Clinical data on injectable tissue fillers: a review

Figures & data

Table 1. Overview of the most frequently observed types of complications.

Short-term	Swelling, bruising, direct hypersensitivity, necrosis
Mid-term	Lumpiness, increased sensitivity, sensitization reaction, infection, granuloma or enlargement of implant, mild prominence of implant, occasional pain when scrubbing face
Long-term	Nodule formation, migration of the product, accumulation of the product, persistent swelling or redness, persistent pain, delayed hypersensitivity reactions after retreatment

Table 2. Type of injectable tissue fillers.

Type of filler	Duration of correction	Filler material
Biodegradable fillers	± 6 months	Bovine collagen
		Human-derived bioengineered collagen
		Hyaluronic acid
Semi-permanent fillers	7–24 months	Hyaluronic acid (cross linked)
		Polyvinyl alcohol 8%
		Porcine collagen gel (cross linked)
		Carboxymethylcellulose & polyethylene oxide
		Poly-L-Lactic acid, non-animal derived
		Synthetic calcium hydroxyapatite suspension in a gel carrier
Permanent fillers	>24 months	Polymethyl methacrylate
		Polyethyl methacrylate (copolymer of hydroxyethylmethacrylate and ethylmethacrylate in hyaluronic acid)
		Polyacrylamid solution
		Polyalkylimide solution
		Silicone

Table 3. Type of studies and complications of semi-permanent tissue fillers.

Filler material ^†	Study, participants (n), follow-up	Complications	Cause of complication	Ref.
Hyaluronic acid (cross-linked)	Prospective study (n = 15), 6 months follow-up	All patients noted short-term complications	Not specified/Not known	[25]
	Prospective study (n = 76), 6 months follow-up	Mild short-term complications, such as bruising, lumps and bumps, edema	Treatment related	[73]
	Prospective study (n = 150), 6 months follow-up ^‡	Short- and mid-term reactions. Treatment-related adverse events tended to occur more frequently on the non-animal-stabilized filler treated site	Treatment related	[74]
	Prospective study (n = 248), 6 months follow-up	Short-term complications were observed in more than half of the subjects. In 2 cases treatment of the adverse event was necessary	Treatment related	[75]
	Prospective study (n = 439), 6 months follow-up ^‡,§	Most mild or moderate adverse events, in 1 subject an abscess was reported after 4 months	Treatment related	[27,201]
	Prospective study (n = 56), 6 months follow-up	Mild injection site reactions	Treatment related	[76]
	Prospective study (n = 60), 6 months follow-up ^‡	Short term complications erythema, edema/swelling, bruising, pruritus, pain, tenderness	Treatment related	[77]
	Prospective study (n = ?), 6 months follow-up	No adverse events		[78]
	Prospective study (n = 40), 12 months follow-up ^‡	Mild adverse events: application site erythema was observed in approximately 40% of the subjects, hematoma, swelling, induration, numbness. Moderate adverse events: infection (5%), hematoma (5%), pain (5%). Severe adverse events pain (5%)	Treatment related	[79]
	Prospective study (n = 57), 12 months follow-up	Short-term complications in 30 cases	Treatment related	[80]
	Prospective studies (n = 72), 12 months follow-up	Short-term complications in 7 cases. In 2 cases migration and swelling was observed after 8 weeks	Treatment related	[81]
	Prospective studies (n = 709), 12 months follow-up	Delayed skin reaction in 3 cases	Product related	[82]
	Prospective study (n = 208), 12 months year follow-up ^¶	Short-term complications resolved in 7 days. Injection site cellulites occurred in 1 case	Treatment related	[207]
Hyaluronic acid (cross-linked)	Prospective study (n = 60), 18 months follow-up	No reported adverse events		[83]
	Prospective study (n = 75), 18 months follow-up ^#	Short-term complications	Treatment related	[26]
	Prospective study (n = 95), 18 months follow-up	Thirty-four adverse events were reported, only 1 was considered to be related to the treatment	Treatment related	[84]
	Prospective study (n = 36), 3–38 months follow-up^††	Short-term complications in 3 subjects (lumpiness)	Treatment related	[35]
Hyaluronic acid (cross-linked)	Retrospective study (n = 5), 12 months follow-up	One patient experienced a vasovagal episode lasting 3 hours, 1 patient had postoperative pain. In 1 patient the gel migrated	Not specified/not known	[85]
	Retrospective study (n = 4320), 12 months follow-up	Sixteen cases of acute and 18 cases of delayed hypersensitivity reactions	Product related	[86]
	Retrospective study (n = 155), follow-up not specified	Lumps or contour irregularities 11%, bruising 10%, color change 7% and accumulation of fluid 15%	Not specified/not known	[29]
	Retrospective study (n = 286), follow-up not specified	Short-term complications in 14 subjects	Not specified/not known	[87]
	Retrospective study 1999 (n = 144,000), follow-up not specified ^‡‡	Localized hypersensitivity reactions occurring in approximately 1 of every 1400 patients treated. Short-term complications 1 of every 650 patient	Product related	[12]
	Retrospective study 2000 (n = 262,000), follow-up not specified ^‡‡	Hypersensitivity occurred in 1 of every 5000 patients treated	Product related	[12]
Hyaluronic acid (cross-linked)	Various case reports (n = 27)	Granulomatous reactions 10 days to several months past treatment. Arterial embolization resulted in necrosis 2 weeks after treatment. Scleromyxedema 9 months past treatment. Persistent inflammatory reaction. Formation of nodules 5 months past treatment. Infection 1 day after injection. Several cases of inflammatory nodules 1–60 months past treatment	Product and treatment related	[5,22–24,88–92,208]
Porcine collagen gel (cross linked)	Prospective study (n = 149), 6 months follow-up ^§,§§	In 123 of the subjects injection site reactions were observed. Subjects were injected at multiple sites. 326 reactions were reported as mild, 18 as moderate and 3 severe	Product related	[202]
L-Polylactic acid (PLLA), non-animal derived	Prospective study (n = 96), 6 months follow-up	Mild transient bruising was observed in 15% of the patients. Formation of nodules was observed in 56% of the cases	Not specified/not known	[93]
	Prospective study (n = 14), 6 months follow-up ^§§,¶¶	No adverse events		[94]
	Prospective study (n = 30), 6 month follow-up ^¶¶	Short-term complications in 2 subjects	Treatment related	[95]
	Prospective study (n = 61), 6 months follow-up ^¶¶	Two patients developed persistent asymptomatic palpable intradermal papules	Treatment related	[96]
	Prospective study (n = 20), 7 months follow-up	Purpose of the study was to obtain preliminary data on efficacy and safety of the PLLA filler. Injections were given at 1-month intervals (total of 7 treatments). Injection sites were assessed after each treatment. No adverse events		[97]
	Prospective study (n = 50), 12 months follow-up ^¶¶	No adverse events		[98]
	Prospective study (n = 100), 12 months follow-up	Only 54 participants completed the 1 year follow-up. Device related subcutaneous papule at injection site was observed at 13 patients	Product related	[99]
	Prospective study (n = 30), 18 months follow-up	Mainly short-term complication, in some cases nodule formation	Treatment related	[100]
	Prospective study (n = 50), 24 months follow-up ^¶¶	In 22 patients, palpable but non-visible subcutaneous micronodules were observed	Not specified/not known	[101]
	Prospective study (n = 116), 25 months follow-up	Only 1 case of injection site bruising	Treatment related	[102]
	Prospective study (n = 10), 36 months follow-up	Short-term complications	Not specified/not known	[34]
	Prospective study (n = 65), 36 months follow-up	In only a few cases small subcutaneous papules were developed	Treatment related	[103]
Poly-L-Lactic acid (PLLA), non-animal derived	Retrospective study (n = 300), 12–24 months follow-up	Subcutaneous papules in 30 cases. These papules resolved, without treatment in 12–24 months	Treatment related	[104]
	Retrospective study (n = 281), 36 months follow-up	Transient side effects (e.g., bruising) and nodule formation	Treatment related	[105]
Poly-L-Lactic acid (PLLA), non-animal derived	Retrospective study (n = 100), up to 60 months follow-up ^‡‡	Papules observed in one case. Formation of nodules observed in another case after PLLA injections approximately 15 years after the use of silicone. In both case the problems resolved after treatment with triamcinolone injections. One case of diffuse hardening was observed, after treatment with intralesional steroids plus minocycline this was resolved	Treatment related	[32]
L-Polylactic acid (PLLA), non-animal derived	Various case reports (n = 21)	Only mild transient reactions were observed after injection, no adverse events were observed 12 and 48 months past treatment. Orofacial foreign body granulomas were observed 6 months to more than 12 months after treatment. Late-onset facial nodules 12–18 months past treatment	Product and treatment related	[3,54,106–109]
Synthetic calcium hydroxyapatite suspension in a gel carrier	Prospective study (n = 72), 15 months follow-up	Short-term complications occurred in 7 cases. Temporary visible product nodularity occurred in 15 patient, in 2 cases the product had to be removed from the skin	Treatment related	[110]
	Prospective study (n = 40), 18 months follow-up	Ecchymosis and hematoma occurred in 2 of the subjects	Treatment related	[111]
	Prospective study (n = 100), 18 months follow-up	Adverse events reported through 12 months were ecchymosis, edema, erythema, pain, and pruritus. Eighteen months safety data were not available at the time of submission	Not specified/not known	[28]
	Prospective study (n = 117), 6 months follow-up	Mainly short-term adverse events were observed. One nodule was observed	Treatment related	[112]
	Prospective study (n = 113), 6–12 months follow-up	Seven short-term adverse events were observed and resolved within 1 month	Not specified/not known	[113]
	Prospective study (n = 30), 12 months follow-up ^¶¶	Mainly short-term complications were observed, 1 incident of lumpiness	Not specified/not known	[114]
	Prospective study (n = 60), 12 months follow-up	Adverse events were hematomas (n=2) and 1 nodule. The hematomas resolved in a few days, the nodule was treated	Not specified/not known	[115]
	Prospective study (n = 100), 12 months follow-up ^§	Mid-term complications (e.g., contour irregularities, rash) were observed after 14 weeks on 89 injection sites	Not specified/not known	[203]
Synthetic calcium hydroxyapatite suspension in a gel carrier	Prospective study (n = 107), 12 months follow-up	Swelling (74%), redness (70%), bruising (63%), lumps or bumps (6.5%), nodules (2.8%)	Treatment related	[116]
	Prospective study (n = 609), 24 months follow-up	Nodule formation occurred in 48 cases	Not specified/not known	[117]
	Prospective study (n = 102), 36 months follow-up	Only short-term adverse events (e.g., edema, erythema)	Not specified/not known	[33]
Synthetic calcium hydroxyapatite suspension in a gel carrier	Retrospective study (n = 1000), 12–52 months follow-up	Mild and transient adverse events (e.g., edema, erythema)	Treatment related	[36]
Synthetic calcium hydroxyapatite suspension in a gel carrier	Case report (n = 1)	Granulomatous response	Product related	[118]

† Not all studies with the same filler material were performed with the same product from the same manufacturer.

‡ Split face-design: clinical study in which subjects were randomized to contralateral treatment with two types of fillers.

§ Pre-market clinical study.

¶ Summary of Safety and Effectiveness data; follow-up of 12, 18, 24 and 36 months are available [209].

# Data of 30 months study not published yet

†† The follow-up period was different for all the 36 subjects (e.g. for three subjects the follow-up period was 36 months or more, for nine subjects the follow-up was less than 12 months).

‡‡ Anecdotal case reports.

§§ Summary of Safety and Effectiveness data; follow-up of 12,18 and 24 months are available [210, 211]

¶¶ Clinical study with HIV subjects.

Note: For polyvinyl alcohol 8% and carboxymethyl cellulose & polyethylene oxide injectable fillers no information on complications could be found.

Table 4. Type of studies and complications of permanent tissue fillers.

Filler material^†	Study, participants (n)	Complications	Cause of complication	Ref.
PMMA in collagen or carboxymethyl-cellulose	Prospective study (n = 14), 8 months follow-up	No adverse side effects		[48]
	Prospective study (n = 290), 12 months follow-up	Swelling after implantation, longer lasting redness and transparency of the product were observed. In one case an allergic reaction occurred	Product and treatment related	[47]
	Prospective study (n = 1008), 18 months follow-up ^‡	Preliminary results of this study with a 60 months follow-up period (start 2009) adverse events were observed (e.g., lumpiness, swelling, pain, granuloma)	Product and treatment related	[63]
	Prospective study (n = 119), 60 months follow-up	Twenty adverse events, e.g., lumpiness, granuloma, sensitivity at 15 subjects were observed. Previous results (results after 12 months) of this study are described by Cohen in 2004	Treatment related	[61,62]
	Prospective study (n = 118), follow-up period not specified	Acute side effects, like swelling and delayed side effects, e.g., persistent redness	Product and treatment related	[119]
PMMA or carboxymethyl-cellulose	Retrospective study (n = 72), mean follow-up 34 months	Four times nodule formation and once persistent lip pain was reported	Not specified/not known	[120]
PMMA in collagen or carboxymethyl-cellulose	Various case reports (n=43)	Blindness after incorrect injection technique. Granuloma reactions immediate to 48 months past treatment. Necrosis immediate to 7 days after treatment. Nodule formation 1–10 years past treatment. Infection 12 months past treatment. Chronic inflammatory reaction 1–10 years past treatment. Formation of nodules, inflammatory reactions.6 months to 10 years past treatment	Product and treatment related	[16,19,54,55,58,59,121,122]
Polyethyl methacrylate (copolymer HEMA and EMA) in hyaluronic acid	Prospective study (n = 455), 36 months follow-up ^§	Swelling, formation of nodules, redness on average six months after the injection (percentage is not specified)	Not specified/not known	[123]
Polyethyl methacrylate (copolymer HEMA and EMA) in hyaluronic acid	Retrospective study (n = 19), mean follow-up 22.8 ± 18.9 months ^¶	Main adverse reactions were nodules, discoloration, erythema and swelling	Not specified/not known	[124]
	Retrospective study (n = 118), mean follow-up 23.1 ± 22.8 months ^¶	Main adverse reactions were nodules, discoloration, erythema and swelling	Not specified	[125]
Polyethyl methacrylate (copolymer HEMA and EMA) in hyaluronic acid	Various case reports (n = 14)	Granuloma reactions 4–36 months past treatment, nodules 24 months past treatment Several cases of inflammatory nodules 7–48 months past treatment. Keratoacanthoma-like reaction	Product and treatment related	[59,126–130]
Polyacrylamid solution (PAAG)	Prospective study (n = 59), 9 months follow-up	Short-term reactions	Not specified/not known	[49]
	Prospective study (n = 31), 12 months follow-up ^#	Ecchymosis (58%) and small palpable but not visible nudules (29%)	Not specified	[131]
	Prospective study (n = 315), 12 months follow-up	Mild adverse events (e.g., bruising, redness), one infection	Treatment related	[51]
	Prospective study (n = 40,0000), 12 months follow-up ^††	Fifty-five cases of swelling at the injection site, often combined with tingling sensation, redness, pain, purulent secretion or cysts occurred	Treatment related	[50]
	Prospective study (n = 88), 24 months follow-up ^#	Of the initial study population (n= 115) 88 completed the 24 months follow-up. Subcutaneous nodules (n = 3), transient local inflammatory reactions ( n = 3)	Product related	[132]
	Prospective study (n = 290), 24 months follow-up ^#	Treatment-emergent adverse events; product 18.3%, injection procedure 24.5%, injection-site nodules 8.3% and papules 8.6%	Treatment and product related	[133]
	Prospective study (n = 145), 48 months follow-up ^#	Small nodules, one serious adverse event (local infection) 32 months past treatment	Not specified/not known	[64]
Polyacrylamid solution (PAAG)	Prospective study (n = 141),60 months follow-up ^#	Acute adverse events: temporary swelling (18.42%), subcutaneous hematoma (7.9%), localized accumulation of the gel (2.6%). Late adverse events (after 1 year): localized permanent indurations (blebs: 10.52%), migration of the gel (7.9%). Of the initial study population (n= 314) 141 completed the 60 months follow-up. Adverse events in patient who did not complete the follow-up were also reported. These complications were: 8 patients developed localized infection. Two of these patients developed definite abscess 2 weeks after treatment	Treatment related	[134]
	Prospective study (n = 251), 60 months follow-up	A total of 104 adverse events (e.g., edema, gel accumulation, infection) in 73 patients were reported throughout the 60 months follow-up period. Previous results of this study are described by von Buelow (12 and 24 months)	Product and treatment related	[65,135,136]
Polyacrylamid solution (PAAG)	Retrospective study (n = 104), mean time since injection ± 47 months	In 30 subjects the injectable was palpable not visible in the lips. In 3 subjects the gel migrated and formation of edema occurred by 2 subjects	Not specified/not known	[137]
	Retrospective study (n = 542), one day to 60 months follow-up	Abscess formation, displacement of the gel, infection, etc.	Not specified/not known	[138]
Polyacrylamid solution (PAAG)	Various case reports (n = 7)	PAAG material migrated 36–60 months past treatment due to muscular activity or gravity and capsule was broken by incorrect massage or incidental force. Infection one week after injection. Extreme pain 18 months and edema 7 months past treatment. Inflammatory reactions more than 2–36 months after injection	Product and treatment related	[60,139,140]
Polyalkylimide solution	Prospective study (n = 17), 11 months follow-up ^#	Four cases of complications, varying from capsule formation or gel migration to an infection at 1 injection site	Not specified/not known	[52]
	Prospective study (n = 31), 12 months follow-up ^#	Only mild and transient adverse events	Not specified/not known	[53]
	Prospective study (n = 11), 18 months follow-up ^#	Only mild and transient adverse events	Not specified/not known	[141]
	Prospective study (n = 31), 22 months follow-up ^#	Only mild transient adverse events (e.g., bruising, pain, swelling)	Not specified/not known	[142]
	Prospective study (n = 9), 24 months follow-up ^#	Only mild transient adverse events (e.g., modest inflammatory reaction, edema)	Treatment related	[143]
	Prospective study (n = 73), 36 months follow-up ^#	Only swelling after implantation	Treatment related	[144]
	Prospective study (n = 2,000), follow up not specified	In 12 cases staphylococcus infections occurred, of which 3 cases could be directly described to the implanted material	Product related	[145]
Polyalkylimide solution	Retrospective study (n = 4), 24–48 months follow-up ^‡‡	Abscess formation, infection, migration, inflammatory nodules	Product and treatment related	[146]
	Retrospective study (n = 3,196), 24–48 months follow-up	Inflammation and accumulation years after treatment, hardening of the capsule and migration	Not specified/not known	[147]
Polyalkylimide solution	Various case reports (n = 63)	Abscess, late inflammatory reaction, migration of the filler 24 h to 36 months past treatment [148]. Infection, migration and capsule formation 12–36 months past treatment. Inflammatory reactions more than 12 months after injection. Foreign body granuloma 12 months past treatment. Infection to 36 months past treatment. Facial nodules and facial edema 6–52 months after injection with filler	Product and treatment related	[129,148–152]
Silicone	Prospective study (n = 77), 6 months follow-up ^#	No adverse events		[45]
Silicone	Retrospective study (n = 179), 36–84 months follow-up	In 6.2% mild transient complications were observed, and in 2.2% small nodules were observed	Treatment related	[153]
	Retrospective study (n = 235), follow up not specified ^‡‡	Over a period of 20 years 2 cases of complications (local infections) were observed	Not specified/not known	[40]
	Retrospective study (n = 347), follow up not specified ^‡‡	Over a period of 20 years 1 complication (nodule formation) was observed	Not specified/not known	[41]
	Retrospective study (n = 916), follow-up not specified	Overcorrection 1 year past treatment, hyperpigmentation within a few months past treatment	Product related	[154]
	Retrospective study (n = 4,862), follow up not specified ^‡‡	Over a period of 22 years complications (e.g., migration) were observed due to large volumes and contamination. Due to decreasing the injection volume and purifying the silicone gel the incidence of complications decreased considerably over the years	Product and treatment related	[43]
Silicone	Various case reports (n = 586)	Development of pseudo-lymphoma beside silicone related granulomas 60 months past treatment. Severe granulomatous reaction and facial ulceration. Facial nodules, cellulites, ulceration and migration between 5 and 20 years after treatment with silicone injections	Product and treatment related	[44,56,57]

† Not all studies with the same filler material were performed with the same product from the same manufacturer.

‡ This study started in 2009. The interim results covers the 18-month period after treatments.

§ Data from the 60 months follow-up are not yet available. An undefined part of the subjects was injected with another injectable. Results from this study are mixed with results from other studies.

¶ Database: population-based registry for collecting adverse reactions to injectable fillers.

# Clinical study with HIV subjects.

†† Information from questionnaires distributed along with the product and follow-up information from involved physicians was collected into a database.

‡‡ Anecdotal case reports.

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