Injectable filler is a substance made to be injected into connective tissues, such as skin, cartilage or even bone, for cosmetic or medical purposes. The most common application of injectable fillers is to change one's facial appearance, but they also are used to reduce symptoms of osteoarthritis, treat tendon or ligament injuries, support bone and gum regeneration, and for other medical applications. Injectable fillers can be in the form of hydrogel or gels made from pulverized grafts. Injectable fillers have risen in popularity mostly due to the wide application of dermal fillers in 1980s. Their premise is to help fill in facial wrinkles, provide facial volume, and augment facial features. Potential side effects include bruising, allergic reactions which may cause scarring or lumps, or infections from improper sterilisation. This may include HIV infection. Blindness due to retrograde (opposite the direction of normal blood flow) embolization into the ophthalmic and retinal arteries can occur.
Materials used Injectable fillers are composed of a wide range of natural and synthetic biomaterials, which can be categorized as resorbable or non-resorbable polymers. Injectable fillers are frequently formulated as hydrogels composed of hydrophilic polymer networks that can retain large amounts of water while maintaining structural integrity. Common materials include naturally derived polymers such as hyaluronic acid, gelatin, collagen, chitosan, alginate, and polysaccharides, as well as synthetic polymers like polyethylene glycol (PEG), poly(lactic acid), poly(methyl methacrylate), polyacrylamide, and dextran. These materials are often selected for their biocompatibility and structural similarity to the extracellular matrix, enabling integration with surrounding tissues. To enable in situ gelation, polymers are typically functionalized with reactive groups such as phenols, amines, or glutamine residues, allowing controlled crosslinking after injection. In advanced formulations, these hydrogel matrices may also serve as carriers for therapeutic fillers, including cells, proteins, or drugs, expanding their functionality beyond structural augmentation. Hyaluronic acid
Hyaluronic acid is one of the most common materials used for injectable filler procedures due to its natural presence in vertebrates. Its inherent biocompatibility and biodegradability makes it particularly well suited for these applications, contributing to its widespread use in aesthetic and medical treatments. The chemical structure of hyaluronic acid is made up of repeating disaccharide units that consist of N-acetyl-D-glucosamine and D-glucuronic acid. Crosslinking Mechanisms in Injectable Fillers Crosslinking mechanisms determine the mechanical stability, degradation behavior, prolonged in vivo retention time, and in situ gelation properties of the injectable filler material. Hydrogels used as injectable fillers may be formed through physical (non-covalent) interactions or chemical (covalent) crosslinking, with chemical crosslinking generally providing greater stability and tunability. In collagen-based fillers, crosslinking methods such as glutaraldehyde treatment have been used to enhance integration, while synthetic fillers like poly(methyl methacrylate) rely on particulate scaffolds that induce fibrotic tissue formation rather than on degradable networks. Among chemical approaches, enzymatic crosslinking has gained prominence for its ability to proceed under physiological conditions without toxic catalysts or external stimuli such as ultraviolet light. Common enzymatic crosslinking mechanisms include horseradish peroxidase (HRP), tyrosinase, and transglutaminase. Horseradish peroxidase catalyzes the formation of phenolic radicals in the presence of hydrogen peroxide. Tyrosinase oxidizes phenolic groups into reactive quinones capable of forming crosslinks. Transglutaminase creates covalent bonds between glutamine and lysine residues in polymer chains. These mechanisms enable precise control over crosslinking density, which in turn governs key material properties such as stiffness, degradation rate, and pore size. 1,4 – Butanediol diglycidyl ether (BDDE) Cross-Linked Hyaluronic Acid Fillers
Most hyaluronic acid injectable fillers are cross-linked using chemicals such as 1,4 butanediol ether (BDDE) to enhance their stability and resistance to enzymatic degradation. Cross-linking significantly improves pharmokinetics and allows the filler to remain in the body for a longer duration. However, concerns have been raised regarding the long-term safety of BDDE, which remains incompletely understood. A 2024 review reports that the long-lasting side effects and potential harm of BDDE has caused allergic reactions in patients. A 2015 study found that 34.3% of patients in a cohort of 452 experienced allergic reactions associated with BDDE exposure. Self-Cross-Linkable Hyaluronic Acid
Natural hyaluronic acid rapidly degrades in vivo, which limits its effectiveness as a long-lasting injectable filler due to the lack of cross-linking chemistry. A 2019 study investigated a self-cross-linkable form of hyaluronic acid modified with gallol groups that can form a stable hydrogel in vivo through autoxidation. The technique eliminates the need for commonly used cross-linkers in hyaluronic acid fillers like BDDE. The gallol groups on the hyaluronic acid contain three hydroxyl groups on the benzene ring, allowing for spontaneous oxidative crosslinking in vivo without the need for additional cross-linking agents. The study confirmed that this self-cross-linkable hyaluronic acid improves pharmokinetics and the long-term performance of the filler compared to non-cross-linked forms of hyaluronic acid. Self-cross-linkable hyaluronic acid is proposed for use in applications such as tissue augmentation and wrinkle correction. Other studies report that hyaluronic acid is used for tissue engineering as well as drug delivery mechanisms. Polylactic Acid
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