The PMMA/collagen predecessor to ArteFill was first developed by the senior author in Germany more than 20 years ago, and his persistent efforts led to the current (third generation) product, ArteFill . The combination of two widely used and proven biocompatible materials, bovine collagen (sutures, hemostatic agents, implants) and PMMA (orthopedic bone cement, craniectomy plates), satisfies biocompatibility issues. The microscopically small particles of PMMA in the bovine collagen carrier are enveloped by autologous collagen as the byproduct of natural connective tissue turnover, leaving a pliable, and permanent, tissue residual.
After seeking the optimal collagen/PMMA ratios in laboratory animals, trials on humans were initiated. The first-generation product, called Arteplast®, as well as its successor, Artecoll®, proved efficacious, although adverse events did emerge [3–5]. Most of these adverse events were firm nodularities at injection sites, occasionally with an associated inflammatory response. In several instances, surgical removal of the implant was required.
Further investigation led to the conclusion that there is a specific threshold of PMMA microsphere size that is critical to avoid phagocytosis by macrophages and giant cell formation with resulting granulomatous inflammation. Associated observations suggested that small PMMA microspheres, less than 20 μm in diameter, engendered a foreign body response . ArteFill embodies the lessons learned from both the Arteplast and Artecoll experiences.
The key to ArteFill’s biocompatibility and safety, as documented in animal experiments , is the extremely uniform, round and smooth PMMA microspheres , and especially the absence of particles less than 20 μm in diameter (Fig. 1). The novel purification process established for the production of the final product explains the absence of documented granulomas with ArteFill in over 15,000 patients. These observations differ from the granuloma rates reported after the injection of first-generation Arteplast and second-generation Artecoll . In those cases, host cellular reaction was histologically attributed to PMMA impurities and PMMA particles smaller than 20 μm that could be phagocytized . In the earlier processing of the PMMA microspheres, the small particles appeared to adhere to the larger microspheres during the sieving step, probably due to electrostatic charges.
The smooth surface morphology of ArteFill’s PMMA microspheres also appears to mitigate an inflammatory response. Microscopically, macrophages and foreign body giant cells, also called “frustrated macrophages,” can be detected around particles with an irregular surface . This may explain the rather high rate of granulomas after injection of Dermalive®, whose particles are characterized by an irregular, rugged surface . It has also been observed that spiculated and small, irregular particulate materials such as polyurethane foam and the silicone particles on the surface of textured breast implants often elicit a chronic granulomatous tissue reaction .
ArteFill, as with implantation of any particulate material in humans, invariably elicits an initial foreign body reaction. As with normal wound healing, the initial event consists of a tissue-material interaction whereby serum proteins (fibronectin and fibrinogen) are deposited at the microsphere surface. The next event is the invasion of neutrophils and monocytes, which release their granular components and rapidly differentiate into macrophages. They attach to the microspheres and form a monocellular layer over all smooth surfaces. When rough surfaces are present, even on larger particles, macrophages may morph into giant cells in a frustrated attempt to phagocytize the offending foreign body.
The third reaction to foreign material is the formation of “granulation tissue,” composed of macrophages, fibroblasts, capillaries, and collagen that fill the interstitial spaces between the microspheres. The bovine collagen [1, 2] appears to maintain the separation between the microspheres and facilitates tissue ingrowth (Fig. 2). Without ArteFill’s collagen component the microspheres would clump together—a phenomenon observed in other filler formulations using hyaluronic acid-based or methylcellulose carriers .
Approximately 4 weeks after implantation the ArteFill implant consists of 20% inert microspheres and 80% granulation tissue. This ratio may vary at 4 weeks depending on the volume of the material implanted (Fig. 3). Subsequently, over time the connective tissue matures through a natural process similar to scar formation and the interstices are filled with fibroblasts and autologous collagen fibers.
Histology at 3 months demonstrates that all of the PMMA microspheres are completely encapsulated and are surrounded by fibroblasts and collagen fibers. Macrophages are rare and capillary in-growth is evident (Fig. 4).
Human histology after 10 years revealed strong bands of mature collagen fibers with fully intact capillary vasculature surrounding intact PMMA microspheres (which were dissolved by alcohol during histology processing) (Fig. 5). In essence, the ArteFill injection serves as a scaffold to promote a “living implant.” The PMMA components of ArteFill become fully integrated into the connective tissue, whether dermis or subdermal spaces. As in normal tissue with sufficient blood supply, there appears to be constant turnover of cells, including fibroblasts and macrophages.