Early‐stage volume effect difference between injectable poly‐l‐lactic acid and injectable poly‐d,l‐lactic acid

Biostimulators, or collagen-stimulating fillers, have been increasing in popularity for facial rejuvenation in recent years. Among these biostimulators, injectable poly-l-lactic acid (PLLA; Sculptra; Galderma) was first available in Europe in 1999.1, 2 Another biostimulator, injectable poly-d,l-lactic acid (PDLLA; AestheFill; REGEN), was first approved for use in South Korea in 2014.2-4 They are both supplied as lyophilized powders in vials, which need to be reconstituted with sterile water before injection.1-3 Although they are identical, there are some dissimilarities in collagen formation mechanisms between them. Because the collagen stimulation effect of PLLA is not immediate, after the mechanical distension of the suspension is resolved, the mechanism of action enables the product to gradually restore volume.1 However, we have an interesting finding that the volume restoration with PDLLA seems immediate after the mechanical distension of the suspension is resolved. To explain this phenomenon, we elaborate on and illustrate the PDLLA collagen formation mechanism. Based on the mechanism of action, we compare and discuss the early stage volume effect difference between these two identical biostimulators. There are some composition differences between injectable PLLA and PDLLA. One vial of injectable PLLA contains 150 mg of solid PLLA microparticles, whereas one vial of injectable PDLLA contains 154 mg of porous PDLLA microspheres (Figure S1).2, 3 The collagen formation mechanism of PLLA has been well-studied.1 When mechanical distension from the suspension of the microparticles resolves a few days after PLLA injection, the residual volume comes from PLLA microparticles. Because the density of poly-lactic acid is between 1.25 and 1.36 g/ml,5 the total volume of all the microparticles is <0.12 ml. For this reason, the visible volume effect disappears almost totally. The volume effect cannot be seen until several weeks to months later, when collagen fibers around PLLA microparticles accumulate gradually.1 As a result, the early-stage volume effect of PLLA is “resolving a few days after injection, followed by growing gradually in the following months.” Due to the high porosity property of PDLLA microspheres,2-4 the total volume of all PDLLA microspheres is several folds higher than PLLA microparticles (Figure 1). As a result, although mechanical distension from the suspension also resolves a few days after PDLLA injection, the volume effect still exist due to these large volume PDLLA microspheres. Based on previous studies,4, 6 we can find out that the porous PDLLA microspheres can not only stimulate neo-tissues formation but also provide scaffolds for them. The neo-tissues first grow on the surface of these microspheres, then they grow more to fill the interspace of microspheres. At the same time, these porous microspheres degrade gradually while neo-tissues grow inside microspheres. The original volume of these microsphere scaffolds is replaced by neo-tissues and remains the same in the following months. For better understanding of the PDLLA collagen formation mechanism, see Figures S2 and S3. As described above, the early-stage volume effect of PDLLA is “resolving partially a few days after injection, followed by maintaining in the following months” (Figure 2). Our clinical findings are compatible with these mechanisms. However, the amount of volume induced by a biostimulator depends on various patients' tissue responses in producing neo-tissues. The individual differences can be enormous. Besides, Figure 2 was plotted according to our clinical observations. If we had a series of three-dimentional photographs, we could calculate the volume change and plot these volume/time curves more precisely. Further studies should be designed to investigate the influence factors and measure the volume of neo-tissues formation with different biostimulators. In conclusion, although injectable PLLA and PDLLA are identical biostimulators, there are some differences in the collagen formation mechanisms and particle morphology, which result in different early-stage volume effects between them. The early-stage volume effects of these two fillers come from the total volume of PLLA microparticles or PDLLA microspheres. After that, via different neo-tissues growth patterns, the volume effect of injectable PLLA increases, whereas that of injectable PDLLA remains the same. The authors want to give special thanks to Chia-Ti Pan for her kindly assistance with manuscript editing; to Hyegyeong Jo and Tung-Hsuan Lin for their kindly assistance with art works drawing. Dr. Lin J-Y and Dr. Lin C-Y are medical directors of REGEN Biotech., and medical consultants of Jiangsu Wuzhong Aesthetic Biotech. Dr. Hsu N-J is a speaker of Galderma and a medical consultant of Jiangsu Wuzhong Aesthetic Biotech. Dr. Fu J-P has no conflict of interest to disclose. The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a review article with no original research data. FIGURE S1 Scanning electron microscopic pictures of poly-d,l-lactic acid microspheres. (A) Multiple micropores on the surface; (B) High-porosity structure inside the microsphere. FIGURE S2 Schematic representation of the collagen formation mechanism of a single porous poly-d,l-lactic acid (PDLLA) microsphere.4, 6 Following implantation of a PDLLA microsphere, a series of inflammation processes called foreign body reaction is initiated. This reaction is divided into acute and chronic phase responses. The acute phase can last for several hours to days. It is initiated by various inflammatory cells, which interact with each other to promote the chronic phase. The acute phase begins by increasing blood viscosity, dilatation of blood vessels, and protein leakage from the blood vessels. Together with tissue-derived proteins, a protein layer is formed on the microsphere. Being attracted by histamine and pro-inflammatory cytokine released from local mast cells, neutrophils and monocytes move concomitantly toward the microsphere surface. Some pro-inflammatory cytokines also induce angiogenesis at this stage. At the beginning of chronic phase, neutrophils are replaced by monocytes. These monocytes adhere to the microspheres where they differentiate into macrophages. Because a PDLLA microsphere is significantly larger than a macrophage, the microsphere cannot be phagocytosed by these macrophages. These macrophages will soon become “frustrated.” Then, they fuse together to form multinucleated foreign body giant cells, which will persist for the whole degrading process of PDLLA microsphere. Fibroblasts synthesize collagen fibers to encapsulate the microsphere. As time goes on, more collagen fibers grow around the microsphere while it degrades gradually. When a microsphere degrades, adjacent pores gradually coalesce into larger pores. When one of these pores becomes large enough, giant cells and fibroblasts will migrate into and synthesize collagen fibers inside the microsphere. More collagen fibers are synthesized thereafter to replace the volume until total degradation of the microsphere. (Artwork courtesy of Hyegyeong Jo) FIGURE S3 Schematic representation of poly-d,l-lactic acid microsphere scaffolds for neo-tissues formation.4 Neo-tissues grow between and then inside the microspheres which are eventually hydrolyzed, and their volume is replaced by neo-tissues. (Artwork courtesy of Tung-Hsuan Lin) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.