Microspheres for Cosmetic and Medical Injections Must be Free of Phagocytosable Microparticles under 20 Microns
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2017, Vol 1, Issue 6
Abstract
A more serious complication after the injection of all dermal fillers is the late occurrence of foreign body granulomas. The reason must be the retention of a foreign material in the memory of the macrophages, which likely had phagocytosed it years before a granuloma manifests itself as reddish-blue, dense nodules. This sudden granulomatous immune reaction is probably triggered by a sudden systemic bacterial infection which can be recalled by one-third of all granuloma patients. A vigorous removal of small PMMA particles < 20 μm in the only FDAapproved permanent injectable wrinkle filler ArteFill® and deep dermal injections, have decreased the granuloma rate from 0.5%, experienced with earlier-generation products of Artecoll® in Europe, to 0.01% (4 in 42,000 patients) in China when injected in the deep dermis. a) Injectables: When collagen injections for wrinkle correction and lip augmentation became fashionable in the early 1980ies, dermatologists and plastic surgeons quickly realized that they did not last for 2 years beneath facial wrinkles, as promised by the manufacturer, but their positive effects rather vanished within 3 months. In order to prolong the effectiveness of collagen-based dermal fillers, a mixture with highly tissuecompatible and non-biodegradable PMMA-microspheres was suggested and tested in pre-clinical studies at the University of Frankfurt/Main Germany in 1985 [1]. Subsequently, after positive results in a limited number of volunteer patients, European clinical trials were initiated [2] and a new permanent injectable wrinkle filler Artecoll® has been marketed in Europe since 1994 (Figure 1)[3], in Brazil since 2009 [4], and in China since 2002 [5]. In the US, next-generation product ArteFill® received FDA-approval in 2006 as the first and only permanent dermal filler (now Bellafill®) [6]. b) Granulomas: Since granulomas have occurred after all dermal filler injections, including collagen and hyaluronic acid, the authors have investigated possible causes for granuloma formation. Foreign body granulomas can occur suddenly in approximately 1:2,000 injected patients months or even years after the injection [7]. They appear suddenly in all injected sites, grow rather rapidly to the size of peas or even beans, and, if untreated, usually remain for a few years untilthey disappear spontaneously [8]. Histologically, granulomas after PMMA-fillers show further than normal separated PMMA microspheres due to an over production of collagen, hyalinization, macrophages engulfing microspheres, and a high number of giant cells. The latter originate from a fusion of up to 40 “frustrated macrophages” that cannot destroy or remove the microspheres (Figure 2). The treatments of choice are repeated intralesional corticosteroid injections (triamcinolone, Kenalog®) in rather high doses [7]. c) Macrophages: All injectable microspheres made from either PMMA (Artecoll®/Bellafill®), calcium-hydroxyapatite (Radiesse®), polylactic acid (Sculptra®), polycaprolactone (Ellanse´®), etc. have an average diameter of 40μm, just small enough to pass through a tiny 26g needle (with an inner diameter of 260μm), yet large enough to escape phagocytosis by macrophages, the cells which clean the inner vertebrate tissues from all foreign materials (Figure 3) [7]. Macrophages have a diameter of 10-20μm and migrate through all connective tissues of the body, phagocytosing cell debris of dead cells, bacteria, and foreign particles, up to a size below their own. The migration of macrophages is facilitated by swelling (postinjection edema), which widens the “openings” between the fibers of the connective tissue from 5μm up to about 20μm. Since the life circle of macrophages is only 2 days before they are indigested by their younger peers, their “memory” on former immune stimulants like bacteria and the surface structure and chemistry of foreign bodies appears to be transferred as well, from one generation of macrophages to the next one (Figure 4) [7]. The process of PMMA-microsphere production starts with the injection of hot PMMA-syrup into floating cold water: as faster thewater runs or is stirred, as smaller the microspheres develop from the injected droplets. In a round drum, the small microspheres originate in the periphery, the larger around the center. Unfortunately, after all different production methods are very small microspheres or irregular PMMA-particles contained or attached to the smooth and identical bigger microspheres (Figures 5 & 6). These small particles must be removed by sieving and washing, since they may be the reason for the memory of the macrophages (Figure 4).
Authors and Affiliations
Gottfried Lemperle, Peter Neugebauer, Ruth Kernke, Karl-Heinz Lerche, Stefan Lemperle
Keywords
Related Articles
- EP ID EP578505
- DOI 10.26717/BJSTR.2017.01.000512
- Views 185
- Downloads 0
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