Introduction
Material and methods
Study protocol and study registration
Information sources, literature search, and eligibility criteria
Data collection and extraction
Risk of bias assessment
Synthesis of results and statistical analysis
Quality of evidence (GRADE)
Results
Study selection and characteristics
Study population
Study (year) Study design | Treatment model Treatment site | Species | Application form | Treatment groups | Follow-up | Outcome parameters |
---|---|---|---|---|---|---|
Mendes (2008) Randomized | Extraction socket UM1 | Holtzman rats | 1% HyA gel (Nikkol; intraoperative) | HyA | 1st–5th, 7th, 21st day | BMP-2 and OPN expression Bone formation |
Carbopol | ||||||
Blood clot | ||||||
Sa (2013) Non-randomized | Extraction socket in healthy and diabetic specimen UM1 | Wistar rats | 0.25, 0.5, 1, 2, 4% HyA gel (Galena; intraoperative) | Carbopol (non-diabetic) | 7th, 14th day | Bone formation |
Carbopol (diabetic) | ||||||
HyA (diabetic) | ||||||
HyA + SWCNT (diabetic) | ||||||
Kim (2016) Randomized | Infected extraction socket LM3 | Beagle dogs | 1% HyA gel (Healon; intraoperative) | HyA | 3rd month | Bone formation |
Blood clot | ||||||
Kim (2019) Randomized | Infected extraction socket LPM3, LPM4 | Beagle dogs | 1% HyA gel (Healon; intraoperative) | ACS | 3rd month | Bone formation |
HyA + ACS | ||||||
rhBMP-2 + ACS | ||||||
Blood clot | ||||||
Lee (2021) Randomized | Infected extraction socket LPM3, LPM4, LM1 | Beagle dogs | 1% HyA gel (Healon; intraoperative) | ACS | 1st, 3rd month | Bone formation |
HyA + ACS | ||||||
DBBM-C | ||||||
HyA + DBBM-C |
Study (year) Study design | Patient characteristics Gender (f/m) Age (years) Health status Smoking status | Inclusion criteria (site) | Site number (no. at baseline/follow-up) | Treatment groups and product details | Application form | Follow-up | Postoperative medication | Outcome parameters |
---|---|---|---|---|---|---|---|---|
Test | Test | |||||||
Control | Control | |||||||
Lower third molar (LM3) | ||||||||
Koray (2014) RCT, split-mouth | 15/19 23.4 ± 3.9 Healthy NR | Bilateral, symmetrically impacted LM3 with total or partial bone cover and comparable surgical difficulty | 34/34 | 50 ml Gengigel HyA spray (0.2%) | Spray 3 × /day for 7 days | 2nd, 7th day | 1 g amoxicillin 2 × 1; 550 mg naproxen 3 × 1 for 4 days | Edema, pain (VAS), trismus |
34/34 | BnzHCl spray | |||||||
Gocmen (2015) RCT | 20/20 26.6 ± 6.3 ASA I-II NR | Vertically positioned, erupted/half impacted LM3 without bone retention | 20/20 | 0.2 ml Gengigel Prof HyA gel (0.8%) | Intra-operative | 7th day | NR | Pain (VAS), trismus, inflammatory response, oxidative stress |
20/20 | Nothing | |||||||
Gocmen (2017) RCT | NR 24.8 ASA I-II Non-smoker | Vertical, half impacted LM3 without bone retention | 20/20 | 0.2 ml Gengigel Prof HyA gel (0.8%) | Intra-operative | 1 h, 3rd, 7th day | 1 g amoxicillin 2 × 1 for 7 days; ibuprofen 400 mg 4 × 1 for 2 days | Trismus, bleeding time, tissue factor, edema, pain (VAS) |
20/20 | Nothing | |||||||
Yilmaz (2017) CT, split-mouth | 12/13 21.2 ± 3.0, > 18 Healthy Non-smokers | Bilaterally impacted LM3 (class 3-B, Pell-Gregory) | 25/25 | 2 ml Gengigel HyA gel (0.8%) | Intra-operative | 1st, 3rd, 7th day | 1 g amoxicillin 2 × 1 for 5 days; 550 mg naprexon sodium as needed | Edema, pain (VAS), trismus, number of pain killers |
25/25 | Nothing | |||||||
Afat (2018)* RCT | 38/22 18–30 ASA I Non-smoker | Unilaterally vertically impacted, partially erupted LM3 (class 2-B, Pell-Gregory) | 20/20 | L-PRF + HyA sponge | Intra-operative HyA sponge between 2 layers of L-PRF | 6 h, 24 h, 2nd, 3rd, 4th, 5th, 6th, 7th day | “Standard postoperative medication”—no details reported | Edema, pain (VAS), trismus |
20/20 | L-PRF | |||||||
20/20 | Nothing | |||||||
Bayoumi (2018) RCT, split-mouth | 7/7 25.3 ± 3.1 Healthy NR | Bilateral symmetrical asymptomatic impacted LM3 | 14/14 | 0.33 ml HyadentBG HyA gel (0.2%) + Gelfoam | Intra-operative | 2nd, 4th, 7th day | 625 mg amoxicillin 3 × 1 for 5 days; 1 g paracetamol 3 × 1 for 5 days | Edema, pain (VAS), trismus |
14/14 | Gelfoam | |||||||
Guazzo (2018) RCT | 88/48 21.7 ± 2.4 ASA I-II < 10 cigarettes / day | Need of LM3 removal | 65/56 | 2 ml Aminogam HyA gel + amino acid | Intra-operative | 7th, 14th day | 1 g amoxicillin 2 × 1 for 6 days; 1 g Paracetamol 3 × 1 | Wound dehiscence, trismus, pus, pain on palpation, alveolitis, local lymphadenopathy, adverse reactions, number of pain killers |
71/50 | Nothing | |||||||
Merchant (2018) RCT, split-mouth | 15/15 25.8 ± 4.7 Healthy NR | Bilateral symmetrical impacted LM3 | 30/30 | 30 ml Kojimax Cosderma HyA spray (0.5%) | Spray 3 × /day for 7 days | 2nd, 5th, 7th day | 500 mg amoxicillin 3 × 1; 500 mg paracetamol/50 mg tramadol 2 × 1 | Edema, pain (VAS), trismus |
30/30 | Saline spray | |||||||
Afat (2019)* RCT | 38/22 18–30 ASA I Non-smoker | Unilaterally vertically impacted, partially erupted LM3 (class 2-B, Pell-Gregory) | 20/20 | L-PRF + HyA sponge | Intra-operative HyA sponge between 2 layers of L-PRF | 7th, 14th, 21st day | 1 g amoxicillin 2 × 1; 500 mg paracetamol 3 × 1 | Mucosa healing score, prolonged bleeding, alveolitis, wound infection |
20/20 | L-PRF | |||||||
20/20 | nothing | |||||||
Munoz-Camara (2020) RCT | 54/36 > 18 ASA I-II NR | Single asymptomatic impacted LM3 | 30/30 | CHX + carbopol gel | Intra-operative | 1st, 2nd, 3rd, 7th day | 500 mg amoxicillin 3 × 1 for 7 days; 1 g paracetamol 3 × 1 for 4 days | Pain (VAS), trismus, alveolitis, wound infection, surgical difficulty, surgery duration |
30/30 | 1% HyA + carbopol gel | |||||||
30/30 | Carbopol gel | |||||||
Yang (2020) RCT | 67/45 18–71 NR NR | Need of LM3 removal | 56/52 | 0.25% HyA, Mucobarrier | Mouthwash | 7th day | NR | Overall discomfort, pain (VAS), burning sensation, redness, swelling |
56/52 | Aloclair | |||||||
Extraction socket | ||||||||
Favia (2008) CT, split-mouth | NR NR NR NR | Bilateral extraction of molars | 20/20 | Aminogam HyA Gel (1.33%) | 3 × /day | Up to 15 days | NR | Socket healing and keratinization |
20/20 | Nothing | |||||||
Bayoumi (2015) RCT | NR 18–60 Healthy NR | Any permanent tooth | 28/28 | 0.3 ml Hyadent HyA gel + Gelfoam | Intra-operative | 1st, 2nd, 7th day | NR | Pain (VAS), alveolitis |
23/23 | Gelfoam | |||||||
57/57 | Nothing | |||||||
Alcantara (2018) RCT, split-mouth | NR 18.7 ± 8.0 Healthy Non-smokers | Lower first premolar | 16/16 | 1 ml Nikkol HyA gel (0.1%) | Intra-operative | 30th, 90th day | 750 mg paracetamol 4 × 1 for maximum 4 days | Alveolar dimensional changes, percentage of newly formed bone, mean fractal dimension |
16/16 | Nothing | |||||||
Lorenz (2018) Prospective case series | 11/10 51.4 Healthy Non-smokers and smokers | Any extraction socket with intact vestibular lamella for socket preservation | 21/21 | β-TCP, cellulose, HyA-IBS, collagen membrane | Intra-operative | 4–6 months | Ibuprofen 400 mg | Amount of newly formed bone, vascularization, remaining biomaterial, connective tissue |
Cocero (2019) RCT, split-mouth | NR NR Liver failure NR | Two symmetrical extraction sites | 58/58 | HyA gel | Intra-operative and 3 × /day | 7th, 14th 21st day, until socket closure | NR | Alveolar diameter reduction, pain (VAS) |
58/58 | Nothing | |||||||
Marin (2020) RCT, split-mouth | NR NR Type 2 diabetes Non-smokers | Two anterior teeth in the lower jaw | 38/30 | Gengigel Prof HyA gel (0.8%) | Intra-operative | 1st, 2nd, 3rd, 5th, 10th, 15th, 20th, 25th day | NR | Wounds closure rate, wound healing score, pain (VAS) |
38/30 | Nothing | |||||||
Mostafa (2021) RCT, split-mouth | 9/6 18–44 Healthy Non-smokers | Two non-restorable single-rooted teeth | 15/10 | Gengigel HyA gel | Intra-operative and 3 × /day | 1st, 5th, 10th day | NR | Socket length, socket healing scores, pain (VAS), soft tissue healing |
15/10 | Nothing | |||||||
Eeckhout (2022) RCT | 22/16 52.9 ± 15.8 Healthy Non-smokers | Need of extraction of 1 or 2 teeth in the aesthetic zone with > 50% buccal bone | 23/23 | Gengigel HyA gel (0.8%), BioOss collagen, Mucograft Seal | Gel 3 × /day for 7 days (i.e., not mixed with the other material in the socket) | 7th, 21st day, 4th month | Amoxicillin 2 g for 4 days; ibuprofen 600 mg | Wound and alveolar dimensional changes, number of pain killers, pain (VAS), swelling, bleeding, socket healing |
23/23 | BioOss collagen, Mucograft Seal | |||||||
Cosola (2022) RCT | 20/20 46.5 ± 9.8 Healthy Non-smokers and smokers | Need of single tooth extraction | 20/20 | Aminogam HyA gel 0.2% CHX rinse, collagen sponge | Gel 1 × /day for 15 days (i.e., not with the collagen sponge into the socket) | 7th, 14th, 30th, 60th day | NR | Pain (VAS), swelling, number of pain killers |
20/20 | 0.2% CHX rinse, collagen sponge | |||||||
Alveolar osteitis (AO) | ||||||||
Dubovina (2016) RCT | 24/36 NR NR NR | AO defined by Bloom et al. (2002) | 10/10 | HyA (0.2 ml Gengigel Prof, 0.8%) + irrigation | Intra-operative | Every 2nd day until absence of pain | No additional medication | Pain (VAS), pain irradiation, local lymphadenopathy, redness of gingiva, halitosis, number of visits |
10/10 | HyA + ACA + irrigation | |||||||
10/10 | Alvogyl + irrigation | |||||||
10/10 | HyA + curettage | |||||||
10/10 | HyA + ACA + curettage | |||||||
10/10 | Alvogyl + curettage | |||||||
Suchanek (2019) Prospective case series | 35/23 36.1 ± 12.2 NR ≤ 10 cigarettes/day | Any extraction site (including wisdom teeth) diagnosed with AO | 58/50 | Lyophilized water solution of 2.5% HyA, ODC, and calcium chloride | Sponge-like medical device inserted daily | Daily and 2 more days after resolving of pain | NR | Pain (VAS), adverse reactions |
Study intervention
HyA information
Product (Trade name) | Producer (Manufacturer, country) | HyA concentration (%) | Chemical form | Application form | Study (year) |
---|---|---|---|---|---|
Aminogam | Errecappa Euroterapici, Italy | 1.33 | Non-cross-linked | Gel | Favia (2008), Guazzo (2018), Cosola (2022) |
Galena | Campinas, Brazil | 1 | NR | Gel | Sa (2013) |
Gengigel | Farmalink, Turkey | 0.2 | Non-cross-linked | Spray | Koray (2014) |
Gengigel | Ricerfarma, Italy | 0.8 | Non-cross-linked | Gel | Gocmen (2015, 2017), Dubovina (2016), Marin (2020), Eeckhout (2022) |
NR | NR | NR | Yilmaz (2017), Mostafa (2021) | ||
Healon | Pharmacia & Upjohn, Sweden | 1 | NR | Gel | Kim (2016, 2019), Lee (2021) |
Hyadent | BioScience, Germany | 1.4 | Non-cross-linked | Gel | Bayoumi (2015) |
HyadentBG | BioScience, Germany | 1.6 0.2 | Cross-linked Non-cross-linked | Gel | Bayoumi (2018) |
Hyalomatrix | Anika Therapeutics, USA | NR | NR | Sponge | Afat (2018, 2019) |
Kojimax | Cosderma, India | 0.5 | NR | Spray | Merchant (2018) |
Mucobarrier | NR | 0.25 | NR | Mouthwash | Yang (2020) |
Nikkol | BS Pharma, Belo Horizonte, Brazil | 1 | NR | Gel | Mendes (2008), Alcantara (2018) |
Purpose-made HyA product | Sigma-Aldrich Chemistry, Spain | 1 | NR | Gel | Munoz-Camara (2020) |
Purpose-made HyA product | Contipro, Czech Republic | 2.5 | NR | Sponge | Suchanek (2019) |
HyA-based injectable bone substitute material | Unknown | NR | NR | Injection | Lorenz (2018) |
HyA gel | Unknown | NR | NR | Gel | Cocero (2019) |
Clinical setting and funding details
Reported outcome variables and follow-up
Summary of the results of the individual studies
Study (year) | Intervention | HyA concentration | Evaluation time | Bone formation (Histologic1, radiologic2, and immunohistochemical analysis3) | |||||
---|---|---|---|---|---|---|---|---|---|
Extraction sockets in healthy rats | |||||||||
Mendes (2008) | 1% | 21st day | Bone trabeculae (%)1 | ||||||
Apical third of socket | Medial third of socket | ||||||||
HyA | 71.6 ± 2.8 | 67.9 ± 2.6 | |||||||
Carbopol* | – | – | |||||||
Blood clot | 60.6 ± 1.7 | 59.4 ± 1.5 | |||||||
Extraction sockets in healthy and diabetic rats | |||||||||
Sa (2013) | 1% | 14th day | Bone trabeculae (%)1 | ||||||
Apical third of socket | Medial third of socket | ||||||||
Carbopol (non-diabetic) | 40.6 ± 4.9 | 43.3 ± 8.4 | |||||||
Carbopol (diabetic) | 16.6 ± 7.2 | 5.8 ± 3.5 | |||||||
HyA (diabetic) | 34.9 ± 5.3 | 23.9 ± 4.3 | |||||||
HyA + SWCNT (diabetic) | 38.2 ± 1.1 | 35.6 ± 6.3 | |||||||
Infected extraction sockets in dogs | |||||||||
Kim (2016) | 1% | 3rd month | MB (%)1 | Bone marrow (%)1 | |||||
HyA | 63.3 ± 9.8 | 34.7 ± 8.9 | |||||||
Blood clot | 47.8 ± 6.6 | 50.5 ± 6.4 | |||||||
Kim (2019) | 1% | 3rd month | Net area (%)2** | BV/TV (%)2 | OCN3 | ||||
ACS | − 6.5 ± 9.8 | 17.9 ± 6.0 | 83.0 ± 27.6 | ||||||
HyA + ACS | 11.7 ± 4.7 | 20.1 ± 6.3 | 319.0 ± 138.6 | ||||||
rhBMP-2 + ACS | 15.9 ± 3.1 | 20.1 ± 6.6 | 281.7 ± 125.7 | ||||||
Blood clot | − 10.7 ± 1.8 | 18.0 ± 6.6 | 88.7 ± 43.0 | ||||||
Lee (2021) | 1% | 3rd month | MB (%)1 | NFB (%)1 | CT (%)1 | RGP (%)1 | BV/TV (%)2 | BS/TV (%)2 | |
ACS | 45.2 ± 3.1 | 7.5 ± 2.2 | 17.1 ± 6.8 | 36.0 ± 10.4 | 18.6 ± 4.1 | ||||
HyA + ACS | 64.7 ± 3.9 | 15.5 ± 2.4 | 10.8 ± 4.9 | 53.3 ± 7.4 | 22.7 ± 3.6 | ||||
DBBM-C | 41.9 ± 5.0 | 5.6 ± 1.4 | 35.1 ± 10.5 | 3.7 ± 1.4 | 38.2 ± 7.9 | 24.7 ± 5.6 | |||
HyA + DBBM-C | 59.9 ± 5.4 | 11.3 ± 3.1 | 12.3 ± 5.6 | 2.9 ± 2.0 | 46.3 ± 13.0 | 24.7 ± 2.3 |