2Department of Biomedical Research,
3Division of Oculofacial Plastic and Reconstructive Surgery, Department of Ophthalmology,
Correspondence Address: Dr. Wendy W. Lee, Division of Oculofacial Plastic and Reconstructive Surgery, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami-Miller School of Medicine, 900 NW 17th St, Miami, FL 33136, USA. E-mail: email@example.com
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Soft tissue fillers are a mainstay in contemporary, minimally invasive facial rejuvenation procedures owing to timely results and minimal recovery period. Although associated with a low complication rate, soft tissue fillers are not without risk. Complications range from mild superficial skin irregularities to granuloma formation to vascular occlusion leading to skin necrosis or even blindness. Fillers vary in composition, elasticity, hydrophilicity and duration of effect that is tailored to specific cosmetic indications. Selecting the right product for the desired effect can cut down on unwanted outcomes. Severe adverse events can be avoided with safe injection technique, early recognition of symptoms and a thorough knowledge of the local anatomy. This review outlines several complications all providers should recognize and discusses strategies for their prevention and management.
Fillers, hyaluronic acid, rejuvenation, periorbital, aesthetic, skin necrosis, complications, blindness
Soft tissue fillers have become an increasingly popular intervention for facial rejuvenation over the past two decades with quick results, minimal recovery time and relatively low complication rate. Since their approval by the FDA in 2004, the number of hyaluronic acid (HA) filler injections performed in the United States has steadily risen to nearly 2.7 million procedures per year as of 2018. As a naturally occurring component of skin and connective tissue, HA is highly biocompatible and non-immunogenic. HA is a favored choice for patients with little to no history with injectables as its effects are temporary, lasting between 6 to 24 months with natural degradation. This process can be accelerated with the use of hyaluronidase providing some ability to reverse unwanted effects.
While soft tissue fillers and HA in particular are non-incisional and less invasive than other interventions for facial rejuvenation, they still carry a number of risks when performed without proper precautions. In the United States, soft tissue filler injections are performed by a wide variety of health care providers, including but not limited to facial plastic surgeons, dermatologists, oculoplastic surgeons, plastic surgeons and the nurse practitioners and physician assistants working under their supervision. While such providers may be fully licensed to perform these procedures, there are considerable differences in training, familiarity with relevant anatomy, and ability to manage complications. Furthermore, the black market in cosmetic fillers and ready availability of unlicensed injectors provides a steady source of complications that licensed providers should be prepared to encounter[2,3]. Between 2013 and 2017 over 2800 reported adverse events occurred in the United States according to FDA databases.
Complications vary and range from the mild, self-resolving ecchymoses to the more persistent irregular surface contours, festoons, and the bluish hue (Tyndall effect) seen with superficial filler placement. Severe granulomas have also been seen long after filler injection. The most severe complications are due to filler vascular occlusion, which can result in skin necrosis and sometimes irreversible vision loss. This review focuses on filler-associated complications that are most commonly encountered by ophthalmologists and oculoplastic surgeons, and addresses various preventative and management strategies.
A thorough knowledge of the local anatomy, use of safe injection techniques and timely recognition of symptoms can help minimize the risk of the most severe complications. The face and periorbita are supplied by a rich network of blood vessels that communicate through complex anastomoses. Iatrogenic perforation or cannulation of the arterial wall during filler injection can introduce emboli that may cause vaso-occlusion either up- or downstream of the site of injection.
Particularly high-risk zones for vascular complications include the glabella, temporalis fossa, tear trough, midface, nasolabial grooves, and nasal dorsum owing to the large vessels in these areas [Figure 1]. In the glabellar region, the supratrochlear branch of the ophthalmic artery exits along the orbital rim approximately 2 cm lateral to midline superficial to the corrugator and deep to the orbicularis and frontalis, before becoming more superficial and entering the subcutaneous plane 2 cm above the orbital rim. The supraorbital branch of the ophthalmic artery exits along the orbital rim through the supraorbital notch approximately 3 cm lateral to midline. Similar to the supratrochlear artery, the supraorbital artery courses deep to the orbicularis and frontalis before entering the subcutaneous plane anywhere from 2 to 6 cm above the orbital rim[8,9].
Figure 1. Vascular anatomy relevant to cosmetic filler injection and their relation to commonly targeted zones including the forehead, glabella, temporalis fossa, tear trough, midface, nasolabial groove and nasal dorsum
The temporalis fossa consists of skin, subcutaneous fat, temporoparietal fascia, superficial and deep temporal fascia surrounding loose areolar tissue, temporalis and periosteum. The frontal branch of the superficial temporal artery courses within the temporoparietal fascia approximately 2 cm superior and lateral to the peak of the brow. The middle temporal vein and the temporal branch of the facial nerve also course near this region, posing the additional risk of pulmonary embolism and nerve injury. There is also a connection between the temporal fossa and the orbit. The zygomatico-temporal artery connects the anterior deep temporal artery to the lacrimal artery and runs through the zygomatico-temporal foramen. This foramen is located on the posterior surface of the zygomatic bone. Filler injected in the region of this foramen could potentially travel directly into the orbit via this route.
In the tear trough and midface regions, the infraorbital artery and nerve emerge through the infraorbital foramen approximately 3 cm lateral to midline just inferior to the orbital rim[11,12]. Along the nasolabial groove, the facial artery and its branches course in a highly variable pattern. The facial artery can be found medial, lateral or crossing the nasolabial folds. On average it is found 1.7 mm medial to the folds at the upper middle third and 0.3 mm medial at the lower middle third. The inferior alar artery and lateral nasal artery branch off from the facial artery at the level of the ala. At the takeoff of the lateral nasal artery, the facial artery becomes more superficial and continues as the angular artery, which crosses the nasojugal groove medially where it is prone to injury during tear trough injections.
After branching into the inferior alar branch and lateral nasal artery, the angular artery continues towards the medial canthus and connects to the dorsal nasal arterial system. The nasal dorsum contains a larger arterial and venous system superficial to nasal musculature in the subcutaneous plane. Sparse vascular networks are located within the areolar layer, including a marginal artery, which courses over the lower lateral cartilage caudal border, and the dorsal nasal artery, a terminal branch of the ophthalmic artery that courses above the muscular layer. Both of these arteries course superficially towards the nasal tip. Each of the arteries listed above have a connection with the ophthalmic and central retinal arteries so injection in each of these areas carries the risk of blindness.
A safe injection begins with selecting the appropriate needle. We advocate the use of smaller needles such as 30 G for injecting into the superficial and mid-dermis, and 27 G for deeper injections. Some injectors recommend the use of large (25 or 22 G) blunt cannulas as they may provide a lower risk of iatrogenic vessel puncture. After the patient has been properly cleansed and anesthetized, digital pressure can be used to mark and occlude vessels at anatomic landmarks to prevent inadvertent puncture and back flow[14,15]. Needles should be introduced perpendicular or parallel to vessels with the tip pointed towards the direction of arterial flow. If a cannula is being used, it should always be parallel to the vessel. Prior to injecting, the syringe is gently aspirated to ensure no blood return, though the absence does not guarantee a vessel has not been punctured. The product is then introduced at low flow to avoid overcoming mean arterial pressure should intra-arterial cannulation occur. Keeping the needle in constant motion during injection will also help prevent product from depositing inside a vessel. If resistance is felt, then the needle should be repositioned.
As product is injected, the needle tip should be maintained at a depth to minimize contact with any vessels. The appropriate depth depends on the region being treated. In the glabella the needle tip is kept either superficially in the dermis or deep to the frontalis muscle to avoid vessels in the subcutaneous plane. In the temporalis fossa, filler is placed under the temporalis muscle to avoid vessels coursing in the temporoparietal fascia. As an alternative, a cannula can be used in more superficial tissues of the temple. In the tear trough and midface, filler should be placed just above the periosteum with special care medially where the infraorbital canal is located. If filler is needed medially, it can be injected laterally then massaged into place.
Safely injecting along the nasolabial groove can be challenging due to the variable course of the facial artery. In the lower two-thirds, the facial artery generally runs at the muscular plane or deeper. We therefore advocate keeping the needle tip in the superficial subcutaneous plane in this region and then moving deeper to the preperiosteal plane near and above the alar base. At the nasal dorsum the vascular network is located entirely in the subcutaneous plane so injections are kept deep in the preperichondrial and preperiosteal planes.
Vascular compromise must be treated urgently once recognized. All filler procedures must be performed with a “filler crash cart” in the immediate vicinity. This kit should contain at minimum 10 vials of unexpired hyaluronidase (e.g., Hylenex, Halozyme Therapeutics, San Diego, CA; Vitrase, Bausch & Lomb, Irvine, CA). Other items recommended by many providers include aspirin to prevent clot propagation, and warm compresses and nitroglycerin to promote vasodilation. A quick referral system for ophthalmic care should be in place in the event the ophthalmic artery is injured.
Vascular injury can cause a range of complications. Early signs that an artery has been punctured include the appearance of blood upon aspiration, formation of a hematoma, skin blanching or discoloration, and intense pain at the injection site. Should any of these occur, the procedure must be aborted immediately. If not promptly recognized, continued injection after intra-arterial cannulation can lead to vascular occlusion resulting in skin necrosis or worse, vision loss. Skin necrosis occurs in < 0.001%-0.5% of patients but accounts for 43% of serious complications related to soft tissue filler injections in the MAUDE database. Early on the skin takes on a blanched then mottled and dusky appearance in the distribution of the injured vessel [Figure 2]. The surrounding area may also appear erythematous.
Figure 2. A 38-year old female developed pain, redness and swelling of the left cheek hours after Radiesse injection to the zygoma for midface augmentation. She came to our care two days later. Note the erythema and dusky appearance to the skin in the distribution of the infraorbital artery and facial artery. The patient developed pustules and sloughing the following day. She was treated with aspirin, topical nitroglycerin, oral prednisone, intradermal sodium thiosulfate, hyperbaric oxygen and manual debridement with gradual improvement in tissue perfusion over two weeks and minimal scar tissue buildup
Emboli can also travel retrograde up through the ophthalmic artery resulting in ocular complications. The first reported case of vision loss due to cosmetic soft tissue filler injection occurred in 1988 and was due to retinal artery occlusion. These patients report sudden profound unilateral vision loss, but may have preservation of central vision if the cilioretinal artery is spared. Emboli traveling to other branches of the ophthalmic artery can result in ischemic optic neuropathy presenting with altitudinal vision loss[23,24] or oculomotor nerve palsy presenting with diplopia and in some cases ptosis[25-27]. Complete occlusion of the ophthalmic artery results in orbital infarction syndrome which is characterized by severe orbital pain, vision loss, loss of extraocular motility and ptosis. On ophthalmic exam these patients also demonstrate hypotony, corneal edema and persistent ocular inflammation owing to poor perfusion of all ocular structures[28-30]. The number of ophthalmic complications related to cosmetic filler continues to rise with the growing demand for these procedures. In the period between January 2015 and September 2018, there were 48 published cases of filler induced ophthalmic complications; the majority were related to vision loss.
Certain fillers are associated with a greater risk of vascular compromise owing to differences in particle size, viscosity, cohesivity and effect on inflammation and clotting [Table 1][16,32-35]. The incidence of vascular occlusion from hyaluronic acid fillers has been reported to be approximately one tenth the overall incidence from all fillers, which includes polymethyl-methacrylate microspheres (Bellafill, Suneva Medical, San Diego, CA), calcium hydroxylapatite (e.g., Radiesse, Merz Pharmaceuticals, Greensboro, North Carolina) and poly-L-lactic acid (e.g., Sculptra, Valeant Aesthetics, Bridgewater, New Jersey). The risk is also highest from injections of the glabellar and nasolabial regions[19,37]. If a hyaluronic acid product was injected, the area should be immediately flooded with injections of hyaluronidase. While allergic reactions to hyaluronidase have been reported, in the acute setting the benefits of this therapy far outweigh the risks. For other products topical nitroglycerin can be considered and warm compresses can be rapidly applied, and if available the patient can be referred for hyperbaric oxygen. Few reports suggest sodium thiosulfate can be used to dissolve calcium hydroxylapatite[39,40]. However, apart from injection of hyaluronidase, no other therapy has been proven effective. There is no consensus on how to treat vision loss from filler-associated vascular occlusion, though anterior chamber paracentesis, ocular massage, hyperbaric oxygen and retrobulbar hyaluronidase injection have all been tried[37,42]. Fortunately, with proper attention to anatomy vascular complications are exceedingly rare.
Summary of hyaluronic acid dermal fillers currently commercially available in the United States
|Product||Site||[HA] (mg/mL)||G' (Pa)||Duration (months)|
|Belotero Balance||Superficial - mid-dermis||22.5||30||6|
|Restylane-L||Superficial - mid-dermis||20||565||6|
|Restylane||Medium - deep||20||544||9|
|Restylane Silk||Superficial - sub-mucosal||20||344||6|
|Restylane Lyft||Medium - deep||20||545||9|
|Restylane Refyne||Medium - deep||20||47||12|
|Restylane Defyne||Medium - deep||20||260||12|
|Restylane Kysse||Superficial- sub-mucosal||20||156||12|
|Juvéderm Ultra XC||Superficial - medium||24||207||12|
|Juvéderm Volbella XC||Superficial - medium||15||274||12|
|Juvéderm Vollure XC||Medium - deep||17.5||317||18|
|Juvéderm Voluma XC||Medium - deep||20||353||24|
|Juvéderm Ultra Plus XC||Medium - deep||24||244||12|
|Revanesse Versa Plus||Medium - deep||28||130||12|
|Teosyal RHA 2||Superficial - mid-dermis||23||144||15|
|Teosyal RHA 3||Medium - deep||23||184||15|
|Teosyal RHA 4||Deep - sub-cutaneous||23||296||15|
There are four basic injection techniques associated with dermal fillers. The most basic technique is threading, which involves the application of a continuous line of filler injected in a retrograde fashion to correct discrete rhytids. The crosshatching technique builds upon this and involves continuous overlapping horizontal and vertical lines to build volume. The third technique is fanning, which involves drawing filler lines in a fan-shaped projection. Finally, serial puncture involves the injection of discreet aliquots of product to correct deep deformities.
Superficial irregularities are commonly encountered in regions with minimal subcutaneous fat. To avoid this complication, filler must be placed deeply. In the tear trough region, we use a serial puncture technique to advance the needle to the periosteum along the inferior orbital rim and deliver small boluses of product working from medial to lateral. Similarly, in the temporalis fossa, we inject deeply under the fascia of the temporalis muscle in the area of maximal volume loss attempting to avoid vessels and nerves while providing a nice contour. In areas that require more superficial injection such as along the nasolabial groove, using hyaluronic acid fillers with higher cohesivity will diminish surface irregularities. Any lumps or bumps noticed early on are addressed with manual massage, while persistent irregularities generally must be dissolved with hyaluronidase.
Festoons or chronic fluid collections often become more noticeable following filler injection with particular hydrophilic hyaluronic acids. Tear trough filler is particularly prone to this complication and it is therefore important to select a product with low water affinity such as Restylane-L (Galderma, Lausanne, Switzerland).
The Tyndall effect is characterized by a blue-grey discoloration of filler placed superficially under the skin. This occurs primarily in the tear trough region where there is minimal subcutaneous fat and the overlying skin is very thin. The phenomenon is due to the scattering of blue light as it passes through small particles in suspension[44,45]. As all fillers are similarly prone to this complication, the primary preventative measure is deep injection. Belotero Balance (Merz, Frankfurt, Germany) is made with varying particle sizes, a product characteristic thought to decrease the chances of the Tyndall effect.
Granulomas may appear anywhere from 6 to 24 months after injection, and is estimated to occur in 0.1%-1% of patients. Presentation usually consists of a constellation of swelling, tenderness, erythema and possible suppuration[19,47]. The foreign body reaction results in prolonged inflammation that results in the formation of a nodule comprised of macrophages producing inflammatory products. HA fillers reinforced with hydroxyethyl-methacrylate fragments have been associated with late-onset granuloma formation. It is postulated that impurities and surface irregularities associated with formulations containing particles < 20 µm in size, are phagocytosed which propagates granuloma formation[47,50-52]. Granulomas typically resolve within two years without the need for intervention, but if the lesion persists can be treated with intralesional corticosteroids or surgical excision. Supplemental laser resurfacing or dermabrasion can help improve superficial surface irregularities. Attempt at dissolving the granulomas with hyaluronidase is also a good option.
Infections, while rare, can present in a variety of forms, ranging from erythematous nodules to abscesses. The most common culprits are usually bacterial skin flora (Streptococcus pyogenes and Staphylococcus aureus), or in some cases herpes simplex virus[18,48,54]. In some cases, latent infections or atypical bacteria can be explained by biofilm formation. In the event of an abscess, incision and drainage is indicated followed by empiric antibiotics to cover the previously mentioned bacteria. Prophylaxis for herpes simplex infections is indicated for patients with a history of cold sore outbreaks.
With the growing number of filler injections used, awareness and prevention of ocular and facial complications is paramount. While the majority are self-resolving, such as ecchymoses at the injection site, ocular complications such as irreversible blindness and orbital and ocular ischemia are detrimental to patients’ visual prognosis and general quality of life. Through a strong grasp of the local anatomy, periodicity and presentation of complications, safe technique and knowledge of the available formulations on the market, these adverse events can be mitigated or prevented completely.
Conceptualization, writing, and editing of this manuscript: Zein M, Tie-Shue R, Pirakitikulr N, Lee WWAvailability of data and materials
Not applicable.Financial support and sponsorship
This work was supported in part by the NIH Center Core (P30EY014801). The sponsor or funding organizations had no role in the design or conduct of this research.Conflicts of interest
All authors declared that there are no conflicts of interest.Ethical approval and consent to participate
Not applicable.Consent for publication
All photographs were obtained and used with consent.Copyright
© The Author(s) 2020.
1. American Society of Plastic Surgeons: 2018 Plastic Surgery Statistics Report. Available from: https://www.plasticsurgery.org/documents/News/Statistics/2018/plastic-surgery-statistics-full-report-2018.pdf. [Last accessed on 5 Aug 2020].
2. Chayangsu O, Wanitphakdeedecha R, Pattanaprichakul P, Hidajat IJ, Evangelista KER, et al. Illegal injectable fillers: the adverse effects comparison study. J Cosmet Dermatol 2020; doi: 10.1111/jocd.13492.DOIPubMed
3. Brennan R, Wells JSG, Van Hout M. “Saving face”: an online study of the injecting use of diy botox and dermal filler kits. Plast Surg (Oakv) 2018;26:154-9.DOIPubMed PMC
4. Beauvais D, Ferneini EM. Complications and litigation associated with injectable facial fillers: a cross-sectional study. J Oral Maxillofac Surg 2020;78:133-40.DOIPubMed
5. Rayess HM, Svider PF, Hanba C, Patel VS, DeJoseph LM, et al. A cross-sectional analysis of adverse events and litigation for injectable fillers. JAMA Facial Plast Surg 2018;20:207-14.DOIPubMed PMC
6. Tansatit T, Apinuntrum P, Phetudom T. A dark side of the cannula injections: how arterial wall perforations and emboli occur. Aesthetic Plast Surg 2017;41:221-7.DOIPubMed
7. Scheuer JF 3rd, Sieber DA, Pezeshk RA, Campbell CF, Gassman AA, et al. Anatomy of the facial danger zones: maximizing safety during soft-tissue filler injections. Plast Reconstr Surg 2017;139:50e-8.DOIPubMed
8. Kleintjes WG. Forehead anatomy: arterial variations and venous link of the midline forehead flap. J Plast Reconstr Aesthet Surg 2007;60:593-606.DOIPubMed
9. Erdogmus S, Govsa F. Anatomy of the supraorbital region and the evaluation of it for the reconstruction of facial defects. J Craniofac Surg 2007;18:104-12.DOIPubMed
10. Jang JG, Hong KS, Choi EY. A case of nonthrombotic pulmonary embolism after facial injection of hyaluronic acid in an illegal cosmetic procedure. Tuberc Respir Dis (Seoul) 2014;77:90-3.DOIPubMed PMC
11. Aziz SR, Marchena JM, Puran A. Anatomic characteristics of the infraorbital foramen: a cadaver study. J Oral Maxillofac Surg 2000;58:992-6.DOIPubMed
12. Ercikti N, Apaydin N, Kirici Y. Location of the infraorbital foramen with reference to soft tissue landmarks. Surg Radiol Anat 2017;39:11-5.DOIPubMed
13. Yang HM, Lee JG, Hu KS, Gil YC, Choi YJ, et al. New anatomical insights on the course and branching patterns of the facial artery: clinical implications of injectable treatments to the nasolabial fold and nasojugal groove. Plast Reconstr Surg 2014;133:1077-82.DOIPubMed
14. Scheuer JF 3rd, Sieber DA, Pezeshk RA, Gassman AA, Campbell CF, et al. Facial danger zones: techniques to maximize safety during soft-tissue filler injections. Plast Reconstr Surg 2017;139:1103-8.DOIPubMed
15. Tansatit T, Moon HJ, Apinuntrum P, Phetudom T. Verification of embolic channel causing blindness following filler injection. Aesthetic Plast Surg 2015;39:154-61.DOIPubMed
16. DeLorenzi C. Complications of injectable fillers, part 2: vascular complications. Aesthet Surg J 2015;34:584-600.DOIPubMed
17. Breithaupt AD, Jones DH, Braz A, Narins R, Weinkle S. Anatomical basis for safe and effective volumization of the temple. Dermatol Surg 2015;41 Suppl 1:S278-83.DOIPubMed
18. Sclafani AP, Fagien S. Treatment of injectable soft tissue filler complications. Dermatol Surg 2009;35 Suppl 2:1672-80.DOIPubMed
19. Daines SM, Williams EF. Complications associated with injectable soft-tissue fillers: a 5-year retrospective review. JAMA Facial Plast Surg 2013;15:226-31.DOIPubMed
20. Li X, Du L, Lu JJ. A novel hypothesis of visual loss secondary to cosmetic facial filler injection. Ann Plast Surg 2015;75:258-60.DOIPubMed PMC
21. Shin H, Lemke BN, Stevens TS, Lim MJ. Posterior ciliary-artery occlusion after subcutaneous silicone-oil injection. Ann Ophthalmol 1988;20:342-4.PubMed
22. Doguizi S, Sekeroglu MA, Anayol MA, Yilmazbas P. Central retinal artery occlusion with double cilioretinal artery sparing. Retin Cases Brief Rep 2019;13:75-8.DOIPubMed
23. Chen Y, Wang W, Li J, Yu Y, Li L, et al. Fundus artery occlusion caused by cosmetic facial injections. Chin Med J (Engl) 2014;127:1434-7.PubMed
24. Kim A, Kim SH, Kim HJ, Yang HK, Hwang JM, et al. Ophthalmoplegia as a complication of cosmetic facial filler injection. Acta Ophthalmol 2016;94:e377-9.DOIPubMed
25. Bae IH, Kim MS, Choi H, Na CH, Shin BS. Ischemic oculomotor nerve palsy due to hyaluronic acid filler injection. J Cosmet Dermatol 2018;17:1016-8.DOIPubMed
26. Dagi Glass LR, Choi CJ, Lee NG. Orbital complication following calcium hydroxylapatite filler injection. Ophthalmic Plast Reconstr Surg 2017;33:S16-7.DOIPubMed
27. Myung Y, Yim S, Jeong JH, Kim BK, Heo CY, et al. The classification and prognosis of periocular complications related to blindness following cosmetic filler injection. Plast Reconstr Surg 2017;140:61-4.DOIPubMed
28. Kim YJ, Kim SS, Song WK, Lee SY, Yoon JS. Ocular ischemia with hypotony after injection of hyaluronic acid gel. Ophthalmic Plast Reconstr Surg 2011;27:e152-5.DOIPubMed
29. Ramesh S, Fiaschetti D, Goldberg RA. Orbital and ocular ischemic syndrome with blindness after facial filler injection. Ophthalmic Plast Reconstr Surg 2018;34:e108-10.DOIPubMed
30. Silva MT, Curi AL. Blindness and total ophthalmoplegia after aesthetic polymethylmethacrylate injection: case report. Arq Neuropsiquiatr 2004;62:873-4.DOIPubMed
31. Beleznay K, Carruthers JDA, Humphrey S, Carruthers A, Jones D. Update on avoiding and treating blindness from fillers: a recent review of the world literature. Aesthet Surg J 2019;39:662-74.DOIPubMed
32. Kim YK, Jung C, Woo SJ, Park KH. Cerebral angiographic findings of cosmetic facial filler-related ophthalmic and retinal artery occlusion. J Korean Med Sci 2015;30:1847-55.DOIPubMed PMC
33. Park KH, Kim YK, Woo SJ, Kang SW, Lee WK, et al. Iatrogenic occlusion of the ophthalmic artery after cosmetic facial filler injections: a national survey by the Korean Retina Society. JAMA Ophthalmol 2014;132:714-23.DOIPubMed
34. Barbucci R, Lamponi S, Magnani A, Poletti LF, Rhodes NP, et al. Influence of sulfation on platelet aggregation and activation with differentially sulfated hyaluronic acids. J Thromb Thrombolysis 1998;6:109-15.DOIPubMed
35. Braverman IM, Keh-Yen A. Ultrastructure of the human dermal microcirculation. IV. Valve-containing collecting veins at the dermal-subcutaneous junction. J Invest Dermatol 1983;81:438-42.DOIPubMed
36. Beleznay K, Humphrey S, Carruthers JD, Carruthers A. Vascular compromise from soft tissue augmentation: experience with 12 cases and recommendations for optimal outcomes. J Clin Aesthet Dermatol 2014;7:37-43.PubMed PMC
37. Narins RS, Jewell M, Rubin M, Cohen J, Strobos J. Clinical conference: management of rare events following dermal fillers--focal necrosis and angry red bumps. Dermatol Surg 2006;32:426-34.DOIPubMed
38. Landau M. Hyaluronidase caveats in treating filler complications. Dermatol Surg 2015;41 Suppl 1:S347-53.DOIPubMed
39. Rullan PP, Olson R, Lee KC. The use of intralesional sodium thiosulfate to dissolve facial nodules from calcium hydroxylapatite. Dermatol Surg 2019; doi: 10.1097/DSS.000000000000223.DOI
40. Robinson DM. In vitro analysis of the degradation of calcium hydroxylapatite dermal filler: a proof-of-concept study. Dermatol Surg 2018;44 Suppl 1:S5-9.DOIPubMed
41. Hwang CJ. Periorbital injectables: understanding and avoiding complications. J Cutan Aesthet Surg 2016;9:73-9.DOIPubMed PMC
42. Chesnut C. Restoration of visual loss with retrobulbar hyaluronidase injection after hyaluronic acid filler. Dermatol Surg 2018;44:435-7.DOIPubMed
43. Sundaram H, Rohrich RJ, Liew S, Sattler G, Talarico S, et al. Cohesivity of hyaluronic acid fillers: development and clinical implications of a novel assay, pilot validation with a five-point grading scale, and evaluation of six u.s. food and drug administration-approved fillers. Plast Reconstr Surg 2015;136:678-86.DOIPubMed
44. DeLorenzi C. Complications of injectable fillers, part I. Aesthet Surg J 2013;33:561-75.DOIPubMed
45. Rootman DB, Lin JL, Goldberg R. Does the tyndall effect describe the blue hue periodically observed in subdermal hyaluronic acid gel placement? Ophthalmic Plast Reconstr Surg 2014;30:524-7.DOIPubMed
46. Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg 2007;33 Suppl 2:S168-75.DOIPubMed
47. Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M, Zimmermann U, et al. Foreign body granulomas after all injectable dermal fillers: part 1. Possible causes. Plast Reconstr Surg 2009;123:1842-63.DOIPubMed
48. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Clin Cosmet Investig Dermatol 2013;6:295-316.DOIPubMed PMC
49. Capodiferro S, Sportelli P, Limongelli L, Dell’Olio F, Tempesta A, et al. Delayed sclerosing granulomatous reaction to dermal filler injection of poly-hydroxyethyl-methacrylate suspended in hyaluronic acid: histochemical and confocal laser scanning microscopical analysis. Clinical Case Rep 2019;7:2215-9.DOIPubMed PMC
50. El-Khalawany M, Fawzy S, Saied A, Al Said M, Amer A, et al. Dermal filler complications: a clinicopathologic study with a spectrum of histologic reaction patterns. Ann Diagn Pathol 2015;19:10-5.DOIPubMed
51. Ledon JA, Savas JA, Yang S, Franca K, Camacho I, et al. Inflammatory nodules following soft tissue filler use: a review of causative agents, pathology and treatment options. Am J Clin Dermatol 2013;14:401-11.DOIPubMed
52. Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesthetic Plast Surg 2003;27:354-66. discussion 67PubMed
53. Lafaille P, Benedetto A. Fillers: contraindications, side effects and precautions. J Cutan Aesthet Surg 2010;3:16-9.DOIPubMed PMC
54. Alijotas-Reig J, Fernandez-Figueras MT, Puig L. Inflammatory, immune-mediated adverse reactions related to soft tissue dermal fillers. Semin Arthritis Rheum 2013;43:241-58.DOIPubMed
55. Dumitrascu DI, Georgescu AV. The management of biofilm formation after hyaluronic acid gel filler injections: a review. Clujul Med 2013;86:192-5.PubMed PMC
56. Rohrich RJ, Bartlett EL, Dayan E. Practical approach and safety of hyaluronic acid fillers. Plast Reconstr Surg Glob Open 2019;7:e2172.DOIPubMed PMC
57. Bogdan Allemann I, Baumann L. Hyaluronic acid gel (Juvederm) preparations in the treatment of facial wrinkles and folds. Clin Interv Aging 2008;3:629-34.DOIPubMed PMC
58. Lee W, Hwang SG, Oh W, Kim CY, Lee JL, et al. Practical guidelines for hyaluronic acid soft-tissue filler use in facial rejuvenation. Dermatol Surg 2020;46:41-9.DOIPubMed
59. Ballin AC, Cazzaniga A, Brandt FS. Long-term efficacy, safety and durability of Juvederm(R) XC. Clin Cosmet Investig Dermatol 2013;6:183-9.DOIPubMed PMC
60. Öhrlund Å. Evaluation of rheometry amplitude sweep cross-over point as an index of flexibility for ha fillers. J Cosmet Dermatol Sci Appl 2018;8:47-54.DOI
Zein M, Tie-Shue R, Pirakitikulr N, Lee WW. Complications after cosmetic periocular filler: prevention and management. Plast Aesthet Res 2020;7:44. http://dx.doi.org/10.20517/2347-9264.2020.133