Biological Tests V.01/2018-11 Compatibility of Axelmed ...1.500 x se1 2.500 x se1 5.000 x se1 7.500 x se1 10.000 x se1

AXELMED S.R.L. DENTAL IMPLANT SYSTEMS AXELMED ZAHNIMPLANTATSYSTEME

Via della Liberazione, 58 / IT 20098 S. Giuliano Milanese (MI) / Italy Via dei Pioppi, 10 / Mail Box 949 / CH 6616 Losone / Switzerland

Tel: +39 02 9828 2694 / Fax: +39 02 9828 5327 / [email protected] Ph. +41 091 756 69 56 / Fax +41 091 756 69 57 / [email protected]

C.F. e P.IVA (VAT#): IT 09541170966 / R.E.A. MI 2097286 www.axelmed.com / Axelmed® and Paradigma® are trade marks

Biological Tests

V.01/2018-11

Compatibility of Axelmed Paradigma Dental Implants

Index

SAP Surface Analysis Immersion Test Mutagenicity Test (AMES) Acute Systemic Toxicity Irritation Tests (Intradermal) Suitability Test Sterility Test Seal Integrity Test (under pressure) Accellerate Aging Test 2,5 years Bacterial Endotoxins (LAL Test Chromogenic) Test in Vitro Citotoxicity Accellerate Aging Test 5 years Bioburden Microorganism Population before sterilization Reciprocity Report Clinical Investigation (ISO 14155)

May not be reproduced in print or any other media without written permission of AXELMED SRL

REPORT: HIGH PURITY SURFACE WITH MICRO-ROUGHNESS

MORFOLOGY (SAP) ON THE AXELMED PARADIGMA DENTAL IMPLANTS

JUNE 2016

Following classification procedure Codification system to describe the

chemical and morphological characteristics of dental implants surface

REPORTS BY NOBIL BIO RICERCHE SRL - ANALYSIS and EVALUATION of

AXELMED PARADIGMA SURFACE

Dr.ssa Clara CASSINELLI Dr. Marco MORRA

Analysis of the surface composition through XPS (X-ray Photoelectron

Spectroscopy) and valuation at scanning electron microscope (SEM).

Conclusions.

NBR5 – June 2016

58 X 58 X

250 X 500 X

1.500 X SE1 2.500 X SE1

5.000 X SE1 7.500 X SE1

10.000 X SE1

Elements (%>) : Oxygen 39.5, Carbon 39.3, Titanium 17, traces

XPS Analysis.

The results obtained indicate that the surface is clean and free from residues of sand blasting or

other contaminants. In particular, the main elements observed (O, I, C) are present in expected

quantities and the remaining elements, with the low percentages observed concentrations, are

commonly found on titanium surfaces and do not constitute an anomaly.

Observation by SEM.

The main results of the analysis at the scanning electron microscope are shown in the images

attached, also supplied as individual files.tif. The microscopic examination revealed only very few

dark micro residues visible, indication of the fact that there are very few elements of atomic number lower

than that of Titanium (generally attributable to the carbonaceous or residual blasting agent). There are,

moreover, complete absence of “light color” residues (contaminants with atomic number higher than that

of Titanium).

Conclusions.

The analyzes performed allow to say that the dental implant analyzed has a roughened surface,

obtained through a sandblasting process of which no trace remains. Not even carbon residues

are highlighted. The measured surface chemical composition does not show any anomalies or

unexpected elements and implant chemical and morphological features are in line with what is

today scientifically considered suitable for the clinical intended use.

*Report No. 2011600272 of 24.05.2016 Authors: dr. Clara Cassinelli e dr. Marco Morra

Test Report N° 18-1015-05 Page 1/4

VIA BENINI 13– 40069 ZOLA PREDOSA BO – TEL +39-051755295 – FAX +39-051754622 www.biochem-bcm.com E-mail: [email protected] - C.F. e P.IVA IT 03531810376 – R.E.A. BO-297535

Identification and quantification of degradation pr oducts from metals and alloys: Immersion test

Test Sample

AXELMED PARADIGMA DENTAL IMPLANT

Test Report N° 18-1015-05

Test performed for

AXELMED S.R.L. Via Liberazione, 58

20098 SAN GIULIANO MILANESE MI

by

BIOCHEM S.r.l. Via Benini, 13

40069 ZOLA PREDOSA BO



TIME SCHEDULE OF TEST

The test was started on 22/10/2018 and was completed on 30/10/2018 Ref. Your Order of 28/08/2018 SAMPLE DESCRIPTION

Denomination: AXELMED PARADIGMA DENTAL IMPLANT Code: 82124 Lot: 01216 Sterilization: Gamma Ray Steriliz. Receipt number: 8589 Receipt date: 29/08/2018 Sampling carried out by: AXELMED S.R.L. Part of the sample to be tested: the whole sample (dental implant) Composition: Pure Titanium Grade 4 ASTM F 67 The sample is composed by 3 parts as shown in figure 1 but only the implantable part, indicated by the arrow has been submitted to the test because the screws are external and temporary.

Figure 1: sample components

According to the 10993-1: 2018 standard, the device is classified as a "tissue / bone implant device" with a permanent contact time.

TEST METHOD:

• ISO 10993-9:2009 Biological evaluation of medical devices, Part 9: Framework for identification and quantification of potential degradation products

• ISO 10993-15:2000 - Biological evaluation of medical devices, Part 15: Identification and quantification of degradation products from metals and alloys.

• ISO 10993-12:2012 Biological evaluation of medical devices Part 12: Sample preparation and reference materials

• ICH Guideline for elemental impurities Q3D • USP <232> Elemental Impurities-Limits

OTHER REFERENCES Test protocol n° 119/18 “Identification and quantif ication of degradation products from metals and alloys”



TEST DESCRIPTION To identify and quantify degradation products the immersion test (part 7 of ISO 10993-15:2000) was used to chemically degrade the test material to generate products to be analysed. The samples have been immersed in a solution of artificial saliva to simulate the intended use of the device in a ratio of the exposed surface area of the sample to the volume of the electrolyte solution of 1,18 ml/cm2. The artificial saliva was composed of (ISO 10993-15:2000, Annex C.2):

• Na2HPO4 0,260 g/l • NaCl 0,700 g/l • KSCN 0,330 g/l • KH2PO4 0,200 g/l • NaHCO3 1,500 g/l • KCl 1,200 g/l

The pH value of the electrolytic solution was measured at the beginning of the test. The test container has been closed to prevent evaporation and maintained at (37 ± 1) °C for (7 ± 1) days. Then the samples have been removed and the pH of the solution has been measured. The solution was analysed by means of Inductively coupled plasma atomic emission spectroscopy (ICP-OES) to identify and quantify the presence of the listed metals below and suggested in ICH Q3D and in USP <232> Elemental Impurities-Limits. A blank and a calibration curve at three concentration levels of the listed metals have been executed for the quantification of analytes.

RESULTS pH values

pH at the beginning of the test pH at the end of t he test Difference

Control 8,90 (at 23,5°C) 9,31 (at 24,1°C) 0,41

Sample 8,90 (at 23,5°C) 9,31 (at 24,1°C) 0,41

No difference in pH variation was quantified between the beginning and the end of the control and sample test. No significant changes to the surface has been observed.

Metals

Metal Result (µg/cm 2)

Ag <0,01

Al <0,01

As <0,01

Au <0,01

B <0,01

Ba <0,01

Cd <0,01

Ce <0,01

Co <0,01

Cr <0,01



Cs <0,01

Cu <0,01

Fe <0,01

Hg <0,01

Ir <0,01

Li <0,01

Mn <0,01

Mo <0,01

Ni <0,01

Pb <0,01

Pd <0,01

Pt <0,01

Rh <0,01

Ru <0,01

Sb <0,01

Se <0,01

Sn <0,01

Ti <0,01

Tl <0,01

V <0,01

W <0,01

Zn <0,01

The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Rancan Milena, Dr. Issue authorized by: Head of Laboratory, Giovanni Bassini, Ch. Eng.

Mod.Ames Rv22 Test Report N° 18-1015-03 Page 1/11

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Signatory of EA, IAF and ILAC

Mutual Recognition Agreements


MUTAGENICITY TEST - AMES TEST

Test Sample



Test performed for



by

BIOCHEM S.r.l. Via Benini 13



LAB N. 0283




MANAGEMENT OF TEST Head of Biology substitute: Giulia Arniani, Dr. QUALITY ASSURANCE Quality Assurance Manager: Alessandra Marchesi, PhD TEST DIRECTOR Giovanni Bassini, Ch.Eng. TIME SCHEDULE OF TEST The test was started on 19/11/2018 and was completed on 23/11/2018.


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Ref. Your Order 02-18 of 28/08/2018 Sample description

Description: AXELMED PARADIGMA DENTAL IMPLANT Code: 82124 Lot: 01216 Sterilization: Gamma Ray Sterilization Receipt number: 8433 Receipt date: 29/08/2018 Sampling carried out by: AXELMED S.R.L. Part of the sample to be tested: the whole sample Pretreatment: / Extraction conditions: one sample (0,64 grams) was extracted with 6,4 ml (ratio 1g / 10 ml) of acetone for 24 hours at room temperature in agitation. Then, the solvent was evaporated and the test sample residue was suspended in MEM with 5% of serum. Test method

1) ISO 10993-3:2014 2) OECD 471 (1997) 3) ISO 10993-12:2012 Other references

Ref. Haemolysis test protocol: / Bibliography

1) Maron D.M. and Ames B.N. (1983): Revised methods for the Salmonella mutagenicity test. Mutation Res, 113 (1983), 173-215.

2) Kristien Mortelmans, Errol Zeiger: The Ames Salmonella/Microsome mutagenicity assay. Mutation Research, 455 (2000) 29-60.

Principles of the method

AMES TEST is a reverse mutation test in Salmonella typhimurium. Reverse mutation assays employ bacterial strains which are already mutant at a locus whose phenotypic effects are easily detected. The Salmonella tester strains have mutations causing dependence on a particular amino acid (histidine) for growth. The ability of test substances to cause reverse mutations (reversions) to histidine-independence can easily be measured. Several strains are used to circumvent the problem of mutagen specificity. Since many chemicals only demonstrate mutagenic activity after their transformation in reactive forms due to metabolism, in order to detect these "indirect mutagens" the test is performed in the presence and absence of a rat liver metabolising system.


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MATERIALS

Bacterials strains

The following Salmonella typhimurium tester strains are used in accordance with ICH guidelines (07/19/95):

TA 1535 TA 1537 TA 98 TA 100 TA 102

Overnight subcultures (37°C 16-18 hours) of these s trains are usually prepared for each day of work. The presence of the appropriate genetic markers in these strains is checked before each mutagenicity assay, as follows: Histidine requirement no growth on Minimal plates + Biotin growth on Minimal plates + Biotin + Histidine. uvrB: Sensitivity to UV irradiation. NO uvrB: Resistence to UV irradiation. rfa: Sensitivity to Crystal Violet. R-factor: Resistence to Ampicillin. Media The following growth media are used: 1) Nutrient Broth for the preparation of liquid cultures of the tester strains; 2) Nutrient Agar for the growth of the tester strains; 3) Minimal Agar for the Mutagenicity assay; 4) Top Agar for the Mutagenicity assay. S9 Mix The S9 liver tissue fraction is obtained commercially. It is essential to prepare fresh S9 mix for each mutagenicity assay. Control substances Positive control treatments are used in each experiment. The positive control agents are commercially obtained. Sodium azide and Mitomycin C are usually dissolved in sterile injection water; 9-aminoacridine, 2-nitrofluorene, and 2-aminoanthracene are usually dissolved in DMSO. STRAIN ABSENCE OF S9 PRESENCE OF S9 TA 1535 Sodium azide 2-aminoanthracene TA 1537 9-aminoacridine 2-aminoanthracene TA 98 2-nitrofluorene 2-aminoanthracene TA 100 Sodium azide 2-aminoanthracene TA 102 Mitomycin C 2-aminoanthracene

Negative control: MEM with 5% of serum


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ASSAY PROCEDURE Each experiment includes the test extract and the negative and positive controls, tested in the absence and presence of a S9 metabolic activation system. The test extract and the controls are tested in triplicate plating. Negative controls are required to establish the number of colonies that arises spontaneously for each of the tester strains. Plate test

The components of the assay (the tester strain bacteria, the test extract and S9 mix or Phosphate Saline Buffer) are added to molten overlay agar and mixed. The mixture is then poured on the surface of a minimal medium agar plate, and allowed to solidify prior to incubation. The overlay mixture is composed as follows:

Top agar (held at 45°C) 2,00 ml S9 mix or Phosphate Saline Buffer 0,50 ml Bacterial suspension 0,10 ml Test extract or control substance 0,10 ml

Incubation and scoring

The prepared plates are incubated for approximately 48 hours at 37°C. Scoring is effected by counting the number of revertant colonies on each plate. EVALUATION OF DATA

For the test extract to be considered mutagenic, two-fold (or more) increases in revertants average (over the negative control) must be observed at the considered dose-level. Evaluation of Ames test data based on a 'doubling rate' has been shown to be as effective as statistical techniques in allowing the correct interpretation of test results (Chu et al.1981; Mortelmans and Zeiger 2000).


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REVERSE MUTATION: TA 1535 Tester strain: Salmonella typhimurium TA 1535 Negative control: MEM with 5% of serum Positive control without S9: Sodium azide Positive control with S9: 2-aminoanthracene

Histidine requirement (HIS-):

− grown on histidine/biotin plates, − not grown on minimal glucose plates Sensitivity to Crystal violet (rfa):

Clear zone of inhibition 17 mm around the disc with Crystal violet Sensitivity to Ampicillin (R-):

Clear zone of inhibition 28 mm around the disc with Ampicillin Sensitivity to UV irradiation (uvrB):

− grown on UV unexposed side − not grown on UV exposed side Absorbance at 660 nm: Range between 1,200 and 1,400 RESULTS SUBSTANCE (without S9)

Nr. of revertants

Plate 1 Plate 2 Plate 3 Average Increase

Negative control 14 12 16 14

Positive control 58 62 64 61 4,4

Test extract 23 18 16 19 1,4

SUBSTANCE (with S9)

Nr. of revertants




Test extract 9 5 8 7 1,2

CONCLUSIONS

Under the experimental conditions with the tested bacterial strain, in presence and in absence of S9 the test extract did not show a two-fold increase in revertants number vs the negative control.


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REVERSE MUTATION: TA 1537 Tester strain: Salmonella typhimurium TA 1537 Negative control: MEM with 5% of serum Positive control without S9: 9-aminoacridine Positive control with S9: 2-aminoanthracene




Clear zone of inhibition 32 mm around the disc with Ampicillin Sensitivity to UV irradiation (uvrB):


Nr. of revertants





SUBSTANCE (with S9)

Nr. o f revertants





CONCLUSIONS



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REVERSE MUTATION: TA 98 Tester strain: Salmonella typhimurium TA 98 Negative control: MEM with 5% of serum Positive control without S9: 2-nitrofluorene Positive control with S9: 2-aminoanthracene




No zone of inhibition around the disc with Ampicillin Sensitivity to UV irradiation (uvrB):


Nr. of revertants




Test extract 24 15 20 20 0,6

SUBSTANCE (with S9)

Nr. of revertants

Plate 1 Plate 2 Plate 3 Average Increas e



Test extract 45 49 46 47 1,3

CONCLUSIONS



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REVERSE MUTATION: TA 100 Tester strain: Salmonella typhimurium TA 100 Negative control: MEM with 5% of serum Positive control without S9: Sodium azide Positive control with S9: 2-aminoanthracene






Nr. of revertants




Test extract 104 90 93 96 1,0

SUBSTANCE (with S9)

Nr. of revertants




Test extract 88 89 92 90 1,0

CONCLUSIONS



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REVERSE MUTATION: TA 102 Tester strain: Salmonella typhimurium TA 102 Negative control: MEM with 5% of serum Positive control without S9: Mitomycin C Positive control with S9: 2-aminoanthracene






Nr. of revertants




Test extract 628 654 580 591 1,2

SUBSTANCE (with S9)

Nr. of revertants




Test extract 640 500 624 588 1,0

CONCLUSIONS



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The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Sonia Di Deo, Dr. Issue authorized by: Test Director Giovanni Bassini, Ch. Eng. Zola Predosa, 23/11/2018

Mod. Toss ISO Rv23 Test Report N° 18-1015-02 Page 1/5

LAB N. 0283

Signatory of EA, IAF and ILAC Mutual Recognition Agreements


ACUTE SYSTEMIC TOXICITY

Test Sample



Test performed for



by

BIOCHEM S.r.l. Via Benini, 13



LAB N. 0283



MANAGEMENT OF TEST

Head of Biology substitute: Giulia Arniani, Dr. QUALITY ASSURANCE

Quality Assurance Manager: Alessandra Marchesi, PhD

TEST DIRECTOR

Giovanni Bassini, Ch. Eng.

TIME SCHEDULE OF TEST

The test was started on 05/10/2018 and was completed on 12/10/2018.


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Ref. Your Order of 28/08/2018 Sample description Description: AXELMED PARADIGMA DENTAL IMPLANT Code: 82124 Lot: 01216 Sterilization: Gamma Ray Steriliz. Receipt number: 8432 Receipt date: 29/08/2018 Sampling carried out by: AXELMED S.R.L. Part of the sample to be tested: the whole sample (dental implant) Pretreatment: / Test Method

• ISO 10993-11:2017 • ISO 10993-12:2012 Other references Acute Systemic Toxicity Test Protocol - / Summary of practice The liquid extracts are injected into mice and the animals are observed at regular intervals for 72 h for reactions, survival, etc. If during the observation period none of the animals treated with the extract of the Sample shows a significantly greater reaction than the animals treated with the Negative Control, the Sample meets the requirements of this test. Extraction conditions The extraction was performed by Biochem in the following way: 1) 2 grams of the sample were extracted with 10 ml of 9 g/l sterile solution of sodium chloride (following

the ratio of 0,2 g / 1 ml) at 37°C for 72 hours; 2) 2 grams of the sample were extracted with 10 ml of sesame oil (following the ratio of 0,2 g / 1 ml) at

37°C for 72 hours. Negative controls 1) 9 g/l sterile solution of sodium chloride; 2) sesame oil. Animals 5 albino mice are used for each test extract. Procedure Each extract of the Sample and the corresponding negative control, are injected into groups of 5 mice each one. The 9 g/l sterile solution of sodium chloride extract and the negative control are injected by IV route at the dose of 1 ml/20 g; the Vegetable Oil extract and the negative control are injected by IP route at the dose of 1 ml/20 g.


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Grading system Response Score Description

Normal, no symptoms

0 Mouse exhibits no adverse physical symptoms after injection.

Slight 1 Mouse exhibits slight but noticeable symptoms of hypokinesia, dyspnea, or abdominal irritation after injection.

Moderate 2 Mouse exhibits definite evidence of abdominal irritation, dyspnea, hypokinesia, ptosis, or diarrhea after injection. Weight usually drops to between 12 % and 25 %.

Marked 3 Mouse exhibits prostration, cyanosis, tremors, or severe symptoms of abdominal irritation, diarrhea, ptosis or dyspnea, after injection. (Extreme weight loss; weight usually less than 25 %).

Dead, expired 4 Mouse dies after injection

If during the observation period none of the animals treated with the extract of the Sample shows a significantly greater biological reactivity than the animals treated with the Blank, the Sample meets the requirements of the test. If two or more mice die, or if abnormal behavior such as convulsions or prostration occurs in two or more mice, or if a body weight loss greater than 2 g occurs in three or more mice, the Sample does not meet the requirements of the test. Note: Even if occurs a decrease of weight between 10% and 25% in one mouse of the Negative Control Group, the result may be considered valid being involved in such decrease only one subject of the Group and considering the variation as biologically acceptable for an in vivo test assay.

Results

Extraction Vehicle: 9 g/l sterile solution of sodium chloride.

Time Treated animals Negative control animals

1 2 3 4 5 1 2 3 4 5

Immediately 0 0 0 0 0 0 0 0 0 0

24 h 0 0 0 0 0 0 0 0 0 0

48 h 0 0 0 0 0 0 0 0 0 0

72 h 0 0 0 0 0 0 0 0 0 0

Extraction Vehicle: Sesame oil.

Time Treated animals Negative control animals

1 2 3 4 5 1 2 3 4 5

Immediately 0 0 0 0 0 0 0 0 0 0

24 h 0 0 0 0 0 0 0 0 0 0

48 h 0 0 0 0 0 0 0 0 0 0

72 h 0 0 0 0 0 0 0 0 0 0


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Body weights variations

Extraction Vehicle: 9 g/l sterile solution of sodium chloride.

Mouse Number

Sample weight var. (g)

Sample weight var. (%)

Negative Control weight var. (g)

Negative Control weight var. (%)

1 1.39 5.4 -0.17 -0.7

2 -0.54 -2.0 0.58 2.4

3 1.66 5.8 1.24 5.1

4 1.56 5.8 1.64 6.8

5 2.78 10.3 0.19 0.8

Extraction Vehicle: Sesame oil.

Mouse Number

Sample weight var. (g)

Sample weight var. (%)

Negative Control weight var. (g)

Negative Control weight var. (%)

1 1.32 4.9 1.13 4.9

2 1.11 4.1 -0.28 -1.1

3 0.95 3.4 -0.98 -4.0

4 0.92 3.2 1.96 7.7

5 1.55 5.6 1.43 5.7 Legend

Weight var. = t3-t0 t3 = weight on day 3 (g); t0 = weight on day 0 (g) Conclusions

Under the experimental conditions, the test sample does not show significative differences in mice body weight, clinical symptoms and behaviour compared to the negative control, meeting the requirements of the test. The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Pesce Carla, Dr. Issue authorized by: Test Director Giovanni Bassini, Ch Eng. Zola Predosa, 15/10/2018

Mod. Reatt ISO Rv23 Test Report N° 18-1015-01 Page 1/7

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IRRITATION TESTS ANIMAL INTRACUTANEOUS (INTRADERMAL) REACTIVITY TEST

Test Sample



Test performed for



by




LAB N. 0283



MANAGEMENT OF TEST QUALITY ASSURANCE Quality Assurance Manager: Alessandra Marchesi, PhD TEST DIRECTOR Giovanni Bassini, Ch.Eng.

TIME SCHEDULE OF TEST The test was started on 19/10/2018 and was completed on 26/10/2018.


LAB N. 0283



Ref. Your Order of 28/08/2018 Sample description

Description: AXELMED PARADIGMA DENTAL IMPLANT Code: 82124 Lot: 01216 Sterilization: Gamma Ray Steriliz. Receipt number: 8431 Receipt date: 29/08/2018 Sampling carried out by: AXELMED S.R.L. Part of the sample to be tested: the whole sample (dental implant) Pretreatment: / Test Method

• ISO 10993-10:2010 • ISO 10993-12:2012 Other references

Intracutaneous Test Protocol - / Summary of practice

Two liquid extracts are injected into rabbits and the animals are observed at regular intervals for 72 h for erythema and oedema. Extraction conditions

The extraction was performed by Biochem in the following way: - 1,26 grams of the sample were extracted with 6,3 ml of 9 g/l sterile solution of sodium chloride (following

the ratio of 0,2 g / 1 ml) at 37°C for 72 hours; - 1,26 grams of the sample were extracted with 6,3 ml of sesame oil (following the ratio of 0,2 g / 1 ml) at

37°C for 72 hours. Negative controls

− 9 g/l sterile solution of sodium chloride; − Sesame oil. Animals

Healthy thin-skinned albino rabbits, female, from 2 to 4 Kg; three animals are used; on each of them two extracts of the sample are tested.


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Procedure

On the day before testing, closely clip the fur on the animal's back on both sides of the spinal column over a sufficiently large test area. Inject intracutaneously 0,2 ml of each extract at 5 sites on one side of each rabbit. Similarly, at 5 other sites on the other side of each rabbit, inject 0,2 ml of the corresponding control. Examine injection sites at 24, 48 and 72 hours after the injection and rate the observations on a numerical scale according to the Grading System given in Table 1. After the 72 hours grading, for each individual animal are calculated the total scores of erythema and oedema separately for each sample and the corresponding control. The scores so obtained are divided by 15 (3 scoring time points × 5 test or control sample injection sites): these are the two total scores (total sample and total control) for each individual animal. To determine the Overall mean score for each test sample, add the individual scores for the three animals and divide by three (number of treated and observed animals). Similarly is calculated the overall mean score for the corresponding control. The Final test sample score can be obtained by subtracting the score of the control from the test sample score. The requirements of the test are met if the final test sample score is ≤ 1,0. If at any observation period the average reaction to the test sample is questionably greater than the average reaction to the control, repeat the test using three additional rabbits. The requirements of the test are met if the final test sample score is < 1,0. Table 1 Grading system

Erythema: erythema and eschar Score Oedema: oedema formation Score

No erythema 0 No oedema 0

very slight erythema (barely perceptible) 1 Very slight oedema (barely perceptible) 1

well-defined erythema (pale red in colour) 2 Slight oedema (edges of area well-defined by definite raising)

2

moderate to severe erythema (red and area well defined)

3 Moderate oedema (edges raised approximately 1 mm)

3

severe erythema (beet redness) to slight eschar formation (injuries in depth)

4 Severe oedema (raised more than 1 mm and extending beyond area of exposure)

4


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Results Extraction vehicle: 9 g/l sterile solution of sodium chloride

Rabbit N. 95 Test materials sites Negative control sites

Time Reaction 1 2 3 4 5 1 2 3 4 5

24 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

48 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

72 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

Total sample score and total control score 0.0 0.0


Time Reaction 1 2 3 4 5 1 2 3 4 5

24 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

48 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

72 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0


Rabbit N . 97 Test materials sites Negative control sites

Time Reaction 1 2 3 4 5 1 2 3 4 5

24 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

48 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

72 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0


Overall mean sample score 0.0 Overall mean control score 0.0 Final test sample score 0.0


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Extraction vehicle: sesame oil


Time Reaction 1 2 3 4 5 1 2 3 4 5

24 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

48 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

72 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0



Time Reaction 1 2 3 4 5 1 2 3 4 5

24 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

48 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

72 h Eryth ema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0



Time Reaction 1 2 3 4 5 1 2 3 4 5

24 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

48 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0

72 h Erythema 0 0 0 0 0 0 0 0 0 0

Oedema 0 0 0 0 0 0 0 0 0 0


Overall mean sample score 0.0 Overall mean control score 0.0 Fina l test sample score 0.0


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Conclusions

Under the experimental conditions, the Final test sample score is < 1,0 for each extract of the sample. The test sample does not show a significative biological reactivity, meeting the requirements of the test.

The present test exclusively report refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Pesce Carla, Dr. Issue authorized by: Test Director Giovanni Bassini, Ch Eng. Zola Predosa, 29/10/2018

Mod.Ster_val ISO Rv01 Test Report N° 17-0943-01 Page 1/2

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Messrs. AXELMED S.R.L. Via Liberazione, 58 20098 SAN GIULIANO MILANESE MI

Zola Predosa, 26/07/2017 Ref. Your Order of June 2017


SUITABILITY TEST AND STERILITY TEST Sample description

Description: AXELMED PARADIGMA Code: 82114 Lot: 01916 Sterilization: Sì N° of tested samples: 10 Receipt number: 2798 Receipt date: 04/07/2017 Sampling carried out by: AXELMED S.R.L. Test date: from 04/07/2017 to 24/07/2017. Note: Test performed on the whole sample. Test method

ISO 11737-2: 2009 (except 5.2) A) Growth promotion test

Each batch of ready-prepared medium was tested. Portions of fluid Tryptone Soya Broth (TSB) were inoculated with a small number (not more than 100 cfu) of the following micro-organisms, using a separate portion of medium for each of the following species of micro-organism: Clostridium sporogenes ATCC 19404, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538, Aspergillus brasiliensis ATCC 16404, Bacillus subtilis ATCC 6633, Candida albicans ATCC 10231. The bacteria were incubated for not more than 3 days and the fungi were incubated for not more than 5 days at 30 ± 2°C. The media are suitable if a clear ly visible growth of the micro-organisms occurs. Growth promotion test results

Clostridium sporogenes ATCC 19404 Growth Pseudomonas aeruginosa ATCC 9027 Growth Staphylococcus aureus ATCC 6538 Growth Aspergillus brasiliensis ATCC 16404 Growth Bacillus subtilis ATCC 6633 Growth Candida albicans ATCC 10231 Growth

Mod.Ster_val ISO Rv01 Test Report N° 17-0943-01 Page 2/2

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B) Sterility test

10 samples were aseptically taken out of their packages and were incubated directly into Tryptone Soya Broth (TSB). After 14 days of incubation at 30 ± 2°C the sterility was evaluated. The sample is considered sterile if a visible growth of the micro-organisms did not occur. A negative control of the TSB was carried out incubating only the culture medium. Sterility test results

Sterility after 14 days of incubation STERILE 10 / 10 Negative control No Growth C) Method suitability test

At the end of sterility test, a small number of micro-organisms (not more than 100 CFU) was inoculated in six containers with the tested and resulted sterile samples and medium. In the validation test were used the same micro-organism as in the growth promotion test. The containers were incubated at 30 ± 2°C for not m ore then five days. After incubating, if a clearly visible growth of micro-organisms was obtained, as same as in the growth promotion test, then the sample has no antimicrobial activity or such activity has been satisfactorily eliminated. Method suitability test results

Clostridium Sporogenes ATCC 19404 Growth Pseudomonas aeruginosa ATCC 9027 Growth Staphylococcus aureus ATCC 6538 Growth Aspergillus brasiliensis ATCC 16404 Growth Bacillus subtilis ATCC 6633 Growth Candida albicans ATCC 10231 Growth The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Di Deo Sonia, Dr. Issue authorized by: Head of Laboratory, Giovanni Bassini, Ch. Eng.

Mod.Ster ISO Rv02 Test Report N° 17-0836-03 Page 1/2

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STERILITY TEST Sample description

Description: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No N° of tested samples: 10 Receipt number: 2513 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Test date: from 05/10/2017 to 19/10/2017. Note: Test performed on the whole sample after accelerated aging test. Test method

ISO 11737-2: 2009 (except 5.2) A) Growth promotion test

Each batch of ready-prepared medium was tested. Portions of fluid tryptone soya broth (TSB) were inoculated with a small number (not more than 100 cfu) of the following micro-organisms, using a separate portion of medium for each of the following species of micro-organism: Clostridium sporogenes ATCC 19404, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538, Aspergillus brasiliensis ATCC 16404, Bacillus subtilis ATCC 6633, Candida albicans ATCC 10231. The bacteria were incubated for not more than 3 days and the fungi were incubated for not more than 5 days at 30 ± 2°C. The media are suitable if a clear ly visible growth of the micro-organisms occurs.

Mod.Ster ISO Rv02 Test Report N° 17-0836-03 Page 2/2

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Growth promotion test results

Clostridium sporogenes ATCC 19404 Growth Pseudomonas aeruginosa ATCC 9027 Growth Staphylococcus aureus ATCC 6538 Growth Aspergillus brasiliensis ATCC 16404 Growth Bacillus subtilis ATCC 6633 Growth Candida albicans ATCC 10231 Growth

B) Sterility test 10 samples were aseptically taken out of their packages and were incubated directly into Tryptone Soya Broth (TSB). After 14 days of incubation at 30 ± 2°C the sterility was evaluated. The sample is considered sterile if a visible growth of the micro-organisms did not occur. A negative control of the TSB was carried out incubating only the culture medium. Sterility test results Sterility after 14 days of incubation STERILE 10 / 10 Negative control No Growth The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Sonia Di Deo, Dr. Issue authorized by: Head of Laboratory, Giovanni Bassini, Ch. Eng.



Messrs AXELMED S.R.L. Via Liberazione, 58 20098 SAN GIULIANO MILANESE MI


Test Report N° 17-0836-02 Sample description

Denomination: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No Number of samples analyzed: 5 Receipt number: 2512 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Note: Test carried out on the primary packaging after accelerating aging test (see report n° 17-0836-0 1) The test was started on 05/10/2017 and was completed on 11/10/2017 Method: 5 samples have been tested for the seal integrity test under a column of 50 cm of water and methylene blue. RESULTS Seal integrity Conforme







Description: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No Receipt number: 2511 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Devices exposed to accelerated aging: 15 Accelerated aging started on 13/06/2017 and was completed on 05/10/2017. Method

ASTM F 1980-16 Standard Guide for Accelerated Aging of Sterile Barrier System for medical devices. Summary of practice

In order to subject the samples to accelerated aging according to ASTM F 1980-16 Standard Practice, we calculated the parameters through the following formula: − Accelerated Aging Time (AAT) = RT/AAF − Real Time Aging (RT) = 2,5 years − Accelerated Aging Factors (AAF) = Q10exp[(Taa-Trt)/10] − Q10 = 2 − Taa (accelerated aging temperature) = 55 °C − Trt (ambient storage temp) = 25 °C Then the samples were incubated for 114 days at 55 °C temperature. The amount of real-time aging, to which used accelerated aging conditions are estimated to be equivalent, is 2,5 years. The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Rancan Milena, Dr. Issue authorized by: Head of Laboratory, Giovanni Bassini, Ch. Eng.

Mod.LAL Rv23 Solido Test Report N° 17-0835-02 Page 1/1

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Zola Predosa, 22/06/2017 Ref. Your Order of May 2017


DETERMINATION OF BACTERIAL ENDOTOXINS (LAL TEST CHR OMOGENIC) Sample Description Description: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No Receipt number: 2503 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Test date: 21/06/2017. Test Method EU PHARMA 01/2010: 20614 corrected 7.0 - Method D Other references

Lal Test Protocol - /

Extract Preparation Sample quantity 1 Volume of sterile injection water 1 ml Term extraction at room temperature 1 h in agitation Test temperature 37 ±1 °C Results Endotoxin Recovery (Validity range 50-200%) 69 % Extract endotoxin value <0,01 EU/ml Sample endotoxin value <0,01 EU/sample The present Test Report exclusively refers to the referenced test sample. The present Test Report may not be partially reproduced without Biochem authorization. Test verified by: Guardiani Silvia, Dr. Issue authorized by: Head of laboratory Giovanni Bassini, Ch. Eng.

Mod. Cito ISO MEM Rv26 Test Report N° 17-0835-01 Page 1/6

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TESTS FOR IN VITRO CYTOTOXICITY

Test Substance

AXELMED PARADIGMA


Test performed for



by




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MANAGEMENT OF TEST Head of Biology substitute: Giulia Arniani, Dr. QUALITY ASSURANCE Quality Assurance Manager: Alessandra Marchesi, PhD

TEST DIRECTOR Giovanni Bassini, Ch.Eng.

TIME SCHEDULE OF TEST The test was started on 16/06/2017 and was completed on 22/06/2017.


LAB N. 0283




Ref. Your Order of May 2017 Sample description

Description: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No Receipt number: 2502 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Test Method

ISO 10993-5: 2009 ISO 10993-12: 2012 Other references

Cytotoxicity Test Protocol - / Summary of practice Cell cultures are grown to a near-confluent monolayer in cultures dishes. Three dishes for each sample are prepared. Moreover, three dishes are prepared for the Negative control, for the Positive control and for the Extraction solvent control. In the dishes to be treated with the sample, the medium is aspirated and replaced with test extract. Cell cultures are examined microscopically after 24 and 48h-contact to assess the presence or absence of cytotoxic effects due to the test extract. Target cells : BSCL 56 /L 929 (Mouse connective tissue) Culture medium: Minimum Essential Medium (MEM) with Earle’s salts added with 5 % of foetal bovine serum, 1 % of L-glutamine, 0,6 % of penicillin/streptomycin and 0,3 % of fungizone (complete MEM). Extraction conditions : 1,96 grams were extracted with 9,8 ml of complete Cell Culture Medium MEM (ratio 0,2 g / 1 ml) at 37°C for 72 hours. (Ref. IS O 10993-12) Positive control : 6 cm2 of latex extracted with 1 ml of complete Cell Culture Medium MEM under the same conditions of the sample. Negative control : 0,2 grams of polycarbonate extracted with 1 ml of complete Cell Culture Medium MEM under the same conditions of the sample. Extraction vehicle control: complete Cell Culture Medium MEM.


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Incubation : The dishes treated with the Test extract, with the Positive and Negative controls and with the Extraction solvent control are incubated for 48 h at 37 ± 1 °C in a 5% CO2 atmosphere.

Apparatus − Incubator, which maintains the cultures at 37 ± 1°C, 5% CO2; − Microscope, with inverted phase contrast optics; − Laminar Flow Cabinet; − Sterile Disposable; − Tissue Culture Dishes.

Interpretation of Results : The determination of the cytotoxicity is performed after a 24 and 48 h incubation period examining the cells under the microscope to assess general morphology, vacuolation, detachment, cell lysis, membrane integrity. The change from normal morphology of the Negative control is rated on a reactivity grade from 0 to 4 (see Grading system). Moreover, for the dishes treated with the Test extract the confluence of the monolayer is evaluated and the color of test medium is compared to the negative control.

Grading system

Grade Reactivity Reactivity description

0 None Discrete intracytoplasmic granules; no cell lysis.

1 Slight Not more than 20% of the cells are round, loosely attached and without intracytoplasmic granules; occasional lysed cells are present

2 Mild Not more than 50% of the cells are round and devoid of intracytoplasmic granules; no extensive cell lysis and empty areas between cells

3 Moderate Not more than 70% of the cell layers contain rounded cells or are lysed

4 Severe Nearly complete destruction of the cell layers


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Results after 24 h incubation Score

Positive control 4

Positive control 4

Positive control 4

Negative control 0

Negative control 0

Negative control 0

MEM control 0

MEM control 0

MEM control 0

Extract of the test material 0



Confluency of the monolayer Confluent

Color of test medium Comparable to the negative control

Results after 48 h incubation Score

Positive control 4

Positive control 4

Positive control 4

Negative control 0

Negative control 0

Negative control 0

MEM control 0

MEM control 0

MEM control 0




Confluency of the monolayer Confluent

Color of test medium Comparable to the negative control


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OPINIONS AND INTERPRETATIONS – Not included in ACCR EDIA accreditation The cells treated with the Test extract after 24 and 48 hours of incubation do not show any changes from normal morphology of the Negative control. The Test extract does not show any reactivity.

The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization.

Test verified by: Guardiani Silvia, Dr.

Issue authorized by: Test Director Giovanni Bassini, Ch.Eng.

Zola Predosa, 22/06/2017



Messrs AXELMED S.R.L. Via Liberazione, 58 20098 SAN GIULIANO MILANESE MI



Denomination: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No Number of samples analyzed: 5 Receipt number: 2512 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Note: Test carried out on the primary packaging after accelerating aging test (see Report n° 17-0806-0 1) The test was started on 29/01/2018 and was completed on 30/01/2018 Method: 5 samples have been tested for the seal integrity test under a column of 50 cm of water and methylene blue. RESULTS Seal integrity In conformity


Report N° 17-0806-01 Page 1/1




Report N° 17-0806-01 Sample description

Description: AXELMED PARADIGMA Code: 82113 Lot: 01816 Sterilization: No Receipt number: 2507 Receipt date: 13/06/2017 Sampling carried out by: AXELMED S.R.L. Devices exposed to accelerated aging: 25 Accelerated aging started on 14/06/2017 and was completed on 28/01/2018. Method

ASTM F 1980-16 Standard Guide for Accelerated Aging of Sterile Barrier System for medical devices. Summary of practice

In order to subject the samples to accelerated aging according to ASTM F 1980-16 Standard Practice, we calculated the parameters through the following formula: − Accelerated Aging Time (AAT) = RT/AAF − Real Time Aging (RT) = 5 years − Accelerated Aging Factors (AAF) = Q10exp[(Taa-Trt)/10] − Q10 = 2 − Taa (accelerated aging temperature) = 55 °C − Trt (ambient storage temp) = 25 °C Then the samples were incubated for 228 days at 55°C temperature. The amount of real-time aging, to which used accelerated aging conditions are estimated to be equivalent, is 5 years. The present test report exclusively refers to the referenced test sample. The present test report may not be partially reproduced without Biochem authorization. Test verified by: Rancan Milena, Dr. Issue authorized by: Head of Laboratory, Giovanni Bassini, Ch. Eng.

Mod. ConvFiltraz Rv19 Test Report N° 17-0805-01 Page 1/2

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DETERMINATION OF A POPULATION OF MICROORGANISM ON P RODUCTS – VALIDATION OF METHOD

Sample description

Denomination: AXELMED PARADIGMA Code: 82114 Lot: 01916 Sterilization: No N° of tested samples: 5 Receipt number: 2461 Receipt date: 09/06/2017 Sampling carried out by: AXELMED S.R.L. The test was started on 12/06/2017 and was completed on 14/06/2017.

Test method

ISO 11737-1:2006/Cor 1 :2007 Summary of practice

The samples have been contaminated with a know concentration of Staphylococcus aureus ATCC 6538. Micro-organisms were extracted from samples using sterile physiological saline containing 0,05 % of Tween 80 in mechanical agitation. The extract obtained from each sample was filtrated through a 0,45 µm sterile membrane filter. Each filter was incubated on Baird Parker (BP) culture medium for 48 hours at 37°C ± 2°C to evaluate recovered micro-organisms. T hen the correction factor was calculated.

Mod. ConvFiltraz Rv19 Test Report N° 17-0805-01 Page 2/2

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Results

Staphylococcus aureus ATCC 6538

Sample Contamination (cfu/sample)

Recovered micro -organism (cfu/sample) Recovery (%)

1 30 25 83.3

2 30 23 76.7

3 30 32 106.7

4 30 25 83.3

1 30 25 83.3

Mean value 26.0 86.7

Correction factor 1.15

The present test report exclusively refers to the referenced test sample. The present test report may not be reproduced without Biochem authorization. Test verified by: Guardiani Silvia, Dr. Issue authorized by: Head of Laboratory Dr. Giovanni Bassini

Mod.BiobFiltrazRv17 Test Report N° 17-0805-02 Page 1/2

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DETERMINATION OF A POPULATION OF MICROORGANISM ON P RODUCTS Sample description

Denomination: AXELMED PARADIGMA Code: 82114 Lot: 01916 Sterilization: No N° of tested samples: 10 Receipt number: 2462 Receipt date: 09/06/2017 Sampling carried out by: AXELMED S.R.L. The test was started on 09/06/2017 and was completed on 14/06/2017. Test method

ISO 11737-1:2006/Cor 1:2007

Summary of practice

Samples were aseptically treated. Micro-organisms were extracted from samples using sterile physiological saline containing 0,05 % of Tween 80 in mechanical agitation. The extract was collected and filtered through a 0,45 µm sterile membrane filter. One half of the filter was incubated on Triptone Soya Agar (TSA) culture medium for 72 hours at 32 ± 2°C in order to evaluate non-selective aerobic bac teria. The other half was incubated on Potato Dextrose Agar (POT) culture medium for 5 days at 22 ± 2°C in order to evaluate yeasts and moulds. Results were multiplied by correction factor (1,15) obtained from the method validation (see test report N° 17-0805-01).

Mod.BiobFiltrazRv17 Test Report N° 17-0805-02 Page 2/2

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Results

Sample Non-selective aerobic bacteria (cfu/sample) Moulds (cfu/sample) Yeast (cfu/sample)

1 <2 <2 <2

2 <2 <2 <2

3 <2 <2 <2

4 <2 <2 <2

5 <2 <2 <2

6 <2 2 <2

7 <2 <2 <2

8 2 <2 <2

9 <2 <2 <2

10 <2 <2 <2

Mean value <2,0 <2,0 <2,0

Correction factor 1,15 1,15 1,15

Corrected value <2,3 <2,3 <2,3

Sum of micro -organisms on the average present on sample: <6,9 The present Test Report is exclusively referred to the tested sample. The present Test Report may not be reproduced without Biochem authorisation. Test verified by: Guardiani Silvia, Dr. Issue authorised by: Head of Laboratory Dr. Giovanni Bassini

Mod DoseVer Rv04 Report N° 17-0805-03 Page 1/1




Report N° 17-0805-03 Sample description

Denomination: AXELMED PARADIGMA Code: 82114 Lot: 01916 Sterilization: No Receipt number: 2500 Receipt date: 09/06/2017 Sampling carried out by: AXELMED S.R.L. Test method

ISO 11737-1:2006/Cor 1:2007; ISO 11137-2:2013 Procedure

The sterilization dose established for product is calculated to achieve a SAL of 10-1 in accordance with Table n. 9 (ISO 11137-2) and determination of Bioburden (ISO 11737-1). Test Report N. 17-0805-02

Maximum product microbial-count 6,9 cfu/units

Measurement uncertainty applied to Bioburden ± 2,6

Verification dose required for the testing resistance to irradation (SAL 10-1) 7,1 kGy

Toleration: 10 % ± 0.7 kGy

Units of product to expose at the verify dose 10 Calculation verified by: Di Deo Sonia, Dr. and Guardiani Silvia, Dr. Issue authorised by: Head of Laboratory Dr. Giovanni Bassini

Clinical investigation of a new dental immediate implant system.

(according to ISO 14155:2011)

According to the Medical Devices Directive, both the preparation for clinical trials and marketing of implants require that a risk analysis is performed.

This paper presents the evaluation of a dental implant in the framework of the risk management process carried out for the preparation of a multi-centre clinical trial.

The clinical study aimed to demonstrate the conformity of Axelmed Paradigma with the essential requirements and to evaluate the survival rate and the possibility for the implant to be placed with a torque value between 35 and 50 Ncm in order to allow the possibility to perform, if required, an immediate loading procedure.

Introduction

Several directives regulate the marketing and distribution of medical devices in the European Economic Area. The Medical Devices Directive (MDD), which covers most implants, sets conformity assessment procedures depending on the medical device class type, and requires risk analysis to be performed.

The MDD covers medical devices intended for clinical investigations, dictating the procedure to be followed by the manufacturer and provisions under which the clinical investigations must be conducted. As a result, the EN ISO 14155 harmonised standard has been issued, providing guidance to medical device manufacturers for the conduct of their clinical investigations.

The general aim of this paper is to highlight the importance of performing risk assessments of safety and performance and clinical trials of Axelmed Paradigma using them regularly on patients. We describe the application of the dental implant Axelmed Paradigma in the framework of its development.

Confidentiality Statement This document contains confidential information that must not be disclosed to anyone other than the Sponsor and the Investigator Team.

Funder Axelmed s.r.l.

Sponsor Axelmed s.r.l.

Funding Reference Guido Ivo Tissi

Chief Investigator dott. Piero Lazzari

Sponsor Reference Guido Ivo Tissi

CLINICAL INVESTIGATION MANAGEMENT

CLINICAL INVESTIGATION MANAGEMENT GROUP The investigation group was composed by clinicians with different surgical skills and the surgical procedures performed in private clinics. The selection of this investigation group was done to simulate the daily routine in order to analyze the implant features in ordinary conditions. Specifically, the investigation group was composed by six dentists suitably trained about the data collection. This clinical investigation is conducted in full conformity with the current revision of the Declaration of Helsinki.

PARTICIPANT CONFIDENTIALITY The clinical investigation staff will ensure that the participants’anonymity is maintained. The participants will be identified only by initials. All documents will be stored securely and only accessible by clinical investigation staff and authorised personnel.

CLINICAL INVESTIGATION MANAGEMENT GROUP

Chief Investigator

Name: Piero LazzariAddress: via Beato Angelico, MilanoTelephone: 3381917289Email: [email protected]

Co Investigators

Name: Luigi BernardiniAddress: via Imbonati MilanoEmail: [email protected]

Chief Investigator

Name: Piero Lazzari

Title: Doctor

Signature:

Date: 16/01/2018

Sponsor

Name: Axelmed s.r.l - Guido Ivo Tissi

Title: CEO

Signature:

Date: 16/01/2018

Principal Investigator

Name: Piero Lazzari

Title: Doctor

Signature:

Date:16/01/2018

mailto:[email protected]


SPONSOR

Axelmed S.R.L

via della Liberazione, 58 - San Giuliano, Milan - Italy

CLINICAL INVESTIGATION SUMMARY

Co Investigators

Name: Salvatore TerlizziAddress: via Melzo, MilanoEmail: [email protected]

Co Investigators

Name: Daniele CamerucciAddress: via Eustachi MilanoEmail: [email protected]

Co Investigators

Name: Davide CasellaAddress: viale Lombardia, MilanoEmail: [email protected]

Co Investigators

Name: Maurizio SeiditaAddress: BrugherioEmail: [email protected]

Clinical Investigation title

Analysis of the primary implant stability and the proper osseointegration process of Axemled Paradigm Dental Implant.

Sponsor Reference Axelmed S.R.L - Guido Ivo Tissi - via della Liberazione, 58 - San Giuliano, Milan - Italy

Clinical Phase Phase IV

Clinical investigation Design Observational - Population Study

Number of Participants 29

Follow-up Duration 17 months

Primary Objective To evaluate the primary stability of Axelmed Paradigma Implant

Secondary Objective To evaluate the proper osseointegration of Axelmed Paradigm Implant system

Device Name Paradigma

Manufacturer Name Axelmed S.R.L.

Principle Intended Use Tooth replacement





Introduction

Axelmed Paradigma Dental implants are made of titanium alloy and manufactured by Axelmed s.r.l. (Italy). After the milling process the implants are subjected to the surface treatment and to a series of decontamination process through different steps and using different chemical agents. Finally, the implants are packaged, labelled and sterilized. The Axelmed Paradigma implants line acts as anchor for crowns, bridges or prostheses to the bone (both the upper and the lower jaw). They have an internal hexagonal connection, a conical body with two principles thread and are made by titanium Gr. 4 in accordance with the requirement of ISO 5832-2. The Axelmed Paradigma

implants are

present in 5 different diameters with the same prosthetic connection (look the table at the bottom of the page). The surface of the fixture is machined at the portion of the collar and micro-rough at the level of the body with SAP treatment (sandblasting with Al2O fine-grit, double Acidification, double decontamination with Argon Plasma). The surgical positioning of the implant is at the crestal or subcrestal bone level. It is packaged in a titanium cylinder protected by two sealed sterile tubes and a cover and an healing screw are present in the same packaging. It is sterilized by irradiation with Gamma Ray (min 25kGy) and it is “STERILE” until the expiration date.

In order to use the medical device the operators need to be exclusively a qualified Doctors or a Dentist.

Objectives

Aim of the following clinical investigation is to evaluate the Axelmed Paradigma implant System in order to analyze the possibility for the implants to guarantee a good primary stability in most of cases and to provide a proper osseointegration process. The primary stability is evaluated through the analysis of the torque value obtained during the implant placement procedure.

Materials and methods

The subjects were patients with a pre-existing need for treatment with dental implants who provided written informed consent. The surgeries was performed by different clinicians in their own private clinic.

Inclusion criteria were as follows:

• Provision of informed consent ≥ 21 years; • In need of one or more single implants; • Replacing missing or non-restorable teeth in the maxilla and in the mandible; • Absence of periodontal disease; • An opposing dentition with teeth, implant, or opposite fixed prosthesis.

Exclusion criteria were as follows:

• Presence of systemic disease affecting the bone healing; • Jaw fracture; • Radiotherapy; • Severe smoking (>20 cigarettes/day) • Hormonal imbalance;

• Patients with chronic infectious disease; • Patients receiving immunosuppressive therapy; • Pregnant women; • Drug and alcohol addicts; • Patients with severe periodontal diseases.

Parameters recorded were as follows: • Patient name • Surgery date • Implant site • Implant dimension • Mandible or maxilla • Bone quality • Torque of implant insertion • Regenerative procedure • Material used for regenerative procedure • Condition of the implant site (healed site or post extraction site) • Condition of the loading • Smoking • Name of the clinician who performed the surgery

The responsible for identifying the participants were the clinician in according to the inclusion/exclusion criteria. (In Table A there is a summery of the recorded data)

Table A

PATIENT NAME

SURGERIES DATE

IMPLANT SITE

IMPLANT DIMENSION

SIDE BONE QUALITY

TORQUE REGENERATIVE

MATERIAL SITE LOADING SMOKE

CLINICIAN

A.M. 28/04/2015 14 3.8x11 Maxilla III 35 GBR BioOss + Autologo

Healed Immediate SI Camerucci Daniele

A.M. 28/04/2015 22 3.8x11 Maxilla III 35 Healed Immediate SI Camerucci Daniele



A.M. 28/04/2015 32 3.8x11 Mandible II 50 Healed Immediate SI Camerucci Daniele




B.M. 04/03/2015 24 3.8x9 Maxilla III 50 Healed Transmucosal NO Salvatore Terlizzi

B.A. 12/04/2016 14 4.3x11 Maxilla II 50 GBR BioOss + BioGide

Post-extra ractive

Immediate NO Salvatore Terlizzi

B.L.1/7/2015 31 4.3x9 Mandible I 50 Healed Submerged NO Bernardini

Luigi


Luigi


Luigi

B.K. 04/06/2015 46 5.0x11 Mandible II 60 Healed Immediate NO Lazzari Piero

B.R. 13/11/2015 25 5.0x13 Maxilla IV 45 Healed Immediate NO Lazzari Piero

B.R. 13/11/2015 11 4.3x13 Maxilla IV 50 Healed Immediate NO Lazzari Piero

B.R. 13/11/2015 14 4.3x13 Maxilla IV 50 GBR BioOss Healed Immediate NO Lazzari Piero



C.D. 20/01/2015 27 4.3x9 Maxilla III 40 Healed Transmucosal NO Lazzari Piero

C.V. 28/05/2015 37 5.0X11 Mandible II 50 GBR GenOss Healed Transmucosal SI Lazzari Piero

CA.D. 01/04/2015 32 3.8x11 Mandible I 43 GBR Autologo + BioGide

Post-extraction

Submerged SI Camerucci Daniele


Post-extraction



Post-extraction



Post-extraction


C.A. 22/01/2015 11 4.3x13 Maxilla III 50 GBR GenOss + membrana

Post-extraction

Immediate SI Lazzari Piero

F.A. 09/02/2016 24 4.3x13 Maxilla III 20 Sinus Lift Healed Submerged NO Lazzari Piero

F.A. 09/02/2016 26 5.0x13 Maxilla III 30 Sinus Lift Healed Submerged NO Lazzari Piero

F.B. 06/11/2015 44 4.3x11 Mandible III 40 GBR BioOss + BioGide

Healed Immediate NO Lazzari Piero





F.B. 06/11/2015 32 3.4x13 Mandible IV 50 GBR BioOss + BioGide


F.B. 06/11/2015 42 3.4x13 Mandible IV 50 GBR BioOss + BioGide


G.A. 03/11/2015 16 5.0x7 Maxilla IV 10 Healed Transmucosal NO Lazzari Piero

G.A. 03/11/2015 36 3.4x11 Mandible II 50 Healed Transmucosal NO Lazzari Piero

G.A. 03/11/2015 46 4.3x11 Mandible II 50 Healed Transmucosal NO Lazzari Piero

G.Z. 1/7/2015 12 4.3x11 Maxilla III 45 Healed Submerged SI Bernardini Luigi

G.Z. 1/7/2015 14 4.3x11 Maxilla III 45 GBR BioOss + BioGide

Healed Submerged SI Bernardini Luigi



G.M. 04/03/2016 36 5.0x11 Mandible II 35 Healed Transmucosal NO Lazzari Piero

L.G. 25/03/2015 22 3.8x11 Maxilla IV 30 GBR GenOss + membrana

Post-extraction

Submerged NO Terlizzi Salvatore


Healed Submerged NO Terlizzi Salvatore


Healed Submerged NO Terlizzi Salvatore

M.ML. 29/10/2014 34 4.3x11 Mandible II 35 Healed Submerged NO Lazzari Piero

M.ML. 29/10/2014 32 3.4x13 Mandible I 40 Healed Submerged NO Lazzari Piero

M.ML. 29/10/2014 42 3.4x13 Mandible I 40 Healed Submerged NO Lazzari Piero




M.B. 27/02/2015 44 3.8x11 Mandible II 50 GBR BioOss Healed Transmucosal NO Casella Davide

M.B. 27/02/2015 45 4.3x9 Mandible II 70 GBR BioOss Healed Transmucosal NO Casella Davide

R.R. 24/06/2015 36 5.6x11 Mandible II 35 GBR BioOss Healed Transmucosal NO Lazzari Piero

SF.R. 16/04/2015 46 4.3x11 Mandible II 40 Healed Transmucosal NO Lazzari Piero

SF.R. 16/04/2015 17 4.3x11 Maxilla II 60 Healed Submerged NO Lazzari Piero

S.R. 18/11/2015 33 4.3x13 Mandible III 50 GBR BioOss Post-extraction

Transmucosal NO Lazzari Piero

S.R. 18/11/2015 43 4.3x13 Mandible III 50 GBR BioOss Post-extraction

Transmucosal NO Lazzari Piero

S.M. 19/11/2015 45 4.3x11 Mandible II 50 GBR BioOss Post-extraction


S.M. 01/03/2015 25 3.8x11 Maxilla II 20 Healed Transmucosal SI Seidita Maurizio




S.C. 03/12/2014 26 5.0x9 Maxilla I 40 Healed Immediate SI Lazzari Piero



S.C. 03/12/2014 12 4.3x11 Maxilla I 50 Post-extraction


S.C. 03/12/2014 14 4.3x13 Maxilla I 50 Post-extraction



S.E. 10/11/2015 32 4.3x11 Mandible I 20 Healed Transmucosal NO Lazzari Piero




S.E. 10/11/2015 12 4.3x9 Maxilla IV 50 Healed Submerged NO Lazzari Piero




Consenting Participants

The participant must personally sign and date the latest approved version of the informed consent form before any clinical investigation specific procedures are performed. Written and verbal versions of the participant information and Informed consent will be presented to the participants detailing no less than: the exact nature of the clinical investigation; the implications and constraints of the clinical investigation plan; the known side effects and any risks involved in taking part. It will be clearly stated that the participant is free to withdraw from the clinical investigation at any time for any reason without prejudice to future care, and with no obligation to give the reason for withdrawal.

Written Informed Consent will then be obtained by means of participant dated signature and dated signature of the person who presented and obtained the informed consent. The person who obtained the consent must be suitably qualified and experienced, and have been authorised to do so by the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the participants. The original signed form will be retained at the clinical investigation site.

T.I. 2/12/2014 16 5.0x9 Maxilla III 35 Summer Healed Submerged NO Lazzari Piero

Z.A. 5/04/2015 27 Maxilla IV 20 Post-extraction


Z.A. 5/04/2015 17 Maxilla III 35 Post-extraction


















P.A. 7/7/2016 12 Maxilla II 40 Healed Immediate No Lazzari Piero






CLINICAL INVESTIGATION

Obtaining a good primary stability is one of the main objectives during a dental implant placement procedure and the specific geometries for each Axelmed Paradigma diameter were developed to satisfy this requirement. The present report aims at analyzing this feature in different clinical conditions. 29 patients received consecutively a total of 93 Axelmed Paradigm by different operators. The clinical protocol is summarized in the following scheme.

One day prior to surgery, the patients received prophylactic antibiotic therapy: Amoxicillina orally starting 1 day before procedure For patients who cannot use oral medications Clindamicina 300 mg orally starting 1 day before procedure

They also continued the treatment after the procedure, taking 2 capsules daily for 6 days. After surgery, a Chlorhexidine mouthwash was prescribed for twice-daily use for 15 days. Ibuprofen (600 mg, 2 times daily) was prescribed if necessary because of post-operative pain. All patients were treated under local anesthesia using articaine with adrenaline.

Post extraction site A “flapless" approach was chosen for the procedure. Tooth extractions were performed with elevators to help minimize trauma. Great care was taken to maintain the integrity of the buccal bone wall. After extraction, the socket was carefully curetted; subsequently, the implant bed was prepared according to the following procedure. The implant site was prepared using Axelmed drills,

following the palatal bony walls and always placed ≥ 3 mm beyond the root apex. Copious irrigation with saline was done during the surgical procedure. The coronal margin of the implant was located 2 mm below the buccal level of the bone crest. Grafting materials was placed into the peri-implant gap without the use of barriers membranes. Healed site An “open flap" approach was chosen for the procedure. An incision was given to reflect the mucoperiosteal flap. The osteotomy was initiated using a pilot drill of 2 mm through the surgical template followed by sequential drilling to prepare the site according to the selected implant size. Copious irrigation with saline was done during the surgical procedure. The implant was inserted with the help of insertion tool and a torque wrench.

———————————————-

At the end of the surgical procedure, on the basis of primary stability, an immediate loading or a delayed loading were performed. Minimum of 35–40 N-cm of torque was considered useful for the immediate loading procedure.

Immediate Loading Immediately after the end of the surgery an impression trough the “Open tray technique” and using a Polyether material (Impregum - 3M Italia) was made. The day after the temporary crown was delivered to the patient.

Delayed Loading One stage procedure

An impression trough the “Open tray technique” and using a Polyether material (Impregum - 3M Italia) was made and a temporary crown was delivered 7 days after.

Two stage procedure 12 weeks after the implant placement a second surgery was performed in order to replace the cover screw with an healing cap. A minimally invasive approach was preferred and a short incision was performed in correspondence with the implant site. If possible after the healing abutment placement any suture was applied.

In order to shape a proper transmucosal space and to give to the technician the possibility to create a proper emergence profile, in both cases (Immediate ore Delayed Loading), the temporary crown was removed 8 weeks after the delivery.

Of the 93 implants, 39 (41.9%) were loaded immediately, while the remaining 54 (58,1%) were loaded 10 weeks after the placement. 63 (67.7%) Axelmed Paradigma implants were used in a one-step technique, while the remaining 30 (32.3%) received a two-phase approach. Torque insertion was evaluated, postoperative Rx were taken at T0 (immediately after surgery), T1 (1 month), T2 (3 months), T3 (1 year) and the follow up was between 4 and 16 months. 2 implants (2.1%) failed, both in the maxilla, both placed immediately after tooth extraction and both treated with an immediate loading protocol where the initial insertion torque was 50 Ncm in presence of a III Class bone quality (Lekholm and Zarb, 1985). 23 implants (24.7%) were placed in post-extraction sockets, while 70 (75.3%) were in healed sites. The 93 Axelmed Paradigma received

an initial torque with its distribution summarized in the bar graph. These values were recorded using the surgical motor Intrasurgery 2.0. Literature data indicate that it’s desirable to reach a minimum value of 35 Ncm to proceed with an immediate loading protocol. However, some authors advise against using very high torque values (above 70 Ncm) to avoid possible necrosis around the implant fixture. The data and the experience in this report indicate the possibility to achieve good levels of primary stability using Axelmed

Paradigma dental implants that respect bone tissue biology and surrounding structures. The implant thread design (trapezoidal with decreasing depth) and the conical shape of the body allowed to achieve a good primary stability. This is the main objective for the clinicians dealing with immediate loading protocol during their activity. Effectively, this implant design appears to demonstrate in almost 84% of the cases an excellent primary stability with > 35 Ncm torque insertion.

Discussion

Overall survival rates of Paradigma implants of 97.9% have been reported. Failure rates were higher in the maxilla in patients with metabolic diseases, bones of D4 quality and in smokers.

Esposito et al found a set of factors associated with the failures of oral implants, with excessive surgical trauma together with an impaired healing ability, premature loading and infection as the most common causes of early implant losses. Progressive chronic marginal infection and overload, in conjunction with the host characteristics were the major etiological agents causing late failures.

A scientific literature review, together with the personal experience of the surgeons taking part in the clinical study, led to the identification of the main hazards of implant failure. These were the implant insertion operation (and the associated surgical trauma), patient hygiene (including smoking habits), patient bone quality and the mechanical properties of the implant.

It is certainly important a careful selection of the patient who undergoes to the surgical procedure and it is equally important the quality of the medical devices.

Regarding the last point Axelmed Paradigma, with its survival rate which is in accordance with the best standard of data present in literature, seems to respect the quality standard required to perform the procedure safely and properly.

References

Stanford CM1, Keller JC, Solursh Bone cell expression on titanium surfaces is altered by sterilization treatments. J Dent Res. 1994 May;73(5):1061-71.

Lee HJ, Yang IH, KIM SH, Yeo IS, Kwon TkIn vivo comparison between the effects of chemically modified titanium surfaces on initial bone healing. J Periodontal Implant Sci. 2015 Jun;45(3):94-100.

Giroud D. A revised guideline for medical device clinical investigations: ISO 14155 part 1 and 2:2003. Qual Azur J 2003;8(1):37– 40.

ISO 11138:2006. Sterilization of Health Care Products—Biological Indicators. International Organization for Standardization.

The World Medical Association, Declaration of Helsinki,2004version. http://www.wma.net/e/ethicsunit/helsinki.htm.

Mundt T, Mack F, Schwahn C, Biffar R. Private practice results of screw-type tapered implants: survival and evaluation of risk factors. Int J Oral Maxillofac Implants 2006;21(4):607–14.

Wagenberg B, Froum SJ. A retrospective study of 1925 consecutively placed immediate implants from 1988 to 2004. Int J Oral Maxillofac Implants 2006;21(1):71–80.

Kourtis SG, Sotiriadou S, Voliotis S, Challas A. Private practice results of dental implants. Part I: survival and evaluation of risk factors–Part II: surgical and prosthetic complications. Implant Dent 2004;13(4):373–85.

Lemmerman KJ, Lemmerman NE. Osseointegrated dental implants in private practice: a long-term case series study. J Periodonto 2005;76(2):310–9.

Esposito M, Hirsch JM, Lekholm U, Thomsen P. Biological factors contributing to failures of osseointegrated oral implants. II. Etiopathogenesis. Eur J Oral Sci 1998;106(3):721–64.

Braceras I, On ̃ate JI, Goikoetxea L, Viviente JL, Alava JI, De Maeztu MA. Bone cell adhesion on ion implanted titanium alloys. Surf Coat Tech 2005;196:321–6.

Braceras I, Alava JI, Goikoetxea L, De Maeztu MA, Onate JI. Interaction of engineered surfaces with the living world: ion implantation vs. osseointegration. Surf Coat Tech 2007;201(19–20): 8091–8.

AXELMED S.r.l. / Via Liberazione, 58 / 20098 S. Giuliano Milan (MI) / Italy C.F. e P.IVA (VAT#): IT 09541170966 / R.E.A. MI 2097286 / C.S. i.v. Euro 25.000,00 Tel: +39 02 9828 2694 / Fax: +39 02 9828 5327 / PEC: [email protected] eMail: [email protected] / Web: www.axelmed.com / Axelmed® registered mark

Milan, 15/04/2016

CLINICAL REPORT AND EVALUATION TRIAL OF DENTAL IMPLANTS “AXELMED PARADIGMA”

Our Referemnt: PL001 Num. copies 1 Pages: 7 Evaluation by Dr. Piero LAZZARI ...... ......................................... Private Clinic - Via S. Faustino, 10 - 20134 Milano Iscrizione Albo Odontoiatri di Milano al No.5020

THIS REPORT IS STORED IN THE AXELMED COMPANY DIGITAL ARCHIVES UNDER DIGITAL FORM.


REPORT ON "AXELMED PARADIGMA” IMPLANT

In September 2014 I started to follow the "Axelmed Project" to develop a dental

implant designed to solve the majority of clinical situations characterized by single or

multiple endetulism in the areas of the jaws with different bone density.

Several prototypes have been made before the development of AXELMED PARADIGMA

into its current geometry. AXELMED PARADIGMA implants are available in five

diameters and five heights and, in order to obtain a device able to provide a surgical

predictability in terms of primary stability, it was necessary to design 5 different

geometries, each one specific for each implant diameter.

During the period between November 2014 and April 2016, following clinical trials

onanimal models (pork jaw) and before the lunch on the market, 29 patients were treated

with 93 AXELMED PARADIGMA implants by various clinicians with different surgical

skills.

39 (41.9%) implants were loaded immediately, while the remaining 54 (58.1%) were

loaded 10 weeks after the placement. 63 (67.7%) Axelmed® Paradigma® implants were

used in a one-step technique, while the remaining 30 (32.3%) received a two-phase

approach.

For each implant the initial insertion torque was evaluated, postoperative Rx was taken at

T0 (immedialtely after surgery), T1 (1 month), T2 (3 months), T3 (1 year) and all the

implants and the follow-up was between 4 and 16 months.

Two (2.1%) implants failed, both in the maxilla, both placed immediately after tooth

extraction and both treated with an immediate loading protocol where the initial insertion

torque was 50 Ncm in presence of a III Class bone quality (Lekholm and Zarb, 1985).

Therefore, probably the cause of failures need to be found in an inappropriate diagnostic

therapeutic evaluation by the clinician.

23 implants (24.7%) were placed in post-extraction sockets, while 70 (75.3%) were in

healed sites.


Dati Generali

Patients 29

Implants 93

Implants Failure 2 2.1%

Maxillary 52 55.9%

Mandibular 41 43.6%

One-Step Technique 63 67.7%

Two-Steps Technique 30 32.3%

Post-Extraction Sites 23 24.7%

Healed Sites 70 75.3%

Immediate Loading 39 41.9%

Delayed Loading 54 58.1%

The 93 Axelmed® Paradigma® received an initial torque with its distribution

summarized in the following table. These values were recorded using the surgical motor

Intrasurgery 2.0.

Valori Torque (Tq) Numero impianti

Tq < 20 Ncm 2

20 Ncm < Tq < 35 Ncm 12

35 Ncm < Tq < 50 Ncm 69

Tq > 50 Ncm 10

Literature data indicate that it’s desirable to reach a minimum value of 35 Ncm to proceed

with an immediate loading protocol. However, some authors advise against using very

high torque values (above 70 Ncm) to avoid possible necrosis around the implant fixture.

The data and the experience in this report indicate the possibility to achieve good levels

of primary stability using Axelmed® Paradigma® dental implants that respect bone tissue


biology and surrounding structures.The implant thread design (trapezoidal with

decreasing depth) and the conical shape of the body allowed to achieve a good primary

stability. This is the main objective for the clinicians dealing with immediate loading

protocol during their activity.

In attachment a selection of clinical cases treated during this trial is available.




* Impianti utilizzati per le prove cliniche certificati CE

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