ZKKL Academic Sharing | Research Advances in Intralesional Injection Therapy for Keloids

Article reprinted from: Chinese Journal of Dermatology and Venereology

Authors: Li Meiling, Zhu Lianhua, Fang Yuhui, Jin Zhehu

[Abstract] Keloids are pathological scars characterized primarily by excessive proliferation of cutaneous connective tissue and invasive growth. They commonly develop following trauma, inflammation, or surgery and tend to occur on the chest, scapular region, earlobes, and other areas. Keloids located on exposed sites can compromise aesthetic appearance, while those in functional zones may impair local mobility. Moreover, keloids often accompany symptoms such as pruritus, pain, and heightened local sensitivity, imposing a significant psychological burden on patients and, in severe cases, adversely affecting their quality of life. Although a variety of therapeutic approaches are available in clinical practice, the unclear underlying pathogenesis and high recurrence rate render keloids a challenging condition for surgical management. Intralesional injection therapy has been widely employed both domestically and internationally for the treatment of keloids; this article provides a comprehensive review of this modality.

[Keywords] Keloid, intralesional injection, treatment

Keloids are benign neoplasms that arise from excessive collagen deposition following tissue injury, infiltrating and growing within the dermis and subcutaneous tissues. In the early phase of wound healing, an inflammatory response occurs in the dermis, characterized by leukocyte infiltration, fibroblast hyperproliferation, activation, and migration, accompanied by excessive collagen fiber deposition and disorganized matrix organization—these processes constitute the pathological basis of keloid formation. In recent years, a combination of conventional approaches and novel therapeutic strategies has yielded promising results in the management of keloids. Intralesional injection therapy for keloids, owing to its simplicity, efficacy, and low incidence of adverse effects, has been widely adopted both domestically and internationally. This review summarizes current advances in the pharmacological mechanisms and injection techniques underlying intralesional treatment of keloids.

1. Injectable medication injectable medicines

1.1 Corticosteroid hormones Local injection of corticosteroid hormones is one of the most commonly used and effective treatment methods. Currently, the corticosteroids frequently employed in clinical practice include prednisolone acetate, triamcinolone acetonide, and betamethasone dipropionate, among others. Corticosteroids inhibit the expression of type I and type III procollagen genes in fibroblasts, reduce collagen fiber synthesis, accelerate collagen degradation, and decrease hyaluronic acid levels. Additionally, they suppress the release of inflammatory mediators such as histamine, thereby attenuating the intensity of allergic reactions. Corticosteroids are available in short‑acting and long‑acting formulations; accordingly, the frequency of intralesional injections varies: prednisolone acetate is administered once weekly, with each dose not exceeding 2–3 mL; triamcinolone acetonide is injected every 2–3 weeks, with a total adult dose not exceeding 80 mg; and betamethasone dipropionate is given every 3–4 weeks, at a maximum of 1 mL per injection. Local corticosteroid injections are often combined with other medications, but the optimal dosing regimen remains undefined and requires further investigation. Common adverse effects of local corticosteroid injections include atrophy of the skin and subcutaneous tissues, hyperpigmentation, telangiectasia, secondary infections, and tissue necrosis.

1.2 Antitumor Drugs Antitumor agents were among the first to be employed in the treatment of keloids. Commonly used antitumor drugs include 5-fluorouracil (5-FU) and bleomycin. These agents competitively inhibit DNA and RNA synthesis, thereby suppressing fibroblast proliferation and reducing collagen production and secretion, with the aim of treating scars. In overseas clinical practice, 5-FU is typically administered at concentrations of 40–50 mg/mL, whereas in China, low‑dose regimens of 5–10 mg/mL are often combined with lidocaine for injection; however, differences in efficacy and adverse reactions have been observed, suggesting that optimal dosing, injection intervals, and treatment duration require further investigation. As 5-FU is a cell cycle‑specific agent, monotherapy can yield significant therapeutic effects; yet, both domestic and international studies indicate that combining 5-FU with corticosteroids produces markedly superior outcomes, accompanied by lower recurrence rates and fewer adverse events. Adverse reactions to antitumor injections include pain, erythema and edema, hyperpigmentation, and skin atrophy.

1.3 Calcium Channel Blockers Clinically, calcium channel blockers are primarily used to treat cardiovascular diseases; in recent years, they have also been applied to the treatment of keloids, with promising results. Commonly used calcium channel blockers include verapamil and nicardipine. These agents exert an inhibitory effect on fibroblasts, thereby reducing collagen content within the scar and decreasing extracellular matrix synthesis. Studies have shown that verapamil may enhance Smad7 expression, suppress TGF‑β1‑induced α‑SMA mRNA and extracellular matrix production in urethral scar fibroblasts, inhibit interleukin‑6 and vascular endothelial growth factor, and induce apoptosis. Depending on the size of the lesion, verapamil (2.5 mg/mL) is injected at 0.5–2.0 mL per site, with a total dose not exceeding 10 mg per administration; injections are repeated every four weeks, with clinical outcomes monitored until the lesion decreases in volume, softens in consistency, and symptoms such as pruritus and pain are alleviated, thus achieving therapeutic goals. Research indicates that, from the perspectives of inducing apoptosis and potential adverse drug reactions, verapamil is superior to triamcinolone acetonide. Adverse effects include pain, changes in heart rate, and hypotension; therefore, it is contraindicated in patients with bradycardia, conduction blockades, or asthma, as well as in pregnant women.

1.4 Interferon Interferons are widely used in clinical practice for antiviral therapy and immune modulation, and in recent years have also demonstrated some efficacy in combating fibrosis. They can be administered for the treatment of keloids via local injection or topical ointments. Interferons are classified into α‑type (leukocyte), β‑type (fibroblast), and γ‑type (lymphocyte). Currently, INF‑α2b and INF‑γ are the primary agents employed in keloid management. INF‑α2b is a naturally occurring cytokine that inhibits fibroblast proliferation and biosynthesis, suppresses TGF‑β1 expression, but does not induce fibroblast apoptosis; consequently, recurrence is common. When administering INF‑α2b (1.5 million U/mL) intralesionally, injection sites should be spaced at least 2 cm apart. INF‑γ promotes collagenase production by fibroblasts in vitro, facilitating collagen degradation, thereby softening keloids and reducing their volume to achieve therapeutic goals. The typical dose of INF‑γ injected into keloids is 1–3 million U per injection, once weekly, for a course of 10 weeks. Common adverse reactions following interferon administration include headache, myalgia, and flu‑like symptoms.

Type 1.5A botulinum toxin Botulinum toxin type A is a bacterial endotoxin secreted by Clostridium botulinum that primarily acts at the neuromuscular junction to inhibit acetylcholine release, thereby reducing skin tension. It is a safe and effective therapeutic agent that can modulate cellular proliferation and apoptosis, yielding beneficial effects in the treatment of keloids and helping to prevent disease recurrence. Wang Lin et al. found that administering botulinum toxin type A (50 U/mL) at 1‑cm intervals, with 5 U per injection site and a total dose not exceeding 100 U per patient, significantly improved pain and pruritus associated with refractory keloids. Currently, four registered formulations of botulinum toxin type A are available; their potencies vary, as do their diffusion radii. Although no serious adverse reactions have been reported to date with the use of botulinum toxin type A for keloid treatment, potential unforeseen adverse effects remain. Issues such as optimal injection dosage, treatment duration, timing of discontinuation after therapy, and the risk of recurrence following cessation of treatment still require further investigation.

2. Applications of Injection Therapy Injection therapy application

2.1 Combined Application Clinically, a commonly employed combination regimen involves the concurrent use of triamcinolone acetonide and 5-fluorouracil (5-FU). This dual‑drug approach exhibits synergistic effects, significantly enhancing treatment efficacy. Bijlard et al. demonstrated that the combined administration of 5-FU and triamcinolone acetonide yields superior outcomes compared with either agent alone, with response rates ranging from 50% to 90% in patients receiving local intralesional injections of both drugs. Yao Quan et al. used meta‑analysis to confirm the efficacy and safety of this combination; however, the optimal drug ratio and its relationship to therapeutic outcomes and adverse reactions warrant further refinement through long-term follow-up and experimental studies. Concurrent injection of corticosteroids and antineoplastic agents can cause substantial pain; therefore, it is advisable to add 2% lidocaine to the formulation to alleviate discomfort and reduce the concentrations of both agents, thereby minimizing direct irritation at the injection site and lowering the incidence of toxic side effects. Existing research has investigated the role of adding lidocaine to intralesional steroid injections but found that pain relief was not improved when lidocaine was included; conversely, omitting lidocaine naturally decreased the occurrence of lidocaine‑related adverse events. Intralesional drug administration can also be integrated with surgical excision, laser therapy, cryotherapy, or radiotherapy, resulting in favorable outcomes and low recurrence rates.

2.2 Use of Syringes Strictly adhere to aseptic techniques: disinfect the lesion site with an iodophor‑impregnated cotton ball, and administer treatment using a single‑use syringe. Insert the needle obliquely at the margin of the keloid, angling it toward the skin surface; after aspirating to confirm no blood is present, slowly inject the medication into the lesion. Throughout both insertion and injection, ensure the needle remains within the scar tissue, stopping when the injected volume causes only slight whitening of the scar’s surface. Avoid injecting beneath normal skin or into the sub‑scar layer to prevent adverse reactions. For larger scars, consider multiple injection sites while minimizing the number of punctures. Clinically, needle‑free injectors are now being employed: these devices deliver medication without a needle by using a power source to generate high‑pressure gas, which propels the drug into a fine stream that rapidly penetrates the skin and reaches the subcutaneous layer. Due to this altered delivery mechanism, the drug disperses more evenly beneath the skin, resulting in faster onset of action and higher absorption rates. Studies have reported that needle‑free injectors enable the drug to spread in an aerosol‑like pattern at the injection site, increasing the effective absorption area and improving uptake, while significantly reducing the stinging sensation compared with conventional needle‑based injections. The use of needle‑free injectors can address the uneven distribution of drugs seen with traditional syringes and alleviate patient discomfort during treatment.

3. Summary summary

Intralesional injection therapy is widely used in clinical practice; it is simple to perform, yields significant results, and is cost‑effective for patients. However, variations in injection technique, interval between injections, dose, and treatment course can lead to differences in therapeutic efficacy and post‑treatment adverse effects. Although intralesional injections can flatten and soften hypertrophic scars, they cannot completely eliminate them or reduce the area of scar tissue. Clinically, the choice of treatment is determined by a comprehensive assessment of factors such as the scar’s location, size, morphology, patient age, as well as the patient’s preferences and financial capacity. Currently, our understanding of the pathogenesis of hypertrophic scars remains limited, and no standardized curative regimen exists; therefore, clinicians typically employ multimodal approaches to alleviate symptoms and lower recurrence rates. Consequently, further research into the mechanisms underlying hypertrophic scar formation, refinement of existing therapies, and development of novel treatment strategies is urgently needed.