Facial Injectable Fillers in Aesthetic Medicine: Clinical Applications and Safety Strategies

Introduction

In recent years, an aging population, heightened awareness of aesthetic appearance, and advances in medical aesthetic technology have fueled a boom in the global medical aesthetic surgery industry [1]. The global medical aesthetics market is projected to approach $125 billion by 2028, underscoring the widespread and increasing use of aesthetic procedures and the accompanying need for stricter safety protocols and clinical guidelines. A survey by the American Society for Dermatologic Surgery indicates that approximately 70% of consumers consider cosmetic surgery to enhance self-confidence and to appear younger and more attractive. Worldwide, minimally invasive and facial injectable filler procedures are gaining popularity [2]. Facial injectable fillers have become increasingly popular owing to their minimally invasive nature, convenience, quick recovery, and moderate cost; however, their widespread use has raised clinical concerns, as complications such as vascular occlusion, tissue necrosis, and even blindness, although infrequent, can lead to serious outcomes, highlighting the urgent need for a thorough evaluation of the safety and risk profiles of the facial fillers.

Aging causes progressive changes in facial skin and bone structure. Factors such as sunlight exposure, bone resorption, dynamic contraction of sphincter and non-sphincter oral muscle, histological changes of the skin, and unhealthy habits can lead to volume loss, particularly in the perioral region. This volume loss can manifest as deep nasolabial grooves, downturned mouth corners, puppet lines, and chin irregularities [3]. Facial aging is primarily marked by subcutaneous fat loss and skin laxity, often described as a “deflated” appearance. Facial structural decline is due to the loss of adipose tissue, decreased tension in facial ligaments, epidermal thinning, and collagen depletion, which accentuates features like nasolabial folds and jowls. This results in the characteristic “inverted triangle” appearance of aging, in contrast to the “downward equilateral triangle” seen in younger faces.

Individuals concerned about their appearance may be experiencing wrinkles, sagging skin, or hyperpigmentation, which can affect their emotional well-being and induce anxiety. By injecting facial fillers to replace age-related fat loss, deflated contours can be re-shaped, static lines improved, and youthful contours restored [4–6].

As insights into skin volume loss and aging mechanisms advanced, early researchers discovered that restoring facial volume through injectable materials could improve sagging and wrinkles, catalyzing the development of modern dermal fillers. To meet increasing demand, numerous facial fillers were developed by subsequent researchers [7–13]. Today’s market offers facial fillers categorized into autologous and non-autologous tissues, with the latter further divided into degradable and non-degradable types based on their degradation rate and duration of effect [14]. Biodegradable non-autologous tissue fillers, such as hyaluronic acid (HA), collagen, and levulinic acid, are commonly used [15–17]. Non-biodegradable fillers include materials such as polymethyl methacrylate (PMMA) and silicone [18]. Although facial filler injections are minimally invasive and generally considered low-risk, they can still result in complications ranging from mild symptoms, such as pain, edema, and bruising, to severe outcomes, including tissue necrosis and cerebral embolism; however, differences in adverse event rates across filler materials and injection techniques remain insufficiently studied [19–21]. Therefore, it is crucial for practitioners to not only select the appropriate filler, but to also understand potential complications, preventive measures, and the anatomical relationships within facial danger zones to minimize complications risks. Consequently, this review provides a comprehensive analysis of common filler agents, their associated complications, and preventive and therapeutic measures, aiming to improve the safety of facial injections and reduce adverse event incidence (Figure 1) [22–24].

Methodology

Common injectable materials for the face

COMMON INJECTABLE MATERIALS FOR THE FACE:

Soft tissue fillers are categorized as either degradable or non-degradable fillers based on their degradation rate and duration of effect. The primary fillers used today, their mechanisms of action, and degradation times are detailed in Table 1. The common types of facial injection fillers, along with their applications, benefits, and drawbacks, are shown in Table 2.

HYALURONIC ACID: HA is a naturally occurring acidic mucopolysaccharide in the human body. It forms primarily through the polymerization of the disaccharide monomers glucosamine and glucuronic acid. HA provides immediate volume restoration with high biocompatibility and low allergy risk. Its hydrophilicity increases tissue volume, counteracting age-related deflation. Crosslinking extends duration to 6 to 12 months [25–27].

The fundamental role of HA is to stabilize the extracellular matrix and stimulate fibroblasts to produce collagen or adipocytes [28]. Its exceptional capacity to bind up to 1000 times its own volume in water underpins its effectiveness in increasing skin and soft tissue volume, enhancing hydration, and maintaining elasticity and structural support [27]. As HA levels in human skin decrease with age, this leads to reduced tissue elasticity and hydration, thereby contributing to wrinkle formation and facial aging. In the skin, HA is naturally broken down by hyaluronidase and free radicals, with a metabolism time of approximately 1 to 2 days; therefore, most HA products are crosslinked to prolong its duration in the body. When injected too superficially, HA can cause a “Tyndall effect”, leading to blue coloration of the skin [29]. Overfilling can be dissolved by locally injecting hyaluronidase into the affected area [30–32]. A meta-analysis involving 2738 patients demonstrated that HA is a safe and effective alternative to chin augmentation surgery, with most patients reporting high satisfaction [33]. Schuurmans et al chemically crosslinked HA and chondroitin sulfate methacrylate-based hydrogels, achieving increased purity and reduced cost. Cho et al enhanced the biocompatibility of HA by combining it with gelatin, chitosan, cellulose, and polyethylene glycol [34]. Table 3 shows that varying HA’s molecular weight, concentration, pH, crosslinking agents, particle size, and reaction times can produce HA with specific rheological properties. Different rheological characteristics suit different facial filler applications. Dermal fillers with a high stiffness (high G’) are better for deep wrinkles, while those with a low G’ value are more suited for lip enhancements and superficial wrinkles. Ideally, HA fillers used for nonsurgical chin enhancement should have a high G’ value to facilitate deeper injections. Nikolis et al developed a novel HA injectable, HASHA (Restylane Shaype), for treating mildly or moderately constricted chins in adults. After 12 months, patients maintained high satisfaction, with most adverse events being mild or moderate [12]. Ren et al treated patients with midface volume and contour deficits using HA injections, achieving over 97% satisfaction, with no adverse events reported [35].

HA can be categorized as monophasic or biphasic based on the crosslinking method; biphasic HA is easier to inject, whereas monophasic HA injections are less painful and yield longer-lasting results [36]. Although cosmetic products containing HA typically exhibit a high safety profile, occasional adverse reactions, such as allergic responses, infections, skin necrosis, and vascular embolisms, can occur [37–40]. HA generally has a low incidence of allergic reactions, with common symptoms including redness and swelling, often due to technical issues. Statistical analysis reveals that nasolabial fold fillers have the highest rate of HA complications, although these are typically mild, one-time, and reversible [41].

POLYCAPROLACTONE: Polycaprolactone (PCL)-based fillers are biodegradable and collagen-stimulating and have seen increased use in recent years. Among them, Ellansé (AQTIS Medical BV), a new biodegradable collagen-stimulating agent, is highly sought after for its combination of continuity and immediacy [42]. Ellansé is registered and marketed in over 60 countries and regions, becoming the only imported regenerative filler product licensed under the National Medical Products Administration. Ellansé consists mainly of 70% carboxymethylcellulose gel carriers and 30% PCL microspheres. After carboxymethylcellulose absorption (6–8 weeks), PCL microspheres drive collagen neosynthesis via fibroblast activation, hydrolyzing to CO2/H2O over 1 to 4 years [43]. PCL microspheres come in 4 models – S, M, L, and E – each with a duration of 1, 2, 3, and 4 years, respectively. PCL gel is applied to areas such as the forehead, nasolabial folds, midface, nose, jaw, and hands [44,45]. Its clinical efficacy is well established, with PCL demonstrating superior longevity in treating nasolabial folds, compared with HA [46]. Angelo-Khattar conducted a retrospective case study on 9 patients using PLA composite fillers. The Canfield Vectra 3D imaging system revealed that the volume increase in the mid-face exceeded the injected volume, indicating collagen formation induced by PCL microspheres, with high patient satisfaction after 2 years [46]. Sezer et al showed that adding lidocaine to fillers accelerates neocollagenesis [47]. Marefat et al found that PCL fillers significantly improve moderate to severe facial enlarged pores [48]. Jeong et al compared the new PCL-based dermal filler DLMR01 with the purified polynucleotide dermal filler RJR, finding DLMR01 to be more effective and safer in treating crow’s feet [49]. In a 2-year study, Moers-Carpi et al confirmed the safety, efficacy, and tolerability of 2 PCL-based dermal filler formulations [50]. The PLA composite filler showed minimal adverse effects, including swelling, pain, and erythema at the injection site, all resolving within 30 min, thus demonstrating its efficacy and safety [45,51].

CALCIUM HYDROXYAPATITE: Because it is naturally present in bone and teeth, calcium hydroxylapatite (CaHA) offers excellent biocompatibility, underpinning its utility in deeper tissue augmentation, such as nasolabial fold correction and rhinoplasty [52,53]. Unlike purely space-occupying fillers, the CaHA product Radiesse (Merz Aesthetics GmbH) combines immediate volume restoration via its carboxymethylcellulose gel carrier, with long-term structural benefits: the gel is absorbed within 3 to 6 months, while the CaHA microspheres persist, acting as a scaffold to stimulate sustained neocollagenesis by fibroblasts. This dual mechanism underpins its longevity (typically 1–2 years) before the eventual biodegradation into calcium and phosphate ions [54,55]. In a study of 2779 patients, nasolabial folds were predominantly treated, with only 3% of patients experiencing adverse effects, such as nodules, which typically resolved without intervention, indicating a high safety profile [56]. However, the observational nature of such studies limits causal inference and can underestimate rarer complications. Evidence for efficacy extends beyond static wrinkles. Case reports and small series highlight the potential of Radiesse in addressing complex volume deficits and contour irregularities, such as significant facial asymmetry and infraorbital hollowing, with improvements often showing within weeks [57]. Amaral et al used Radiesse with the vector-lift technique for global facial repositioning, achieving upper and midface elevation, improved infraorbital sulcus, and increased facial volume within 90 days [58]. Wollina et al demonstrated that repeated CaHA injections, using multiple Radiesse injections in the mid and lower face, enhanced facial appearance in women aged 50 and 95 years [59]. Radiesse is also effective for skin augmentation and jawline enhancement, particularly when combined with materials like saline, lidocaine, or HA [60–66]. Controlled comparative studies suggest its non-inferiority to HA fillers in terms of efficacy and patient satisfaction for certain indications, broadening its potential role [67]. Although CaHA generally receives high patient satisfaction, it can occasionally cause complications, including nodules, inflammation, localized infections, skin necrosis, and vascular occlusion [56,68,69]. While large observational studies support a generally favorable safety profile, with mostly transient adverse events, the potential for serious complications necessitates rigorous adherence to best practices. Evidence suggests comparable outcomes to HA fillers in specific contexts, positioning CaHA as a versatile tool. Future research should focus on improving long-term outcomes, optimizing combination strategies, refining techniques to further minimize complications, and conducting direct comparative effectiveness studies across diverse indications and patient populations.

POLY-L-LACTIC ACID: Poly-L-lactic acid (PLLA) stands out among FDA-approved biodegradable synthetic biomaterials for its unique mechanism as a collagen biostimulator by offering durable results distinct from immediate volumizers, such as HA. While valued for its biocompatibility, low toxicity, and modifiability, its clinical application requires careful consideration of formulation and technique. Sculptra (Galderma), the primary PLLA product, is supplied as a sterile lyophilized powder, requiring reconstitution. Crucially, clinical evidence strongly links dilution volume and injection technique to complication rates, particularly nodule formation [70]. The common practice of diluting in 9 to 10 mL reflects accumulated experience but highlights the need for standardized protocols based on robust evidence. The inherent hydrophobicity of PLLA particles can contribute to initial poor tissue integration and transient inflammatory reactions as the particles degrade, releasing lactic acid [71]. It is precisely this controlled inflammatory response, recruiting macrophages, which in turn stimulate fibroblasts, that drives the desired neocollagenesis and gradual volumetric improvement over months. This biostimulatory action underpins the classification of PLLA as a “collagen stimulator” rather than a simple filler, translating to long-lasting effects (up to 2 years) that evolve over time [72,73]. Bohnert et al conducted a randomized, double-blind study on 40 women, comparing PLLA and saline injections. They found a significant increase in skin elasticity and hydration in the PLLA group after 1 year [74]. In a study of 80 patients, over 86% showed significant improvement in nasolabial folds after PLLA injections, with most adverse events being minor and transient [75]. Fabi et al found that PLLA injections, compared with no treatment, were well-tolerated and effective in significantly reducing moderate to severe buccal lines and improving skin quality [76].

PLLA should not be used in the periorbital or orofacial areas, as it can form nodules visible to the naked eye, particularly with high-dose injections [77,78]. In conclusion, PLLA is a valuable long-term biostimulator for facial rejuvenation; however, its safety and efficacy are highly operator-dependent. Meticulous technique and patient selection are paramount to mitigate nodule risk. Future research should focus on optimizing protocols.

POLYMETHYL METHACRYLATE: PMMA is a permanent, non-degradable soft tissue filler that historically saw limited use because of the risk of delayed, stubborn granulomas. However, advancements in fabrication processes have improved PMMA microspheres, giving them a rounded shape and smooth surface that significantly reduces the likelihood of immune reactions and granuloma formation [79,80]. A variety of PMMA-based products are currently in clinical use. Artecoll (Canderm Pharma Inc), composed of 80% bovine collagen and 20% PMMA, became the only FDA-approved nonabsorbable filler in 2006. After injection, the bovine collagen component degrades within 1 to 3 months, while PMMA remains encapsulated by fibrous tissue, providing a long-lasting filler effect. However, the product requires preliminary allergy testing because of its composition. In a 2-year prospective study led by Hevia, patient satisfaction levels were high, with 82% and 100% of patients expressing being at least “a little satisfied” at 52 and 104 weeks, respectively. Moreover, more than 90% of patients showed significant improvement in the treatment of the mandibular sulcus, with all reported adverse events being minor [81]. Solomon et al, in a retrospective analysis of a third-generation PMMA filler (Bellafill; Suneva Medical, Inc), recorded only 6 adverse events out of 417 procedures, indicating high patient satisfaction [82]. Data indicate that PMMA-related complications occur at a rate of 4.9%, with granulomas at 1.9%; the incidence of granulomas is approximately 1 per 2075 patients annually, manifesting between 6 and 180 months after treatment. These findings suggest that the safety of PMMA as a filler is reliable when weighing the actual risks against the benefits [80]. Nonetheless, PMMA can cause adverse effects such as nodules and scarring, which respond minimally to corticosteroid injections. Its use should be rigorously weighed against the availability of safer, biodegradable alternatives for most aesthetic indications. Surgical intervention often yields better results in reducing these complications [83–85].

SILICONE: Silicone, primarily silicon dioxide-based, is a chemically inert material historically used for soft tissue augmentation since the 1950s due to its low cost, stability, and theoretical biocompatibility. However, the absence of standardized formulations, injection protocols, and long-term safety data has relegated it to a non-standard, high-risk option in modern aesthetic practice. Silicone can cause irreversible adverse effects, including skin swelling, scarring, and facial deformities [86,87]. Injectable liquid silicone has been widely used for soft tissue augmentation owing to its ease of administration. However, regulatory agencies have issued warnings urging caution with such products, as liquid silicone can migrate through blood vessels to other parts of the body, potentially obstructing vessels in the lungs, heart, or brain, leading to severe health issues or even death [88]. Case reports have documented nasal contracture following silicone implant rhinoplasty, in which severe contracture can affect all layers of the nose, resulting in significant scarring and disfigurement [89,90]. Therefore, injectable liquid silicone must be used with extreme caution, and its application in highly vascularized areas should be avoided.

AUTOLOGOUS FAT: Facial aging is primarily characterized by a loss of facial volume, particularly fat, making fat transplantation an ideal method for facial rejuvenation and contouring [91–93]. Fat from the lower abdomen and medial thigh is preferred for facial lipofilling owing to its higher viability [94]. Factors such as liposuction pressure, cannula diameter and hole number, and the method of extraction – whether dry or wet suction – affect fat cell viability, which is crucial for the success of autologous fillers because of their natural tendency toward low viability and resorption [95]. Debuc et al enhanced autologous fat grafts with stem or progenitor cells to improve viability, although they emphasized the need for new preclinical models to ensure safety [96]. Vallejo et al assessed the efficacy, safety, number of treatments, treatment frequency, dosage, and cost of fillers in 147 patients with fat atrophy, comparing PLLA, CaHA, PMMA, and autologous fat injections. After 24 months, they found all 4 fillers to be highly effective and safe, with autologous fat receiving particularly high scores on patient satisfaction. The study showed no significant difference in the number of sessions and treatment volumes between autologous fat and synthetic fillers; however, autologous fat was significantly less costly [97]. Gadallah et al reported high patient satisfaction following cosmetic surgery and lipofilling in 50 women who had permanent dermal fillers removed [98]. Despite its safety, autologous fat grafting can lead to complications, including hematomas, scar formation, fat necrosis, cysts, contour irregularities, cellulitis, and cerebral embolism [99–102]. These severe risks are highly technique-dependent, underscoring the need for standardized protocols.

PLATELET-RICH PLASMA: Platelet-rich plasma (PRP), obtained by centrifuging whole blood in vitro, is rich in highly concentrated platelets and various growth factors, including platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor. PRP regulates cell proliferation and differentiation and promotes vascular proliferation, and it is widely used as a filler in facial cosmetics. Commonly, PRP refers to a suspension of liquid platelets and leukocytes. In a 12-week randomized, placebo-controlled trial, Hu et al demonstrated that platelet-rich fibrin matrix enhanced skin parameters as measured by the VISIA skin score [103]. Godfrey et al treated women with geriatric skin conditions using plasma growth factor-rich plasma gel, noting significant improvement in fine lines, wrinkles, and skin laxity, which collectively contributed to substantial facial rejuvenation [104]. PRP is now extensively used in fields like wound repair and cosmetic dermatology, frequently combined with adipocytes to enhance grafting success rates [105]. Xiong et al observed that fat particles treated with platelet-rich fibrin and PRP, when grafted into rabbit ears, exhibited higher tissue retention and greater vascular density than did treatment with saline (control group) [106]; however, species differences and absence of human trials limit clinical extrapolation.

FACIAL ANATOMY:

A thorough understanding of facial anatomy is crucial for plastic surgeons to safely and effectively perform facial injections (Figure 2A). The method and depth of needle insertion heavily influence the outcomes of facial injections. The anatomical layers of the face, from superficial to deep, include the skin, subcutaneous tissue, superficial musculoaponeurotic system (SMAS), supporting ligaments and spaces, periosteum, and deep fascial layers (Figure 2B) [107,108]. The SMAS is integral to connecting key facial structures, including blood vessels and motor nerves. The facial vascular system is closely associated with the SMAS in various facial regions, particularly the mandibular line, perioral area, nasolabial folds, sub-brow, and temples. Therefore, familiarity with the SMAS anatomy and careful control of syringe depth are essential to achieve desired outcomes and avoid complications with the facial vascular nervous system [109]. It is crucial to clearly understand the facial fat compartments when performing filler injections, as detailed by Rod et al, who identified several distinct anatomical zones in the facial subcutaneous fat, as illustrated in Figure 3.

COMPLICATIONS AND PRECAUTIONS:

Although commonly used facial cosmetic injectables are considered safe, they are not devoid of risks or complications (Figure 4). The use of facial injectable cosmetics has led to a range of complications, from mild injection site reactions, such as erythema, ecchymosis, and infection, to more severe outcomes, such as scarring, nodule formation, and hypersensitivity reactions, as detailed in Table 4 [37,110]. Although the incidence of adverse reactions to filler injections is very low, healthcare practitioners must familiarize themselves with the necessary precautions to prevent or effectively manage complications, as most adverse events can be mitigated at an early stage or promptly treated.

LOCALIZED REACTIONS: Local adverse reactions to facial injections commonly include edema, pain, erythema, and ecchymosis, which are directly related to local trauma. Erythema appearing immediately after injection usually lasts for several hours, while transient edema can persist for up to 1 week, mostly presenting as transient and mild manifestations [111]. Ecchymosis often occurs several days after the injection of filler materials via fan-shaped or threading techniques (Figure 5). Statistically, the lips and periorbital regions are high-risk areas for complications, due to factors such as injection volume and technique [112].

In terms of prevention, ecchymosis can be reduced by avoiding the use of anticoagulants such as vitamin E and cod liver oil; staying away from highly vascularized areas; using small needles or blunt needles and fillers containing epinephrine; adopting slow injection techniques; and injecting into the superficial fat layer and preperiosteal layer [113,114]. Guarino et al showed that multi-needle devices can precisely distribute the medication in the correct injection plane, significantly reducing patients’ pain, edema, and ecchymosis [115].

For management, bleeding at the needle tip can be stopped by applying pressure for 1 to 4 min. Compared with hypodermic needles, blunt cannulas cause less erythema and edema and allow for faster recovery. Postoperative ice packs can help alleviate pain and edema.

VASCULAR COMPLICATIONS: The accidental intravascular injection of fillers can lead to skin necrosis and impaired blood flow. Although intravascular injection of fillers is rare, the consequences are severe, with a mechanism closely related to the anatomy of facial blood vessels. The ophthalmic artery system – originating from the internal carotid artery, with branches including the supraorbital artery, supratrochlear artery, and dorsal nasal artery – has abundant anastomoses, making areas such as the glabella, nose, and forehead high-risk zones for vascular embolism [116]. In terms of clinical manifestations, a systematic review by Zhuang et al on 165 cases of vascular embolism after facial filling found that the main manifestations include central retinal artery occlusion, posterior ciliary artery occlusion, ophthalmic artery occlusion, and acute cerebral infarction [117] (Figure 6A). Among them, embolism of the ophthalmic artery and central retinal artery often presents as sudden unilateral vision loss, periorbital pain, and headache, which can lead to permanent blindness in severe cases [117]. For example, Madala et al reported a case of a 37-year-old woman who experienced immediate left eye blindness due to retrograde embolism of the ophthalmic artery after injection of PRP filler into the suprachiasmatic artery [20]. The vascular distribution of the eye is shown in Figure 6B. Arterial occlusion can immediately cause severe pain and discoloration, while intravenous injection results in milder dull pain (common in injections into the supraperiosteal artery in the frontal region). Retinal embolism can be caused by intravascular injection into arteries such as the supratrochlear artery and supraorbital artery. Cerebral ischemic events, although rare, are life-threatening. For instance, a 31-year-old woman experienced loss of consciousness 6 h after facial autologous fat injection, and died of cerebral herniation and systemic infection after failed mechanical thrombectomy [101].

Preventive measures should focus on vascular protection. Familiarity with vascular anatomy – especially areas near the angular and supratrochlear arteries, as shown in Figure 6C – can significantly reduce risks. Standardized training and injection techniques, such as controlling speed and using small-caliber needles to slow down the injection rate, are crucial. Additionally, the use of blunt needles in high-risk areas, such as the glabella and nose, can reduce vascular injury. Other measures, such as aspiration before injection, keeping the needle moving, selecting low-density fillers, and limiting the single injection volume, also help avoid risks.

In terms of management, rapid intervention based on occlusion symptoms is required. Patients with retinal artery occlusion need early intravenous injection of acetazolamide, sublingual nitroglycerin, and intravenous mannitol to prevent permanent vision loss. In cases related to HA fillers, hyaluronidase can be injected near the ischemic area [118]. For ocular vascular occlusion caused by fat transplantation, intra-arterial thrombolysis combined with conservative treatment may help with early perfusion and visual recovery [119], but the overall improvement effect of treatment is limited, and most patients still have varying degrees of vision loss [120]. If signs of tissue necrosis appear, injection should be stopped immediately, and hyaluronidase should be administered, supplemented by treatments such as hot compresses, massage, and 2% nitroglycerin ointment to promote vasodilation. Local oxygen therapy and systemic steroids can also be used when hyaluronidase is ineffective.

INFECTION: Infections following filler injections, although clinically uncommon, can be caused by bacteria such as staphylococci and streptococci, mycobacteria, herpes simplex virus, and yeasts [121]. The cornerstone of prevention is rigorous adherence to aseptic techniques and thorough skin preparation. Herpes simplex virus infections, potentially triggered by lip augmentation, can be preemptively managed by initiating antiviral therapy at least 3 days before the procedure in susceptible individuals. Staphylococcal and streptococcal infections, which can lead to abscesses and cellulitis, require treatment with broad-spectrum oral antibiotics. Chronic and delayed manifestations, typically associated with biofilm infections, will be further discussed.

SKIN DISCOLORATION: The mechanism underlying skin reddening following filler injection is attributed to tissue expansion, excessive filler molding, and neovascularization. Clinically, it manifests within several days to weeks postoperatively and typically resolves within several months to 1 year. Laser therapy can be used when necessary [122]. Patients with Fitzpatrick skin types IV through VI are prone to developing post-inflammatory hyperpigmentation [123]. Management can involve topical lightening agents containing hydroquinone, resorcinol, and retinoic acid, or oral tranexamic acid, botanical medicines, and chemical peels to promote epidermal renewal and reduce melanin. Additionally, intense pulsed light, pulsed dye lasers, or fractional lasers can be used [124].

When HA fillers are injected into the dermis or superficial epidermis, a bluish discoloration occurs due to altered light scattering, known as the “Tyndall effect” (“Rayleigh scattering”) [125]. This is most commonly observed in areas with thin skin, such as the lower eyelids, and can persist for several years if not treated promptly. Hyaluronidase, which requires multiple treatment sessions, is the preferred therapy for large-particle or highly crosslinked HA [29,126]. Liu et al randomly assigned 60 patients into 3 groups – HA alone, HA combined with collagen, and collagen alone – and found that the incidence of the Tyndall effect with HA alone was significantly higher than in the other groups, indicating that the combination of HA and collagen can reduce this phenomenon [127].

Local skin discoloration is mostly caused by overly superficial or excessive injection of fillers, which can be prevented through appropriate injection techniques and gentle massage immediately after injection.

NODULES: Nodules are categorized into early-onset and delayed-onset types, with each having distinct underlying mechanisms. Early-onset nodules are induced mostly by medical factors such as excessive filler use, superficial placement, inappropriate type selection, and technical issues; they can also be caused by inflammation resulting from bacterial infections [128]. Delayed-onset nodules manifest months to years after injection, with etiologies including bacterial infections, allergic reactions, and sterile abscesses. Additionally, bacterial infections during or after injection can form biofilms, which are associated with delayed inflammatory nodules [129,130]. Humphrey et al found that the degradation products of HA fillers can trigger immune responses, leading to delayed adverse events such as swelling and nodules [131].

Early non-inflammatory nodules present as painless, localized, and quiescent in growth, emerging in the early post-injection period, while inflammatory nodules, caused by bacterial infections, are accompanied by infectious symptoms [128]. Histologically, delayed-onset nodules lack true granulomas and are microbiologically negative. Their formation is associated with filler type, filler quantity, time of onset, and initial clinical manifestations, while the lack of this information can complicate treatment.

Prevention involves avoiding excessive filler use, superficial placement, inappropriate filler selection, and poor injection technique. For early non-inflammatory nodules, monitoring and massage are feasible, and persistent nodules can be treated with aspiration or minimally invasive puncture incisions. Inflammatory nodules, after confirmation by microbiological testing, require oral antibiotics, and massage should be avoided to prevent the spread of infection [128]. The treatment of delayed-onset nodules needs to be tailored, including topical, oral, or intralesional corticosteroids, oral antibiotics, intralesional hyaluronidase, 5-fluorouracil, allopurinol, surgical excision, laser therapy, hot compresses, and massage [132,133]. Biofilm-associated infections can be diagnosed using molecular techniques such as polymerase chain reaction or fluorescence in situ hybridization, as culture tests often yield negative results.

ALLERGIC REACTIONS: Allergic reactions are a relatively rare complication following facial injections. It is important to note that HA lacks organ or species specificity and is therefore non-immunogenic [134,135]. However, HA is produced through bacterial biosynthesis, and residual protein components or impurities from the fermentation process can trigger allergic reactions [136,137]. Unlike HA, animal-derived fillers, such as bovine collagen, exhibit amino acid sequence differences from human collagen, which can be recognized by the immune system as foreign, leading to a higher risk of sensitization. These fillers can induce localized or systemic allergic reactions shortly after administration, manifesting as urticaria or fever, and can require the use of short-term oral corticosteroids [138]. Skin testing is mandatory before use. Such materials can provoke type I (immediate) or type IV (delayed) hypersensitivity reactions. Type I hypersensitivity can cause symptoms such as erythema, swelling, and pruritus. For mast cell-mediated reactions, oral antihistamines are typically administered, while short-term oral corticosteroids can be used in severe cases or for antihistamine-resistant reactions [138]. Delayed-onset erythema and edema are often manifestations of type IV hypersensitivity, a granulomatous reaction mediated by T lymphocytes. Antihistamines are generally ineffective, and removal of the allergen is usually the only effective intervention.

MATERIAL DISPLACEMENT:

Finding injected material at non-injected sites indicates material displacement, an occurrence with a very low probability. Filler migration can result from poor injection technique, high filler volumes, pressurized injections, and external pressures, such as gravity, muscle action, and excessive massage following injection. Semi-permanent and permanent filler materials are more prone to migration. If necessary, radical surgical excision is the preferred treatment option.

Conclusions

In aesthetic medicine, the rapid adoption of facial injectable fillers demonstrates their efficacy in addressing age-related volume loss and contour deformities, in which material properties and injection techniques play pivotal roles in determining clinical outcomes. HA fillers remain the benchmark for immediate volume restoration owing to their favorable safety profile and adaptability; however, their temporary effects necessitate repeated administrations, and improper superficial injection can result in the Tyndall effect. Collagen-stimulating agents, including PCL, PLLA, and CaHA, offer more durable solutions by stimulating neocollagenesis, with CaHA demonstrating particular effectiveness in HIV-associated lipoatrophy, and PLLA requiring precise reconstitution to minimize nodule formation. Permanent fillers, such as PMMA and silicone, while providing long-lasting results, carry elevated risks of granuloma formation and material migration, mandating rigorous patient selection. Autologous alternatives, including fat grafts and PRP, exhibit superior biocompatibility but present challenges in graft viability standardization and procedural consistency.

The prevention and management of complications, particularly vascular occlusion, infection, and nodule development, demand thorough anatomical knowledge, especially of high-risk zones, such as the angular and supratrochlear arteries, coupled with meticulous technique using blunt cannulas, pre-injection aspiration, and conservative volume administration. Emerging innovations in bioengineered fillers, enhanced crosslinking technologies, and stem cell-enhanced autologous materials promise to advance the field, although additional long-term safety data and standardized protocols remain imperative for optimizing clinical practice. Ultimately, the successful application of facial injectable fillers hinges on a comprehensive understanding of material science, precise anatomical expertise, and judicious clinical judgment to achieve optimal aesthetic outcomes while minimizing adverse events.