Collagen Stimulators vs Hyaluronic Acid Fillers: A Clinical Guide to Evidence-Based Patient Selection

Nurse practitioner Patricia Molloy draws on 12 years of clinical experience to explore the science, indications and patient selection considerations behind two of aesthetics’ most widely used dermal filler categories.

The landscape of aesthetic medicine is evolving rapidly. As patient demand shifts toward treatments that deliver not only immediate cosmetic improvement but also longer-term skin health benefits, practitioners are increasingly required to navigate a growing and sophisticated portfolio of dermal filler options.

Central to this decision-making process is understanding the fundamental differences between two distinct categories of injectable treatment: hyaluronic acid (HA) fillers and collagen-stimulating fillers, specifically those based on polycaprolactone (PCL).

In this article, nurse practitioner Patricia Molloy, who brings 12 years of clinical experience with PCL-based fillers, explores the science underpinning both treatment categories, examines their respective indications and contraindications, and shares her clinical approach to patient and product selection.

Illustrated with real-world case studies, this article aims to provide practitioners with a practical, evidence-based framework for integrating both HA and PCL fillers into their treatment repertoire – ensuring outcomes that are not only aesthetically compelling, but tailored precisely to each individual patient’s needs.

Collagen Stimulator Fillers

Collagen stimulator fillers are made of microspheres of either Polycaprolactone (PCL), Calcium Hydroxyapatite (CaHA), or Poly-L-Lactic acid (PLLA), all suspended in a carrier gel. They all act in a similar way, initially acting as a volumising filler and then acting as a collagen stimulator.

In comparison, I have selected the polycaprolactone (PCL)-based product, with which I now have 12 years of clinical experience in patient treatment. This filler is composed of a unique patented formulation comprising 70% carboxymethyl cellulose (CMC)-based gel carrier and 30% PCL microspheres.

The PCL microspheres are maintained in a homogeneous suspension within the CMC-based gel carrier. Both PCL and CMC demonstrate excellent and well-established biocompatibility profiles.¹

Properties of CMC

CMC is a natural material derived from cellulose; it is not cross-linked and is nontoxic. It is a recognised pharmaceutical excipient. Its other properties include:

• It is hygroscopic
• It has been designated by the Food and Drug Administration (FDA) as generally recognised as safe (GRAS)
• Resorption occurs in 2–3 months²

Properties of PCL

PCL is a non-toxic medical polyester, first synthesised in the early 1930s. It is attractive for use in dermal fillers because of its ease of bioresorption, and it is naturally hydrolysed into carbon dioxide and water within the body.²

The PCL microspheres are designed to offer optimal biocompatibility. They have a smooth surface, a spherical shape and a size of approximately 25–50 μm.¹

PCL has an excellent safety profile and has been used in the biomedical field for more than 70 years in a range of applications, from sutures to tissue, and recently for organ replacements by 3D printing. It is also used in CE-marked and US FDA-approved products.²

The physical properties of this filler differ from those of other dermal fillers on the market in three key ways:³,⁴,⁵

1. Size and volume of particles: PCL microspheres technology was designed to maintain the volume of the particles for a longer time, delaying the triggering of phagocytosis and intensity of the inflammatory reaction.
2. Particle morphology: As the PCL microspheres can maintain their shape and smooth surface during the hydrolysis process, there is reduced risk and decreased intensity of secondary inflammation.
3. Surface area: By maintaining the integrity of the PCL microspheres, the inflammatory reaction responsible for collagen production is sustained at a low intensity, promoting the synthesis of a more mature and organised collagen layer.

It has two distinct phases of activity:

Step 1: Immediately after injection, the CMC component provides temporary volume, which gradually decreases over 2–3 months.

Step 2: The PCL microspheres induce neocollagenesis of types I and III collagen, with more persistent type I collagen structure gradually increasing over 1–3 months and the PCL microspheres becoming embedded in the type I collagen scaffold.

The resulting collagen volume replaces the initial volume increase caused by the CMC gel. The collagen scaffold stimulated by the PCL microspheres persists after they have been resorbed, leading to a durable volume increase.

PCL gel’s elasticity is greater than that of volumising hyaluronic acid (HA), meaning that projection and volumisation of the injected area are instantly visible. Because the collagen-stimulating PCL microspheres are maintained in the injection area, aesthetic improvement is also more long-term than that seen with HAs.⁶

It also has excellent rheological properties and combines high elasticity with specifically designed viscosity that is suitable for subdermal injection.²

In a randomised, prospective, blinded, split-face, single-centre study comparing PCL with HA in 40 patients, nasolabial folds (NLFs) treated with PCL showed statistically significant improvements on the Wrinkle Severity Rating Scale, and greater improvements on the Global Aesthetic Improvement Scale when compared with NLFs treated with an HA-based dermal filler.⁶

PCL also improves skin quality, enhancing density, firmness, tonicity and texture from within. A clinical trial was carried out to assess the effect of PCL on skin quality parameters in 24 patients up to 24 months post-treatment. Although PCL was injected in the subdermis of the midface, patient echographs clearly showed a substantial increase in tissue density in the dermis following treatment with PCL, compared with baseline.⁷

This improvement was statistically significant at all time points during the 24-month study. Skin firmness, tonicity and smoothness were also statistically significantly improved with PCL compared with baseline.⁷

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Hyaluronic Acid Fillers

HA-based dermal fillers are composed of a biocompatible, synthetic gel made from linear polysaccharide chains, often cross-linked with BDDE (1,4-butanediol diglycidyl ether) for longevity. These fillers typically include water for hydration, high-molecular-weight HA to attract water for volume, and often lidocaine to reduce pain during injection.

• Step 1: Hydration. High-molecular-weight, long HA chains are dissolved to form a solution through a hydration system.
• Step 2: Crosslinking. Under inert atmosphere, crosslinking is performed with a low level of 1,4-butanediol diglycidyl ether (BDDE), transforming the solution into a gel.
• Step 3: Extraction. Reactive oxygen species are removed from the gel to better preserve the lightly crosslinked HA network.
• Step 4: Sterilisation. The crosslinked HA network is preserved during sterilisation.⁸

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Clinical Experience with Collagen Stimulating Fillers and Hyaluronic Fillers

Patient and product selection is dependent on a full patient skin assessment, medical history and the patient’s needs.

Why Collagen Stimulating Fillers?

• PCL is a powerful regenerating collagen stimulator. Aesthetic medicine is now concentrating on regenerative treatments and patients are requesting these treatments.²
• PCL is a product that will give long-lasting and natural results.⁷
• PCL is licensed to use both periosteal and subdermal in the face, but not in the lips or tear trough area.⁹
• PCL degradation is completed by hydrolysis, leaving just water and carbon dioxide.²
• The final volume within the treated area is greater than the volume of PCL injected. There is no need for touch-ups. Due to the formation of collagen type I, volume is 20–30% greater.⁶

Why Hyaluronic Acid Filler?

As previously discussed, the rheology makes it easy to understand the beautiful, natural treatments that can be achieved with HA.⁸ The key characteristics include:

• How cohesive it is in the tissues, allowing the patient to use animated expressions without the filler being obvious in the skin. It moves with the skin and springs back to the original position.
• Less inflammatory reaction.
• The suppleness and projection capacity of the product allows natural results, longevity and patient satisfaction.⁸

Indications for Hyaluronic Acid Fillers

Initially, I always carry out a comprehensive consultation to educate the patient on the products and how they perform in the skin. Depending on the patient’s medical history, preference, and my guidance, a filler is selected.

In some cases, a combination of both may be used. If improving skin quality is the goal, PCL is the preferred choice, but if treating the tear trough and lips in the same patient, HA would be used in those areas.

Both give a very natural and effective result. However, the decision to use either, or both, will depend on the patients’ expectations and the effect needed.

Why select PCL?

• It is suitable for patients looking for long-term results.⁷
• To improve skin quality and collagen stimulation.²
• For male patients, PCL can achieve a very structured and non-hydrophilic result, which male patients tend to prefer.

Why select HA?

• If patients are having first-time fillers, HA is recommended.⁸
• HA is effective for tear trough treatment.
• HA low viscosity is effective for lip treatment of mature patients and slightly higher viscosity is effective for lip projection.
• Perfect for immediate effect and beautiful, natural results.⁸

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Case Study 1: PCL

A 58-year-old female patient presented with deep nasolabial folds and pronounced marionette lines. PCL was used to address the lower face with a subdermal threading technique via a 25G cannula: nasolabial folds received 0.3 mL delivered as subdermal linear threads, and marionette lines and prejowl sulcus received 0.7 mL delivered as subdermal linear threads. Immediate structural support was achieved, with visible improvement in tissue support and a noticeable softening of the marionette region.⁶

Before                                                                          After

Case Study 2: HA

Patient:
A 33-year-old female patient presented for non-surgical rhinoplasty.

Treatment:
Hyaluronic acid (HA) filler was administered in the midline using a 30G needle. Two 0.05 mL periosteal bolus injections were placed along the midline dorsum, followed by a single 0.1 mL injection to the nasal tip.

Outcome:
The treatment achieved a noticeable improvement in nasal contour, and the patient reported a high level of satisfaction with the result.

Case Study 3: HA

Patient:
A 38-year-old female patient presented seeking subtle, natural-looking facial rejuvenation.

Treatment:
A full-face hyaluronic acid (HA) treatment plan was performed to restore volume, improve structural support and achieve balanced rejuvenation.

• Temples: Medium-viscosity HA, 0.5 mL per side, delivered as deep supraperiosteal bolus injections via a 27G needle.
• Midface: High-viscosity HA, with two 0.2 mL supraperiosteal bolus injections placed over the zygoma and one 0.3 mL bolus placed in the midface via a 27G needle.
• Nasolabial folds: Medium-viscosity HA, 0.3 mL on the right and 0.2 mL on the left, delivered as linear threads via a 25G cannula.
• Marionette lines and prejowl sulcus: Medium-viscosity HA, 0.6 mL on the right and 0.4 mL on the left, delivered as linear threads via a 25G cannula.
• Chin: High-viscosity HA, 0.3 mL delivered as a supraperiosteal bolus via a 27G needle.
• Lips: Medium-viscosity HA, 0.8 mL placed within the lip body using linear threading via a 30G needle.
• Vermilion border: Low-viscosity HA, 0.5 mL delivered via a 30G needle.

Clinical considerations:
The tear troughs were not treated, as the patient demonstrated poor lacrimal drainage with associated fluid retention, making this area unsuitable for treatment and therefore contraindicated.

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Conclusion

Both PCL and HA are unique, safe and effective dermal fillers.²,⁸ The decision of which to use should be determined by the patient’s skin condition, age, areas to be treated and patient’s expectations. HA will provide the patient with immediate results, whereas PCL will provide a long-term, regenerative collagen-stimulating treatment.²,⁶ These two products give the ability to achieve measurable results and increase patient satisfaction.⁷

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References

¹ Nicolau PJ, Marijnissen-Hofsté J. Neocollagenesis after injection of a polycaprolactone based dermal filler in a rabbit. Eur J Aesth Med Dermatol. 2013;3:19–26.

² Christen M, Vercesi F. Polycaprolactone: How a well-known and futuristic polymer has become an innovative collagen-stimulator in aesthetics. Clin Cosmet Investig Dermatol. 2020;13:31–48.

³ Anderson JM. Mechanisms of inflammation and infection with implanted devices. Cardiovasc Pathol. 1993;2(3):33–41.

⁴ Laeschke K. Biocompatibility of microparticles into soft tissue fillers. Semin Cutan Med Surg. 2004;23(4):214–217.

⁵ Nicolau PJ. Long-lasting and permanent fillers: Biomaterial influence over host tissue response. Plast Reconstr Surg. 2007;119(7):2271–2286.

⁶ Galadari H, Van Abel D, Nuami KA, Faresi FA, Galadari I. A randomized, prospective, blinded, split-face, single-center study comparing polycaprolactone to hyaluronic acid for treatment of nasolabial folds. J Cosmet Dermatol. 2015;14(1):27–32.

⁷ Moers-Capri MM, Sherwood S. Polycaprolactone for the correction of nasolabial folds: A 24-month, prospective, randomized, controlled clinical trial. Dermatol Surg. 2013;39:457–463.

⁸ Sinclair. MaiLi physician leaflet. 2021. Available from: https://sinclairprodbackend.azurewebsites.net/media/aaofhxv4/physcians-leaflet.pdf

⁹ Sinclair. Ellansé 10-year anniversary brochure. 2022. Available from: https://sinclairprodstorage.blob.core.windows.net/media/z4bdzreh/ellansé-an-experts-guide-digital-singles-2-00-stc-28mar22singles-1-27-1.pdf