Hyaluronic Acid, Succinic Acid, and Exosomes in Treating Facial

Facial hyperpigmentation is a frequent dermatologic concern that often results from a combination of intrinsic and extrinsic factors, including hormonal fluctuations, inflammation, skin trauma, acne, and ultraviolet (UV) exposure. Managing this condition remains a significant clinical challenge due to its chronic nature and the limited long-term efficacy of traditional therapies such as topical depigmenting agents, chemical peels, and laser treatments.

Recent advances in regenerative dermatology have introduced innovative therapeutic strategies, including plant-derived exosomes and the combination of non-cross-linked hyaluronic acid with succinic acid. These approaches are increasingly recognized for their anti-inflammatory, metabolic, and tissue-reparative properties, offering potential benefits beyond conventional pigment suppression.

This report presents two cases of facial hyperpigmentation successfully treated with a combined protocol of plant-derived exosomes and hyaluronic acid with succinic acid. The treatment regimen, follow-up, and observed clinical outcomes are described in detail, highlighting the feasibility and potential efficacy of this multimodal regenerative approach.

Introduction

1. Understanding Facial Hyperpigmentation

Cutaneous hyperpigmentation is characterized by abnormal darkening of the skin, resulting from excessive melanin deposition. This condition may be triggered by a variety of endogenous and exogenous factors, including:

• Hormonal changes (e.g., pregnancy, endocrine disorders)
• Chronic inflammation or skin injury
• Acne and post-inflammatory sequelae
• Certain medications (e.g., antimalarials, chemotherapeutic agents)
• Ultraviolet (UV) radiation exposure

Facial hyperpigmentation is particularly challenging in patients with higher Fitzpatrick skin phototypes due to increased susceptibility to post-inflammatory hyperpigmentation (PIH). Its pathophysiology is multifactorial and involves:

• Melanocytic hyperactivity leading to excess melanin production
• Chronic inflammation that perpetuates pigment deposition
• Oxidative stress and reactive oxygen species contributing to cellular damage
• Dermal microenvironment alterations impacting extracellular matrix function

2. Limitations of Conventional Treatments

Traditional therapeutic strategies, such as topical depigmenting agents, retinoids, chemical peels, and energy-based devices, often produce partial or temporary results. They may also cause skin irritation, rebound pigmentation, or inadequate long-term outcomes, especially in darker skin types.

These limitations have prompted the exploration of regenerative approaches that target underlying biological mechanisms rather than solely suppressing pigmentation. In this context, two promising interventions have emerged:

1. Plant-derived exosomes – small extracellular vesicles that mediate intercellular communication, reduce inflammation, and regulate melanocyte activity.
2. Non-cross-linked hyaluronic acid combined with succinic acid – a biostimulatory approach that enhances dermal fibroblast activity, promotes extracellular matrix remodeling, and restores tissue homeostasis.

3. Rationale for Combined Therapy

The integration of exosomes with hyaluronic acid and succinic acid targets both epidermal and dermal factors contributing to hyperpigmentation. Exosomes modulate cellular signaling and inflammation, while succinic acid influences metabolic pathways involved in tissue repair. Hyaluronic acid supports hydration and extracellular matrix synthesis, resulting in:

• Improved skin texture and tone
• Reduction in residual erythema
• Enhanced overall skin quality
• Potential long-term stabilization of pigmentation

This case report demonstrates the clinical efficacy and safety of this combined regenerative approach in two patients with post-acne facial hyperpigmentation.

Case Presentations

1. Patient Profiles

Two female patients, aged 40 and 26 years, presented with long-standing facial hyperpigmentation associated with acne. Both patients reported a history of inflammatory acne since adolescence, followed by persistent pigmentation primarily affecting the:

• Forehead
• Midface
• Mandibular regions

They expressed significant psychosocial impact due to cosmetic concerns and reduced self-esteem.

2. Clinical Evaluation

Initial examination revealed:

• Multiple hyperchromic macules
• Residual erythematous lesions
• Altered skin texture and tone

No active nodulocystic acne or systemic comorbidities were identified. Photographic documentation at baseline was performed to allow standardized evaluation of treatment outcomes.

Treatment Protocol

A standardized multimodal regenerative approach was applied over four sessions, spaced 15 days apart.

Session Breakdown

Sessions 1 & 2: Hyaluronic Acid + Succinic Acid

• Product: Inbiotec Amber® (IT Pharma, Chile; sanitary registration No. EDM 458/19)
• Dosage: 2 mL per session
• Technique: Intradermal microinjections using the micropapule method

Sessions 3 & 4: Plant-Derived Exosomes

• Product: NXO® (IT Pharma, Chile; sanitary registration No. 2601C-7/25), extracted from Panax ginseng
• Dosage: 3 mL per session
• Technique: Microneedling with a Dermapen device, depth 0.5 mm

Treatment Monitoring

• Intermediate evaluation: Conducted during the third session
• Final evaluation: Two and a half months post-treatment
• Assessment tool: Global Acne Scarring Classification system

Observed Clinical Outcomes

Case 1 (40 years old)

• Baseline severity: Grade 2 (moderate)
• Post-treatment: Grade 1 (mild)
• Notable improvements:
  • Visible reduction in facial hyperpigmentation
  • Smoother skin texture
  • More uniform pigmentation
• No adverse events

Case 2 (26 years old)

• Baseline severity: Grade 1–2 (mild to moderate)
• Post-treatment: Grade 1 (mild)
• Observed improvements:
  • Decreased residual erythema
  • Enhanced tone homogeneity
  • Improved skin texture
• No treatment-related complications

Discussion

1. Pathophysiology of Post-Inflammatory Hyperpigmentation

• Melanocytes originate from the neural crest and respond to inflammation by increasing melanin production.
• Persistent post-acne inflammation contributes to acne-induced macular hyperpigmentation (AIMH).
• Conventional therapies focus primarily on pigment suppression, which may not adequately address underlying tissue dysfunction.

2. Limitations of Conventional Treatments

• Topical agents and chemical peels often provide temporary or incomplete results.
• Physical therapies (lasers, microneedling) carry risks of adverse effects, particularly in darker phototypes.
• Treatment adherence and long-term efficacy remain significant challenges.

3. Role of Succinic Acid

• Succinic acid is a key metabolic mediator in cellular energy pathways.
• It regulates inflammation through succinate receptor 1 (SUCNR1) and promotes M2 macrophage polarization, supporting tissue repair.
• By modulating metabolism, succinic acid addresses the subclinical inflammation often responsible for persistent hyperpigmentation.

4. Benefits of Hyaluronic Acid

• Hydrates and stimulates dermal fibroblasts
• Promotes extracellular matrix remodeling
• Enhances tissue repair when combined with metabolically active molecules like succinic acid

5. Exosome-Based Therapy

• Exosomes facilitate intercellular communication and deliver regulatory molecules to target cells
• Reduce inflammation, enhance cell proliferation, and support tissue remodeling
• Contribute to improvements in residual pigmentation and overall skin quality

6. Advantages of Combined Therapy

• Multifactorial approach: Targets both epidermal and dermal contributors to hyperpigmentation
• Enhanced skin repair: Supports extracellular matrix and dermal homeostasis
• Well-tolerated: Minimal risk of irritation or adverse effects
• Improved aesthetic outcomes: Smoother, more uniform skin with reduced erythema

Clinical Implications

This case series highlights the potential of a regenerative, multimodal protocol for managing post-acne facial hyperpigmentation:

Key Takeaways:

• Hyaluronic acid + succinic acid enhances tissue metabolism and dermal repair
• Plant-derived exosomes provide anti-inflammatory and regenerative benefits
• Combination therapy may outperform isolated depigmenting treatments
• Patient satisfaction is high, with minimal adverse effects

Considerations for Practice

• Optimal results require early acne control alongside pigment-targeted therapy
• Treatment intervals and dosages should be individualized based on skin type and severity
• Long-term follow-up is recommended to assess sustained pigmentation improvements

Conclusion

The combination of non-cross-linked hyaluronic acid, succinic acid, and plant-derived exosomes represents a promising, biologically oriented approach for treating facial hyperpigmentation and post-acne sequelae.

Key conclusions:

• The multimodal protocol is feasible and well-tolerated
• Patients demonstrate clinically meaningful improvements in pigmentation, skin texture, and tone
• This approach addresses both pigmentary changes and underlying tissue dysfunction, offering advantages over conventional therapies

While encouraging, these findings are based on a limited number of cases. Larger controlled studies are necessary to confirm:

• Long-term efficacy
• Reproducibility
• Optimal treatment protocols