The science behind biostimulators – and why particle design matters.

Rethinking bio-regeneration through PLLA product design

Poly-L-lactic acid, or PLLA, has been used in aesthetic medicine for several decades. It is a biocompatible and biodegradable polymer with established applications in medical and regenerative research.^1,2

PLLA formulations are not necessarily identical. Manufacturing processes can produce particles with different shapes, sizes, surface characteristics and formulation profiles. These characteristics may influence how a biomaterial is distributed and how cells respond to it under experimental conditions. A study published in the Journal of Biomedical Materials Research Part A in 2025 compared two PLLA formulations with different particle architectures: smooth, spherical microspheres and irregular, flake-like particles.³ The study investigated whether those differences in particle design were associated with different early physicochemical, cellular and molecular responses. It was designed as a mechanistic, non-clinical study and did not evaluate clinical superiority or patient outcomes

What the research looked at – and how

The study was designed in a multi-method approach. Researchers used a combination of:

• Physicochemical particle characterisation,

• In-vitro assays involving human dermal fibroblasts,

• Full-thickness ex-vivo human skin models,

• Gene-expression and RNA-sequencing analyses

Human dermal fibroblasts were treated with both formulations. Full-thickness skin biopsies were injected intradermally and monitored over three days. And the genome-wide transcriptional response was mapped across thousands of genes. The result is a non-clinical, but multi-level comparison of two PLLA formulations, providing new insights into their material characteristics and potential mechanisms underlying their biological effects. ³

Microspheres penetrate deeper and disperse uniformly.

Particle characterization revealed distinct physicochemical properties of the two PLLA formulations. Microspheres showed a uniform spherical morphology, a narrow particle size distribution, and stable surface charge across physiological pH, whereas microflakes displayed an irregular shape, broader size variation, and less stable surface charge under acidic conditions.³

When injected intradermally into ex vivo human skin, these formulations also exhibited different dispersion patterns. Microspheres penetrated deeper into the dermis and dispersed more evenly throughout the tissue, while microflakes tended to remain in the upper dermis and to aggregate near the injection site.³ These distinct morphological and physicochemical properties may contribute to differences in biological activity and therapeutic potential.

Fibroblasts respond differently to each formulation

At the cellular level, using in vitro and ex vivo models, the study also identified distinct differences between microspheres and microflakes.

The microsphere formulation was associated with:

• Increased fibroblast migration,

• increased expression of ACTA2, which encodes α-smooth muscle actin, a marker of fibroblast activation and contractile function

• changes in the expression of genes associated with extracellular-matrix components, including collagen and fibronectin.³

PLLA microflakes showed a different cellular response. They inhibited fibroblast proliferation, suppressed ECM-related gene expression, and upregulated inflammatory markers. They also elevated five matrix metalloproteinases enzymes involved in ECM degradation.³ The same polymer with a different product design can result in divergent biological responses.

The genome tells the same story

To better understand the molecular tissue response, the researchers used RNA sequencing to identify changes in gene expression associated with each PLLA formulation.³

PLLA microsphere treatment

Gene activity shifted toward regeneration: repair and metabolic pathways were switched on, with minimal immune activation.³

PLLA microflake treatment

Gene activity shifted toward inflammation: immune-response and cellular-stress pathways dominated.³ Transcription factor & IncRNA analysis confirmed the same pattern.³ This method provides further insights into how particle design can influence the biological programmes activated by the skin in response.

Regeneration is a measurable biological process

Across particle characterisation, in vitro and ex vivo models, and full RNA sequencing, PLLA-LASYNPRO™ microspheres showed a pro-regenerative gene profile, enhanced fibroblast function, and a low-inflammatory tissue response – compared to a PLLA microflake formulation, which inhibited fibroblast function, suppressed ECM production, activated inflammatory responses, and increased ECM-degrading enzymes.³

These findings are based on non-clinical research, including particle characterization, in vitro, ex vivo, and transcriptomic analyses. They do not replace clinical evidence, and further investigations are needed. However, together these complementary methods provide detailed insights into the role of product design in shaping cellular and molecular tissue responses. This study was conducted by researchers at a renowned Institute in Stockholm. It contributes to the growing body of scientific insights on JULÄINE™.

Interested in offering JULÄINE™ of Sweden in your practice? Get in touch to discuss how JULÄINE™ could support your practice and your patients.

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Science drives us. At Nordberg Medical, we are committed to advancing the field of bio-regeneration through science, innovation and collaboration. Our ongoing research and partnerships with leading scientific institutions, contribute to the growing body of evidence behind our biomaterials.