fibroblast growth while down-regulating TGF-β1. In lab investigations, it has been demonstrated that INF-γ increases myofibroblast death and prevents transformation, while INF-α2b prevents wound contraction. More randomized controlled trials (RCTs) are required to determine their effectiveness because clinical trials have produced inconsistent outcomes. Similar symptoms to the flu, fever, headaches, exhaustion, and muscle pain are among the side effects of interferon therapy. More investigation is required for further information on interferon therapy.

• Stem Cell Therapy - Mesenchymal stem cells (MSCs) are a promising tool in stem cell therapy for treating inflammatory and scarring disorders. MSCs can lessen inflammation and collagen synthesis, which helps avoid severe scarring. Tissue scaffolds or injections can be administered to them. Research has demonstrated that bone marrow-derived stem cells (BMSCs) and adipose-derived stem cells (ADSCs) can suppress genes linked to fibrosis and reduce scarring. MSC treatment is promising for diseases including fibrosis and scarring, but further study is required.

• Fat Grafting - Many studies have demonstrated the potential of autologous fat grafting, also referred to as lipotransfer, in treating keloids. Skin texture, softness, thickness, and elasticity significantly improved after six months in three clinical cases where fat was injected at the dermal-epidermal junction in hypertrophic scars and keloids. Dermal hyperplasia, neoangiogenesis (formation of new blood vessels), and new collagen deposition were found upon histological investigation. Pain and fibrosis decrease and scar tissues become more flexible after this surgery. One possible explanation for these beneficial effects is that the introduction of adipose tissue-derived stem cells (ADSCs) into wounds appears to suppress the growth of keloid fibroblasts and the production of extracellular matrix.

• Electrical Stimulation - Electrical stimulation (ES) has been employed for years to treat unusual scars. More recently, the Fenzian system, which produces degenerate waves, has shown promise in the treatment of hypertrophic and keloid scars.

• RNA-Based Therapies - RNA (ribonucleic acid) interference (RNAi) targets particular genes and degrades their RNA molecules. Researchers have been able to inhibit certain genes in keloid cells by employing small interfering RNAs, or siRNAs. For instance, they observed a reduction in collagen synthesis in keloid cells when they targeted genes such as TIMP-1/-2 or heat shock protein 70. According to a different study, keloid cells grew more slowly. They took longer to proliferate when siRNAs targeting the human wingless-related mouse mammary tumor virus integration site 2 genes were used. These results imply that treating keloids with RNA-based therapies may be a promising option.

• Tamoxifen - Tamoxifen is a synthetic anti-estrogen medication that is mainly used to treat breast cancer, but it has also shown promise in the treatment of keloids. It functions by altering the cell cycle, reducing the proliferation of keloid fibroblasts, and changing RNA transcription (copying deoxyribonucleic acid or DNA to make RNA template strand). Research indicates that Tamoxifen suppresses keloid cell contraction in a dose-dependent way and lowers the production of TGF-β1, a crucial factor in the creation of keloid cells. Tamoxifen ointment applied topically has been demonstrated to promote angiogenesis and reduce the thickness of fibrotic tissue in burn patients. Furthermore, there have been notable decreases in lesion size when Tamoxifen citrate has been applied topically to keloids or hypertrophic scars. In keloid patients, intralesional Tamoxifen injection has also led to a significant decrease in collagen fibers and fibroblasts.

Conclusion

Keloids are difficult to treat, despite the wide range of alternatives. Discovering their molecular structure may aid in the development of more effective therapies. Promising novel treatments include fat grafting, microneedles, stem cell therapy, and RNA therapeutics. However, additional large-scale investigations are still required to ensure their efficacy.