Randomized Controlled Study to Evaluate the Performance and Safety of a Linear Hyaluronic Acid-based Medical Device in the Treatment of Wounds
Phase: NA
Conditions: Wound Healing Disorder
Sponsor: Nova Argentia S.r.l.

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Documento 
Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
 
 
 
Floor of Investigation 
Clinic 
 
 
Study randomized, checked For there assessment from the performance And from 
the safety Of a device doctor to basic Of acid hyaluronic linear In the treatment 
from the wounds. WOUND-H study 
 
 
 
Date and version : 26 June 2023, version 2. 
Typology of the study : Interventional, randomized, checked, monocentric. 
Responsible scientific : Dr. Marco Daniel 
P romotor : Nova Argentia srl 
Typology Study : Profit 
Costs : Not And expected any compensation For The experimenters And no cost additional to load of the 
NHS. 
Responsible of the monitoring of the data : Doctor Brunella Orru 
Centers participants : Home From Treatment Rehabilitation Villa Sofia, Acireale (Ct) 

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Documento 
Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
Summary 
1 
General information  ....................................................................................................................... 4 
1.1 
Identification of the sponsor  ............................................................................................................... 4 
1.2 
Information on the experimenters  ..................................................................................................... 4 
1.3 
Method Of financing of the investigation clinic  ................................................................................. 4 
1.4 
Device Doctor  ...................................................................................................................................... 4 
2 
Introduction And rational:  ............................................................................................................. 5 
3 
Risks and clinical benefits of the device  ........................................................................................ 6 
4 
Objectives  ....................................................................................................................................... 6 
5 
Drawing From Studio  ..................................................................................................................... 7 
5.1 
Scheme of the protocol clinical  ........................................................................................................... 8 
5.2 
Population in study  ............................................................................................................................. 8 
5.3 
Criteria Of selection of the patients:  .................................................................................................. 9 
5.4 
Criteria Of exclusion:  ........................................................................................................................... 9 
5.5 
Intervention  ......................................................................................................................................... 9 
5.6 
Endpoints  ........................................................................................................................................... 10 
5.7 
Strategies For there reduction of the bias  ........................................................................................ 10 
6 
Collection Data  ............................................................................................................................. 11 
6.1 
Consent informed  .............................................................................................................................. 11 
6.2 
Information clinics  ............................................................................................................................. 11 
6.3 
Examination Physique  ....................................................................................................................... 11 
6.4 
Registration of the data  .................................................................................................................... 12 
6.5 
Collection And storage of the questionnaires  .................................................................................. 12 
7 
Management of the data  ............................................................................................................. 12 
8 
Risks for patients  .......................................................................................................................... 13 
9 
Management of adverse events  .................................................................................................. 13 
9.1 
Events adverse  ................................................................................................................................... 13 
9.2 
Definition Of event adverse (AE) and effect adverse of the device (ADE)  ...................................... 13 
9.3 
Hospitalization – Extension of the recovery existing  ....................................................................... 15 
9.4 
SAE/SADE relative at procedures mandatory of the study  .............................................................. 15 

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Documento 
Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
9.5 
Pregnancy  .......................................................................................................................................... 15 
9.6 
Severity of the events adverse/effects adverse of the device ......................................................... 16 
9.7 
Relation with The device doctor  ....................................................................................................... 16 
9.8 
Procedures Of reporting  .................................................................................................................... 17 
9.9 
Procedures Of report For SAE/SADE  ................................................................................................. 17 
10 
Withdraw of patients from study  ............................................................................................ 18 
10.1 
Criteria For The withdraw of the subjects give it study  ................................................................... 18 
10.2 
Follow up of the patients retreat from the investigation clinic  ....................................................... 19 
10.3 
Politics Of replacement of the subjects withdrawn  ......................................................................... 19 
10.4 
Conclusion anticipated of the investigation clinic ............................................................................ 19 
11 
Monitoring plan  ....................................................................................................................... 19 
12 
Changes of the clinical investigation plan  ............................................................................... 20 
13 
Responsibility relating to device  .............................................................................................. 20 
14 
Calculation of sample size  ........................................................................................................ 20 
15 
Analyses statistics  .................................................................................................................... 21 
16 
Timing  ....................................................................................................................................... 21 
17 
Publication of the results  ......................................................................................................... 21 
18 
Ethics and legal requirements  ................................................................................................. 21 
18.1 
Declaration Of Helsinki  ...................................................................................................................... 22 
18.2 
Good practice clinic (EN ISO 14155)  .................................................................................................. 22 
19 
Bibliography  ............................................................................................................................. 22 

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Documento 
Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
 
1 
Generality 
 
 
1.1 
Identification of the sponsor 
 
Nova Argentia srl- Street Carlo Brings 49 – 20064 – Gorgonzola (Me) | PI 02387941202 | REA: no 
1737348 
 
 
1.2 
Information on experimenters 
Experimenter principal: Dr. Marco Daniele, Manager Doctor, Home From Treatment Rehabilitation 
Villa Sofia, Acireale (Ct). Contacts of emergency: +39 095 763 1997 
 
1.3 
Method Of financing of the investigation clinic 
The study is financed by the sponsor. A contract/agreement will be stipulated between the sponsor and 
the experimental site where compensation and responsibilities are established. A draft of this 
convention was submitted to approval of the competent Ethics Committee. 
 
1.4 
Device Doctor 
Nova.Emostop Re-epithelizing [Acid hyaluronic linear 0.2%] 
 
The device Yes presents in formulation gel to basic Of acid hyaluronic linear. Yes deals with Of a 
device medical based substances, non-sterile. The formulation does not contain substances of animal 
origin, substances deriving from human blood or tissues, CRM substances or substances with 
pharmacological action ancillary. This medical device falls into class IIb, based on the classification 
criteria expressed in the EU Regulation on medical devices 2017/745, Annex VIII, paragraph 5.4, rule 
4 That defines "Everyone the devices Not invasive in contact with there skin or there mucosa injured 
they fall… in the class IIb if they are intended to be used primarily for skin wounds that have 
vulnerated The dermis or there mucosa And That can heal Alone second intention,". 
 
Intended use : The medical device promotes the healing of wounds thanks to its action Hyaluronic 
acid moisturizer. Hyaluronic acid deposited on the wound surface forms a film moisturizing That 
protects The tissue give it agents external And maintains The correct degree Of hydration promoting 
there healing from the wound. 
 
Directions : treatment Of injuries acute superficial, burns superficial And small wounds. 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
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Codice 
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v. 2 del 26 giugno, 2023 
 
 
 
Traceability: there traceability of the device And guaranteed from the a number identifier of the 
lot Of production. 
 
Materials That they enter in contact with The body human: Everyone the materials That make up The 
device they have a long history Of usage within clinical e a proven one profile of safety. 
They are: 
High molecular weight sodium hyaluronate (2500-3500 
Kd) D-Panthenol 
Triethanolamine 
(TEA) Carbomer 940 
Symdiol 68T 
 
Medical or surgical procedures related to the use of the device and experience necessary for its use 
usage 
The device must be applied to the wound which must then be covered with an appropriate bandage. 
Considered there simplicity from the procedure Of application That Not differs from numerous others 
devices having the same indications, the device can be applied by healthcare personnel (doctors or 
nurses) without there need Of a specific training. 
 
 
 
2 
Introduction And rational: 
Wound healing is a complex and dynamic process, which is still far from being completely 
understood. Wounds can be classified based on different characteristics such as trigger factor, exposure 
to the external environment, the depth of the wound, the period of time recovery, the potential risk of 
infections 1 . Two main processes are involved in healing of wounds: regeneration and repair. 
Regeneration involves the activation of stem cells in able to reconstitute the integrity of the tissue 
which will be indistinguishable from the tissue before the injury. To the Conversely, repair involves 
the formation of fibrotic scar tissue in which the architecture and the functionality of the original 
tissue are partially lost. Wound healing can be classified into three different categories: by primary, 
secondary or tertiary intention. The healing of wound For intention primary happens when there is a 
minimal loss Of tissue, to example suture from the wounded or taped. This wound will heal with a thin, 
clean scar, low inflammation, edema and ache. Wound healing by secondary intention occurs when 
part of the tissue is lost And there is a defect Very more great. In This case, The process restorative 
And Very more complicated That involves a greater inflammation, edema And ache prolonged For a 
time more long respect at the 

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Documento 
Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
wound healing with primary intention. Wound healing by tertiary intention yes verify when a process 
For intention secondary he comes intentionally interrupted And there wound will be closed 
mechanically, for example After That Yes And format the fabric of granulation. 
Many strategies And products I am States proposed to the end Of improve there healing from the 
wounds, reduce The pain and morbidity for patients such as wound dressings, growth factors, 
substitutes for skin, there dressing of the collagen, insulin topical, the antioxidant, there room 
hyperbaric, etc. 1 The acid hyaluronic (HAS) And state discovery In the 1934 from Meyer And 
Palmer In the vitreous bovine eye. AND a glycosaminoglycan present in nature That, in virtue 
from the her viscosity, elasticity And other property rheological, acts as lubricant eye And as fluid 
lubricant And shock-absorbing in joints. He comes product come on fibroblasts inside of from the 
membrane mobile phone And Therefore released in space extracellular. Inside of from the skin, carries 
out a role important in hydration of the space extracellular; constitutes a matrix For hold up the 
normal functions from the cells; has Also functions In the filling of the space, in the lubrication, in the 
healing from the wounds, in the modulation from the cells inflammatory And in scavenging of the 
radicals free 2.3 . There concentration Of HAS in the epidermis And Of 15 μg/g And In the dermis And 
Of 740 μg/g; there mass molecular Of HAS in the skin And Of 1 kDa. IT HAS native And a chain 
polysaccharide linear similar to the HA In the dermis. AND a gel viscoelastic translucent That can be 
obtained in highly purified form from rooster combs or through bacterial fermentation. Not has 
specificity Of species And The risk Of a reaction Of hypersensitivity And Like this Bass That 
Not And necessary The test cutaneous. There her mass molecular varies Between 0.1 And 2.5 kDa. 
A gram Of HAS can bind until to 6 litres Of waterfall. That is it means That greater And there 
percentage Of HAS in a product, greater will be there her capacity Of hold back the water. Thank you to 
the his remarkable potential biomedical And Of regeneration of the fabrics, It has And widely 
employee In the treatment from the wounds under different formulations as gauze, creams And gel 4 , 
showing results clinical significance 5–11 . 
 
3 
Risks And benefits clinicians of the device 
 
AND was prepared a careful one procedure Of check of the risks connected with use of the device. The 
level Of Everything is fine risk And state valued in basic at the her severity and at the chance That it 
Yes check. The level of risk of all risks residues And acceptable result. 
The clinical benefits of the device are supported by substantial supporting scientific literature the use 
of hyaluronic acid-based devices to improve wound regeneration. For an analysis more detailed from 
the literature relevant see there Investigator Brochures. 
 
4 
Goals: 
 
The primary objective of the study is to evaluate the safety and performance of a medical device Of 
Class IIB to basic Of acid hyaluronic linear used In the treatment from the wounds post-surgery. The 
outcomes of the study are the improvement of wound healing assessed through the Clinical Healing 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
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Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
score (score from 0 to 5), That includes there assessment Of: redness, edema, 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
suppuration, healthy granulation tissue and signs of re-epithelization; the percentage of patients with 
wounds completely healed at day 30 post-treatment; the pain perceived by the patient when changing 
from the dressing; there frequency of events adverse. 
 
Team Of operators involved in study 
The team Of operators involved in study And Like this composed: 
Scientific director and coordinator of the study: Dr. Marco Daniele 
Members effective of the team: Dr. Salvo Balm 
All members of the team are surgeons specializing in Physiatry belonging to the Operating Unit 
Simple Rehabilitation Nursing Home Villa Sofia. The CVs of the team members are available in 
attached hereto clinical protocol. 
 
 
5 
Drawing Of the Study 
This is an interventional, single-center study. The aim of the study is to evaluate the safety and 
performance of a class IIB medical device based on linear hyaluronic acid in treatment from the 
wounds surgical. 
Patients who have undergone surgery for knee prosthesis implantation will be chosen hip and 
recruited based on the selection criteria described below. Patients will be randomized into two groups 
in which the control group will receive the normal standard therapies for the treatment of wound 
(typically cleaning and disinfection only) while the treated group will receive two applications daily 
use of the medical device. The following visits are scheduled for patients: screening (visit 0) to 
collect the patient's demographic and clinical data, compliance with the inclusion/exclusion criteria; 
Baseline (visit 1) evaluation of the wound through the Clinical Healing score and start of treatment; 
follow up 1 (visit 2 – 7 days of treatment) clinical evaluation of the wound, Clinical Healing score, 
pain assessment upon dressing change; follow up 2 (visit 3 – de-suturing of the wound (18-20 days 
Of treatment) assessment clinic, Clinical Healing scores, assessment ache to the exchange dressing; 
follow up 3 (visit 4 – 30 days of treatment) clinical evaluation, Clinical Healing scores, assessment 
ache to the exchange dressing, determination healing wound (self completely cured or not). A 
photographic documentation of the wound during the healing process will come collected at visits 1, 
2, 3 and 4. For safety assessment all adverse events and events adverse serious they will come sign in 
And evaluated in relation to those to report from the literature scientific For devices similar doctors. 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
Scheme of the Clinical Healing Score 12 
 
 
 
5.1 
Scheme of the protocol clinical 
 
Visit 0 Screening: collection information clinics on the patient, inclusion 
Visit 1 Baselines: assessment clinic, Clinical Healing scores, photography from the wound, start 
Treatment. 
Visit 2 Follow up 1 (7 days Of treatment): assessment clinic, Clinical Healing scores, assessment ache 
to the dressing change, assessment reactions adverse, photography from the wound. 
Visit 3 Follow up 2 (at the desaturation): assessment clinic, Clinical Healing scores, assessment ache to 
the dressing change, assessment reactions adverse, photography from the wound. 
Visit 4 (30 days Of treatment): assessment clinic, Clinical Healing scores, assessment ache to the 
exchange dressing, determination healing wound, photography from the wound And collection events 
adverse. 
 
 
 
5.2 
Population in study 
The study concerns the population of adult patients who have undergone surgery knee, at the hip or to 
the femur And That present wounds surgical from deal with. The study it will come conducted in a 
hospital setting at the Simple Operational Unit of Orthopedic Rehabilitation - of the Casa di Villa 
Sofia rehabilitation care. The enrollment procedure involves screening of patients who are present the 
UOS Of Rehabilitation orthopaedic Of Villa Sofia with wounds post-surgical And The following 
enlistment Of those patients respondents to the criteria of the study. Not And expected inclusion Of 
subjects fragile in study. The patient can retreat give it study in any moment declaring it to the 
Responsible of the study, in such case he comes asked to the patient Of make the themselves 
procedures expected for visit 4. The patient is excluded from the study if: 1- deviations from the 
protocol are detected; 2- events arise serious adverse events That prejudice the continuation of study. 

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Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
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Codice 
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v. 2 del 26 giugno, 2023 
 
 
 
 
5.3 
Criteria Of selection of the patients: 
● Patients adults with wounds postsurgical. 
● Subjects in degree Of respect the procedures of the protocol; 
● Signature of the Consent informed 
 
 
5.4 
Criteria Of exclusion: 
● 
pregnancy or feeding time; 
● 
procedures contraceptives inadequate in women fertile; 
● 
treatment concomitant chronic with antiseptics locals, use Of drugs anti-inflammatories (steroids 
And Not steroids), analgesics, antineoplastics or immunosuppressants 
● 
use Not therapeutic Of substances psychoactive, abuse Of drugs and/or alcohol 
● 
immunodeficiencies (included infection from HIV) 
● 
Patients oncology; 
● 
allergies Note, hypersensitivity or intolerance to a any from the substances administered in This 
study 
● 
any condition medical or Not medical That can reduce significantly there possibility Of obtain 
reliable data e reach the objectives of study 
● 
Participation to Education clinicians with devices or drugs in the 3 months precedents at the visit Of 
screening. 
 
 
5.5 
Intervention 
THE patients included in study they will be randomized through blocks Of randomization (1:1) 
generated by a computer and assigned to one of the two treatment groups. Patients assigned to the 
group of control will receive the treatment required by normal clinical practice, i.e. cleaning and 
disinfection of the wound the uninjected socket acts as a control; patients assigned to the treatment 
group they will receive, beyond at the cleaning And disinfection, two applications daily of the device 
doctor object of study. The medical device is released in the form of a pre-filled 30 g tube. in tube of 
aluminium with label descriptive of the product. A example Of packaging and labelling And available 
in Annex I. The Follow-up period lasts 30 days from the end of treatment, this corresponds to an 
overall duration (from recruitment to the end of the study) of approximately 40 days For Everything is 
fine patient. 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
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Codice 
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v. 2 del 26 giugno, 2023 
 
5.6 
Endpoints: 
 
Performance 
The endpoint primaries Of This study I am: 
1. The improvement In the Clinical Healing score at the visit 3 (desaturation 18-20 days After 
The treatment) 
2. There reduction from the dimension from the wound at the visit 4 (30 days Of treatment) 
measured through the morphometric analysis of wound. 
 
The endpoints secondary I am: 
 
1. improvement In the Clinical Healing score at the visit 2 And at the visit 4. 
2. There percentage Of patients with wound completely healed at the visit 4. 
3. The ache perceived from the patient to the exchange from the dressing at visits 2, 3 And 4 (stairs 
NRS). 
 
 
Safety 
To evaluate the safety of the devices, all adverse reactions will be collected and recorded (if present). 
The rate of adverse reactions and the occurrence of adverse reactions not described in literature will be 
submitted to assessment descriptive. 
 
 
5.7 
Strategies For there reduction of the bias 
 
To the end Of reduce the possible bias in the assessment from the healing from the wound from part 
of the experimentedori he comes introduced a further analyses For to determine The degree Of healing 
from the wound: morphometric analysis of the wound. A digital photograph of the lesion will be taken 
at each visit for a total Of 4 Images (baseline, visit 1-3). The photos they will be taken following the 
recommendations of the Work Of Checked et to the. “Lieutenant top tips: wound photo documentation” 
13 For obtain Images standardized. The analysis morphometric from the wound consists in the 
assessment from the healing from the wound through there measurement from the wound performed 
with a software specific. Such measurement it is objective and not subject to the experimenter's 
interpretation. The size of the lesion will vary calculated at baseline and visits 1-3, healing will be 
expressed as a percentage of baseline. 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
[acido ialuronico lineare per il 
trattamento delle ferite] 
Codice 
NA-01-23 
v. 2 del 26 giugno, 2023 
 
6 
Collection Data 
 
6.1 
Consent informed 
After have received the instructions complete concerning there nature, The meaning, the impact And the 
risks Of this clinical investigation, the patient must give written consent to participate in the study. 
During education patients must be informed that they can withdraw their consent, without provide 
reasons, at any time without their further medical care being affected in any way. In addition to the 
comprehensive instructions given to patients by the investigator, patients receive Also a form 
information written For The patient in a language understandable, That explains there nature And the 
scope of the study And The his progress. THE patients they must accept there possibility That the data 
concerning at the study are transmitted to the competent authorities. Patients must be informed in detail 
of the They obligations in relation to insurance For Not to compromise there coverage insurance 
 
 
6.2 
Information clinics 
 
The clinical/medical history of the patients will be obtained at the screening visit (Visit 0) with 
particulars Attention to as follows: 
 
● Acquisition of information clinics on state general of the patient included pathologies previous or 
current, including The conditions Of interest, habits regard to smoking. 
● Pharmacotherapy, use chronic Of any drug (prescribed And to the bench, included The 
supplements food); 
● History Of allergies or reactions idiosyncratic to the drugs; 
 
 
6.3 
Examination Physicist 
 
A complete physical examination will be conducted at visit 1 and will include measurements of 
height, weight. The weight will be measured on a standard calibrated scale. Subjects must be dressed 
in indoor clothing light without shoes. Weight will be documented in kilograms to the nearest tenth 
of a kilogram. For the measurements of the height, the subjects they must to be measure yourself 
without shoes. The height will be documented to the tenth Of centimeter more Neighbor. The exam 
physicist will be executed from a doctor authorized. Full details of the physical examination will be 
recorded in the source documents at the implementing site of the study. 

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Valutazione prestazioni e sicurezza 
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6.4 
Registration of the data 
 
The use of black ink is required for completed subject questionnaires. If they are necessary changes, 
subjects need to be asked to make changes by drawing a line on the unwanted response, and then 
recording the desired response. Once a subject returns the questionnaire, it will not be allowed any 
edit. 
 
 
6.5 
Collection And storage of the questionnaires 
 
Upon completion of the questionnaires, the investigator will retrieve the questionnaires and check 
that the section of the header (Number object, Date Of visit, etc.) is was completed. The experimenter 
(or designated qualified member of their staff) will use the questionnaires completed by the 
individual to insert the data sign in in the section appropriate eCFR. There version original of the 
questionnaires filled out will remain with the documents originals of the subject. A survey compiled 
Not needs to to be returned to the subject when they will be returned to the documents originals. 
 
7 
Management of the data 
 
The information on subjects of the study they will be maintained confidential And managed in basic at 
laws in force and regulations. The data collection system for this study uses security features built-in 
for all data to be transmitted in both directions, preventing non-access authorized at information on 
participants. Access to the system will be checked from a sequence Of codes Of identification And 
password assigned to users, returns available Alone to the personal authorized who have completed 
the necessary training. Before starting the study, and at each meeting, the staff will review the 
protocol and CRFs. During the study, you will need to periodically check the completeness from the 
folders clinics of the patients, the accuracy registrations to the CRF, membership to the protocol to 
Good Clinical Practice and the advancement of patient enrollment. The experimenter must maintain 
original documents for each patient in the study including hospital medical records containing 
demographic and medical data, laboratory data, electrocardiograms and the results of any other test 
or assessment. All information recorded on CRFs must be traceable to original documents in the 
patient file. Staff must also keep the consent form informed signed in original (a copy signed he 
comes released to the patient) 

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Studio WOUND-H 
Valutazione prestazioni e sicurezza 
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v. 2 del 26 giugno, 2023 
 
 
 
8 
Risks For the patients 
 
Not I am States identified details risks tied to the treatment topical with acid hyaluronic linear in wounds 
post-surgical. 
 
9 
Management of the events adverse 
 
9.1 
Events adverse 
The events adverse due to use Of acid hyaluronic In the treatment from the wounds I am generally 
traceable to phenomena Of intolerance to the product And solvable in few days without treatment. 
Everyone The events adverse insurgents during The treatment, right away After The treatment And In 
the period Of follow up will be recorded in the “Adverse Event Form” (Annex I of the CRF). Adverse 
events will come classified by severity, relationship with the device being studied, intended or not, 
need Of treatment. 
 
 
9.2 
Definition Of event adverse (AE) and effect adverse of the device (HADES) 
 
A AE / HADES And any change adverse respect at the condition basal of the subject, it's worth it to to 
say any unfavorable and unintended sign including an abnormal laboratory result, symptom or illness 
That And considered clinically relevant For The doctor That Yes verify In the course from the testing, 
regardless of whether it is considered device-related or not doctor. 
The AE /HADES include: 
• Exacerbation Of a illness pre-existing. 
• Increase from the frequency or of intensity Of a illness episodic pre-existing or Of a condition 
medical. 
• Illness or condition medical detected or diagnosed After The treatment with The device doctor, Also 
self could be to be was present Before of the beginning of the investigation clinic. 
• Illness persistent continues or symptoms present to the basal That they get worse After the 
beginning of the investigation clinic. 
• Lack Of effectiveness In the treatment acute Of a illness dangerous For there life. 
• Events considered give it experimenter as related to procedures of the investigation clinic. 
• Abnormal assessments, such as ECG and physical examination findings, should be reported as 
events adverse / HADES self they represent a result clinically significant That Not era present to the 
basal or worsened over the course of the investigation clinic. 
• The anomalies of the test Of laboratory they must to be reported as AE/ADE self they represent a find 
clinically significant, symptomatic or less, That Not era present to the basal or got worse In the 
course 

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of the investigation clinic has carried to the interruption or at the Suspension of the treatment with 
The device doctor. 
 
The AE/ADE Not include: 
• The interventions planned or The occur Of endpoint specified In the CIP Not I am considered 
AE/ADE, self not otherwise defined. 
• Medical or surgical procedure, for example surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the procedure must be 
described in the storytelling SAE/SADE. 
• Illness pre-existing or condition medical That Not it gets worse. 
• Situations in which Not Yes And verified a change adverse, to example hospitalizations For surgery 
aesthetics elective or for reasons social and / you hate convenience. 
• Improper use of medical devices or concomitant medications without signs or symptoms. However, 
the use improper needs to to be mentioned In the register Of inventory of the devices doctors/card Of 
treatment. 
 
Events adverse serious (SAE)/Effects adverse serious of the devices (SADE) 
 
A event adverse serious (SAE)/effect adverse serious of the device (SADE) And defined as any AE/ADE 
That satisfy at least one of the following criteria: 
• bring to death, 
• brings to a serious deterioration from the Health of the subject That 
1) has caused a illness or a wound dangerous For there life, 
2) has behaved a compromise permanent Of a structure corporeal or Of a function bodily, 
3) has behaved The recovery hospital or The extension of the recovery in course, 
4) has behaved a intervention doctor or surgical For to prevent a compromise permanent from the 
structure corporeal you hate a function corporeal. 
• leads suffering fetal, death fetal or anomaly congenital or defect congenital. 
• And a event doctor important That could be Not provoke immediately there death, to be dangerous 
For there life or request The recovery in hospital, but can to be considered as SAE / SADE when, based 
on appropriate medical judgment, it may compromise the subject and may require a intervention 
doctor or surgical For to prevent one of the outcomes listed in definitions Of which above. 
• show the onset Of a cancer malignant. 
 
The danger Of life Yes reports to a event in which The subject era to risk Of death to the moment of the 
event. Not Yes reports to a event That hypothetically it would have could to cause there death self is 
state more serious 
 
 
All adverse events that occurred during treatment, immediately after treatment and in the follow-up 
period up will be recorded in the “Adverse Event Form” (Annex I of the CRF). Adverse events will 
come classified by severity, relationship with the device being studied, intended or not, need Of 
treatment. 

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9.3 
Hospitalization – Extension of the recovery existing 
 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. 
A overnight stay additional defines a extension of the recovery existing. 
How much follows Not And considered a SAE/SADE And needs to to be reported Alone as AE/ADE: 
• Treatment in case Of emergency or For a event That Not satisfies there definition Of severity Of 
which above And does not entail hospital admission. 
 
THE following reasons For the hospitalizations Not I am considered events adverse And Therefore Not 
SAE: 
• Hospitalizations For surgery aesthetics elective, reasons social and/or Of convenience. 
• Monitoring standard Of a illness pre-existing or condition medical That Not And worsened, to 
example, hospitalization For angiography coronary in a subject with angina pectoris stable. 
• Treatment elective Of a illness pre-existing or condition medical That Not And worsened, to 
example, hospitalization For chemotherapy For cancer, replacement elective of the hip For arthritis. 
 
 
 
9.4 
SAE/SADE relative at procedures mandatory of the study 
 
Such SAE/SADE are defined as SAE/SADE that appear to have a reasonable possibility of relation 
causal (valid to to say, a relation Not can to be excluded) with the procedures mandatory of the study 
(excluded there administration Of devices doctors) as the interruption of the previous treatment of the 
subject or the complication of a mandatory invasive procedure (for example, blood sampling, cardiac 
catheterization) or car accident on the way to the hospital for a visit Of study, etc. 
 
 
9.5 
Pregnancy 
Any pregnancy that occurs during study participation must be reported to the sponsor/principal 
investigator. To ensure the safety of the subject, every pregnancy must be reported immediately at the 
sponsor /experimenter principal. A pregnancy needs to to be followed to determine the outcome 
(including premature termination) and the status of the mother and baby. The complications from the 
pregnancy And the interruptions elective For reasons doctors they must to be reported as AE / ADE or 
SAE. Spontaneous abortions they must be reported as SAE. 
Any SAE That Yes check in Association with a pregnancy, scope to your attention of the 
experimenter after the subject has completed the study and considered by the experimenter as possibly 
related to the product in study, needs to to be promptly reported at the sponsor/ experimenter 
principal. 

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9.6 
Severity of the events adverse/effects adverse of the device 
 
The severity of AEs/ADEs is classified on a three-point scale: mild, moderate, severe and reported on 
a specific section of the CRF. 
If the severity of an AE/ADE worsens during administration of a medical device, only the worst 
intensity must be reported on the AE page. If the AE decreases in intensity, it is not necessary no 
change in severity. 
 
Mild 
The event can to be obvious to the subject; Not influence the activity daily; the AE/ADE Yes 
solves spontaneously or can request a therapeutic intervention minimum; 
 
Moderate 
The event can put to unease The subject; the progress from the activity daily can to be influenced; can 
be necessary a intervention; the AE/ADE does not produce sequelae. 
 
Serious 
The event can cause considerable discomfort; usually interferes with daily activities; the subject you 
may not be able to continue studying; AE/ADE produces sequelae, which require a intervention 
prolonged therapeutic. 
 
A AE/ADE light, moderate or serious can or Not can to be serious. These terms I am used For to 
describe the intensity of a specific event (as in mild, moderate or severe myocardial infarction). 
However, a serious event may have relatively minor medical significance (such as a severe headache) 
or otherwise And necessarily serious. To example, there nausea That tough different hours can to be 
classified as serious, but it may not be clinically important. Fever of 39°C which is not considered 
serious can become serious if it prolongs hospital discharge by one day. The clinical importance rather 
than there severity it works from guide to define obligations regulatory Of report. 
 
 
9.7 
Relation with The device doctor 
 
For all, the investigator will evaluate the causal relationship between the medical device and the 
AE/ADE using there her experience clinic And The his judgment second The following algorithm That 
Better Yes suitable at circumstances of the EA / ADE: 
 
Not related 
• Can follow or less a sequence storm reasonable from the administration of the product in study 
• AND biologically Not plausible And Not follows a model Of answer known to the device doctor 
(self The model Of answer And previously known) 
• Can to be explained give her characteristics Note of the state clinical of the subject or from other 
mode Of therapy administered to the subject. 

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Possibly related 
• Continued a reasonable sequence storm from the administration of the device doctor. 
• Can follow a model Of answer known to the device doctor (self The model Of answer And 
previously known). 
• Could be Not to be reasonable Not to be reasonably explained give her characteristics Note of the 
state clinical of the subject or from other mode Of therapy administered to the subject, self applicable. 
 
Surely related 
• Continued a reasonable sequence storm from the administration of the device doctor. 
• Continued a model Of answer known to the device doctor (self The model Of answer And 
known in precedence). 
• Not And present no one else cause reasonable. 
 
 
9.8 
Procedures Of report 
 
A section special And dedicated to AE/ADE In the CRF. They have to Therefore to be inserted the 
following data: 
• Type of AE/ADE 
• Start (date And Now) 
• end (date And Now) 
• Severity (mild, moderate, serious) 
• Serious (no Yes) 
• Unexpected (no / Yes) 
• Outcome (Resolved, in course, in course – improved, in course – worsening) 
• Relationship with the medical device (unrelated, possibly related, definitely related) The events 
adverse related to the device they must to be documented In the CRF in compliance with the criteria 
above mentioned e reported to the Sponsor. 
 
 
9.9 
Procedures Of report For SAE/SADE 
 
In case Of event adverse serious (serious adverse event), the experimenter needs to use all the measures 
support for the best treatment of the patient. A written report must also be prepared And mass 
immediately to disposition of the sponsor. They should to be available at least the following details: 
• Initials And code of the patient 
• Patient: date Of birth, sex, origin ethics 
• The device doctor used 
• The event adverse valued as serious 
• Brief description of the event And of the outcome 

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• Self related or Not related to the device 
 
There relation written And split in two set off: 
• Relationship initial: in shape on that is That And happened (AE / HADES valued as serious), 
self exists a relation with the medical device ... And Which action And was set. 
• Follow-up Report: in shape on the outcome 
 
The Sponsor is responsible for the classification of adverse events and the ongoing evaluation of the 
safety of the investigation clinic And needs to: 
• to review there assessment of the experimenters Of everyone The events adverse And to determine 
And to document For recorded their severity and relationship with the investigation device; in case of 
disagreement between the sponsor and the experimenter principal 
• to examine all the shortcomings of the devices And to determine And to document For signed up self 
they would have could bring to a serious effect adverse of the device; in case Of disagreement Between 
the sponsor And the experimenter principal 
• report or guarantee there report, to the THERE IS And to the AR (Ministry from the Health) Of 
everyone The events adverse serious. 
 
 
10 Withdraw of the patients give it study 
 
 
10.1 Criteria For The withdraw of the subjects give it study 
THE subjects can to interrupt prematurely the investigation clinic in any moment. The interruption 
premature study is to be understood when the subject has not been subjected to evaluation safety it's at 
all the clinical evaluations during the investigation clinic. 
 
THE subjects they must to be retreat in following circumstances: 
• on own request 
• self the investigator believes That Not would be In the improve interest of the subject to continue 
• self The subject viola the conditions established In the module Of consent / form information or 
ignore the instructions receipts. 
• self arise events adverse serious such from to compromise there assessment clinic. 
 
In everyone the cases, The reason For which the subjects they come retreat needs to to be registered in 
detail in the CRF And in the subject's medical records. If the clinical investigation is terminated 
prematurely, all of the material of the investigation clinic (CRF complete, partially completed And 
empty) will be preserved. 

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10.2 Follow up of the patients retreat from the investigation clinic 
 
In case Of break premature After The treatment with The device doctor, the investigations expected 
For there assessment from the safety they will be performed 7 days After the interruption. THE subjects 
they will be informed that participation in these investigations is voluntary. Furthermore, they can ask 
that from the moment of withdraw no more data is recorded. 
 
 
10.3 Politics Of replacement of the subjects retreat 
 
THE subjects That Yes they withdraw give it study Before from the execution from the procedure 
surgical or immediately after, i.e. before visit 2 (7 days after treatment) they may be replaced by new 
subjects who meet the inclusion/exclusion criteria. Those who withdraw give it study after visit 2 will 
be included in the analysis. 
 
 
10.4 Conclusion anticipated of the investigation clinic 
 
The sponsor has The right Of close this investigation clinic in any moment. The THERE IS And The 
AI they must to be informed. 
The investigation clinic can to be interrupted prematurely in the following cases: 
• Self Yes verify events adverse/events adverse of the device Like this serious That The relationship 
risk-benefit Not And acceptable 
• Self The number Of dropouts And Like this high That Not There Yes can realistically wait a 
correct completion of the investigation clinic. 
 
If the sponsor or investigator decides to terminate the clinical investigation before it is completed, yes 
will inform each other in writing indicating the reasons for the early termination. In finishing the study, 
the sponsor and the investigator will ensure that adequate consideration is given to the protection of 
the subject's interests. The sponsor will inform the Competent Authorities and the CE. There 
documentation will be archived in Clinical Trial Masters File in Investigators Files. 
 
 
11 Monitoring plan 
The Monitor will contact and visit the investigator regularly and will be authorized, upon request, to 
have access to all source documents needed to verify entries in CRFs and other documents relating to 
the CIP, provided that the confidentiality of patient data is maintained in accordance with the local 
regulations. It will be the Monitor's responsibility to inspect the CRFs at regular intervals during the 
study, to verify adherence to the CIP and the completeness, consistency and accuracy of the data 
entered on of them. Monitoring standards require full verification of the presence of consent informed, 
adhesion to the criteria Of inclusion/exclusion, there documentation from the SAE/SADE And 
there 

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registration of the main efficacy, safety and tolerability endpoints. To be compliant with ISO 14155 
standard requires at least 3 monitoring visits. A study start visit, a visit routine and a final visit after the 
last patient has finished the study. For the present study 8 monitoring visits are planned: an initial visit 
(centre opening), 6 routine visits and one final visit. Routine visits will be conducted once a month. 
100% of the source data will be monitored by the monitor (which means 100% of Source Data 
Verification). Monitoring will come conducted according to SOPs and will provide an ISO 14155 
compliant monitoring report afterwards each visit for the sponsor and investigator. Depending on the 
quality of the data, they may be necessary more visits Of monitoring a discretion of the sponsor. 
 
12 Changes of the floor Of investigation clinic 
The proposed changes to the clinical investigation plan be submitted to the Competent Authority (CA) 
and to Ethics Committee (EC) of reference. Substantial changes can only be implemented after 
Obtained the approval of AC/CE. The changes intended to eliminate an apparent immediate danger 
for subjects can be implemented before receiving AC/EC approval. However, in this case, approval 
must be obtained as soon as possible after implementation. It is forbidden to apply exceptions to this 
clinical investigation plan without prior authorization from the AC/EC. The deviations from the 
clinical investigation plan occurring for any reason must be reported immediately to the Responsible 
Scientific who will be able to to determine self to exclude The patient from the study. 
 
13 Responsibility relative to the device 
The device will be sent to the Villa Sofia Rehabilitation Care Home Pharmacy which will take care of 
check the good state of conservation of the device and store it in the conditions indicated by 
manufacturer. THE devices they will come delivered to the Responsible Scientific or his delegate That 
will provide to store them in the conditions indicated by the manufacturer. The Scientific Manager is 
responsible for storage and maintenance of devices. Access to the devices is permitted only to 
members of the team Of research And The withdraw Of Everything is fine device needs to to be 
annotated on the Device Log File reporting The first name of the member of the team, there date And 
The lot. THE devices expired or unused they will come retreat give it Sponsors. 
 
 
14 Calculation from the dimension sample collection 
 
The sample size was calculated based on estimates of possible improvement in the Clinical Healing 
score at the desaturation (18-20 days) respect at the baseline using the information obtained from the 
literature 5,6,8,10,11,14 . Sample size estimates were calculate in terms Of a variable Of answer continues 
hypothesizing a distribution Not normal, The change of the Clinical Healing score at the desaturation 
with a effect size (dz) Of 0.5 And considering 80% power. With these assumptions, the minimum 
required sample size is 53 subjects per treatment group. Therefore, considering a dropout rate of 5%, 
it is necessary the recruitment of 112 subjects. 

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15 Analyses statistics 
 
the primary endpoint is the improvement in the Clinical Healing score at visit 3 compared to baseline 
(visit 1). Assuming that the average change in Clinical Healing score for each treatment is Like this 
represented: Prog = result of the Clinical Healing score at the visit 2; BAS = result of the Clinical 
Healing score at baseline, the null hypothesis is represented by Prog = BAS and the alternative one by 
Prog ≠ BAS. Statistical tests (Mann-Whitney test) will be conducted at a significance level of 0.05 per 
show improvement in Clinical Healing score at visit 3. Secondary endpoints will be analyzed as 
follows: Clinical Healing score at visits 2 and 4 - Mann-Whitney tests conducted at significance level 
equal to 0.05; The pain perceived by the patient when changing the dressing visits 2, 3 and 4 - Mann-
Whitney tests conducted at the significance level of 0.05; The percentage of patients with a 
completely healed wound at visit 4 - two proportion z tests conducted at the level of significance even 
to 0.05. 
 
 
16 Timings 
 
The study involves the recruitment of 112 patients, it is estimated that this number of patients will be 
recruited a time of approximately 8 months. Considering that the time required to complete the follow-
up for each patient is 30 days the overall duration of the study is estimated from the first date visit of 
the first patient will be Of 10 months. There relation the final will be provided After 3 months from the 
conclusion of the study. 
 
17 Publication of the results 
Within one year of the end of the trial the results will be published by the sponsor in agreement with 
The investigators second the mode established in the convention Between the sponsor And The center 
experimental. The study data will be published in a scientific journal appropriate to the type of study 
And introduce yourself to congresses scientific. THE data of the investigation clinic they will be 
deposited at a bank data accessible to the public (e.g. clinicaltrial.gov). There confidentiality of the data 
of the participants will be Always guaranteed. 
 
18 Ethics And requirements legal 
 
The investigator will present this CIP and any related documents provided to the subject (such as 
information used For obtain The consent informed) to a Committee Ethical to to the Authority 
Qualified. Approval from the committee and the AC must be obtained before commencing the 
investigation clinic And needs to to be documented. 

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18.1 Declaration Of Helsinki 
The investigator will ensure that this study is conducted in full compliance with the principles of 
"Declaration Of Helsinki" (as modified at the 56a Assembly General of the AMM, Tokyo, Japan, 
2008). 
 
 
18.2 Good practice clinic (EN ISO 14155) 
 
ISO 14155 addresses good clinical practice for design, conduct, recording and reporting of clinical 
investigations performed in human subjects to evaluate safety and performance medical devices to 
ends regulatory . 
 
Specific the requirements general understood to: 
• to protect the rights, there safety And The well being of the subjects humans, 
• guarantee there management scientific of the investigation clinic And there credibility of the results of 
the investigation, 
• assist sponsors, monitors, investigators, ethics committees, regulators and other bodies involved in 
the assessment from the compliance of the devices doctors. 
 
The experimenter principal of the investigation clinic guarantees That you participate Alone personal 
adequately format. All the investigations clinics they must follow the standard EN ISO 14155. 
Therefore, this study follows the EN ISO guidelines incorporated into the Italian device law doctors. 
 
 
19 Bibliography 
 
1. 
Chhabra, S., Chhabra, N., Kaur, A. & Gupta, N. Wound Healing Concepts in Clinical Practice 
of OMFS. Journal of Maxillofacial and Oral Surgery vol. 16 403–423 Preprint at 
https://doi.org/10.1007/s12663-016-0880-z (2017). 
2. 
Clark, R. A. F. Cutaneous tissue repair: Basic biologic considerations. I. J Am Acad Dermatol 
13, 701–725 (1985). 
3. 
Burd, D. A. R. et al. Hyaluronan and wound healing: a new perspective. Br J Plast Surg 44, 
579–584 (1991). 
4. 
Vasvani, S., Kulkarni, P. & Rawtani, D. Hyaluronic acid: A review on its biology, aspects of 
drug delivery, route of administrations and a special emphasis on its approved marketed 
products and recent clinical studies. International Journal of Biological Macromolecules vol. 
151 1012–1029 Preprint at https://doi.org/10.1016/j.ijbiomac.2019.11.066 (2020). 
5. 
Mikosinski, J. et al. Efficacy and Safety of a Hyaluronic Acid-Containing Gauze Pad in the 
Treatment of Chronic Venous or Mixed-Origin Leg Ulcers: A Prospective, Multicenter, 
Randomized Controlled Trial. Wounds 33, 147–157 (2021). 

24 
 
 
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6. 
Kartika, R. W. et al. Wound Healing in Diabetic Foot Ulcer Patients Using Combined Use of 
Platelet Rich Fibrin and Hyaluronic Acid, Platelet Rich Fibrin and Placebo: An Open Label, 
Randomized Controlled Trial. Acta Med Indones 53, 268–275 (2021). 
7. 
Eeckhout, C., Ackerman, J., Glibert, M. & Cosyn, J. A randomized controlled trial evaluating 
hyaluronic acid gel as wound healing agent in alveolar ridge preservation. J Clin Periodontol 
49, 280–291 (2022). 
8. 
Mikosinski, J. et al. Efficacy and Safety of a Hyaluronic Acid-Containing Cream in the 
Treatment of Chronic, Venous, or Mixed-Origin Leg Ulcers: A Prospective, Multicenter 
Randomized Controlled Trial. Wounds 33, 285–295 (2021). 
9. 
Ibraheem, W. et al. Efficacy of hyaluronic acid gel and spray in healing of extraction wound: a 
randomized controlled study. Eur Rev Med Pharmacol Sci 26, 3444–3449 (2022). 
10. 
Humbert, P., Mikosinki, J., Benchikhi, H. & Allaert, F. A. Efficacy and safety of a gauze pad 
containing hyaluronic acid in treatment of leg ulcers of venous or mixed origin: A double-blind, 
randomised, controlled trial. Int Wound J 10, 159–166 (2013). 
11. 
Russo, R. et al. Clinical Evaluation of the Efficacy and Tolerability of Rigenase® and 
Polyhexanide (Fitostimoline® Plus) vs. Hyaluronic Acid and Silver Sulfadiazine 
(Connettivina® Bio Plus) for the Treatment of Acute Skin Wounds: A Randomized Trial. J 
Clin Med 11, 2518 (2022). 
12. 
Wälivaara, D. et al. Effects of Lactobacillus reuteri-containing lozenges on healing after 
surgical removal of mandibular third molars: A randomised controlled trial. Benef Microbes 10, 
653–659 (2019). 
13. 
Estocado, N. & Black, J. Clinical practice Clinical practice Clinical practice Ten top tips: 
wound photo documentation Clinical practice. Wounds International 10, (2019). 
14. 
Dechert, T. A., Ducale, A. E., Ward, S. I. & Yager, D. R. Hyaluronan in human acute and 
chronic dermal wounds. Wound Repair and Regeneration 14, 252–258 (2006).