Evalution Report

Clinical Evaluation Report
Product
COLLAGEN PLAQUE + HA, STERILE
Review Of the Reason for Check Approval

modification
01 23.07.2018 Updated 24.07.2018 24.07.2018
Template – Clinical Evaluation Report V03– 2017-0516
EURORESEARCH s.r.l. Sole-shareholder company

Share capital € 90,000.00 fully paid-in Tax identification n. and VAT registration n. 06901450152 Trade Register of
Milan Economic and administrative index n. 1123845
Registered Office: I-20129 Milan - viale dei Mille, 20 - Head Office: I-20122 Milan - Via Larga, 15
Tel. +39 02 8055660 Fax. +39 02 72011722 - email: assistance@imaitalia.it.
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Index
1 SUMMARY ---------------------------------------------------------------------------------------------------------------------- 4
2 PURPOSE OF THE CLINICAL EVALUATION ----------------------------------------------------------------------------- 5
2.1 DEVICE IDENTIFICATION ------------------------------------------------------------------------------------------------------- 5
2.2 MANUFACTURER IDENTIFICATION -------------------------------------------------------------------------------------------- 5
2.3 REFERENCE DIRECTIVE --------------------------------------------------------------------------------------------------------- 5
2.4 DEVICE - DESCRIPTION -------------------------------------------------------------------------------------------------------- 5
2.5 TECHNOLOGIES USED --------------------------------------------------------------------------------------------------------- 6
2.6 DEVICE GROUP ----------------------------------------------------------------------------------------------------------------- 6
2.7 INTENDED USE AND INDICATIONS PROVIDED --------------------------------------------------------------------------------- 6
2.7.1 Intended use --------------------------------------------------------------------------------------------------------- 6
2.7.2 Indications specified ----------------------------------------------------------------------------------------------- 6
2.7.3 Methods of use ----------------------------------------------------------------------------------------------------- 7
2.7.4 Mechanism of action ---------------------------------------------------------------------------------------------- 7
2.7.5 Warnings and Precautions --------------------------------------------------------------------------------------- 9
2.7.6 Contraindications and Side Effects ---------------------------------------------------------------------------- 9
2.7.7 Storage ---------------------------------------------------------------------------------------------------------------- 9
2.8 DEVICE STATUS ---------------------------------------------------------------------------------------------------------------- 9
3 CLINICAL BACKGROUND, CURRENT KNOWLEDGE, STATE OF THE ART -------------------------------------- 10

3.1 SUMMARY OF THE RESEARCH STRATEGY ------------------------------------------------------------------------------------ 10
3.2 APPLICABLE STANDARDS AND GUIDANCE DOCUMENTS--------------------------------------------------------------------- 10
3.3 CLINICAL CONDITION TO BE TREATED ---------------------------------------------------------------------------------------- 10
3.4 ALTERNATIVE THERAPIES ----------------------------------------------------------------------------------------------------- 13

3.5 ANALYSIS OF THE COMPONENTS OF THE MEDICAL DEVICE ----------------------------------------------------------------- 15
4 DEVICE IN EVALUATION --------------------------------------------------------------------------------------------------- 15

4.1 TYPE OF EVALUATION: -------------------------------------------------------------------------------------------------------- 16
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4.2 DEMONSTRATION OF EQUIVALENCE ----------------------------------------------------------------------------------------- 16
4.3 CLINICAL DATA GENERATED AND STORED BY THE MANUFACTURER -------------------------------------------------------- 17
4.4 CLINICAL DATA FROM THE LITERATURE -------------------------------------------------------------------------------------- 26
4.4.1 Other literature evaluated -------------------------------------------------------------------------------------- 30
4.5 SUMMARY AND EVALUATION OF CLINICAL DATA ---------------------------------------------------------------------------- 33
4.6 ANALYSIS OF CLINICAL DATA ------------------------------------------------------------------------------------------------- 34
4.6.1 Safety Requirement -------------------------------------------------------------------------------------------- 34
4.6.2 Requirements related to the acceptability of the benefit/risk ratio --------------------------- 36
4.6.3 Performance Requirement ---------------------------------------------------------------------------------- 37
4.6.4 Requirement on the acceptability of side effects --------------------------------------------------- 40
5 CONCLUSIONS ---------------------------------------------------------------------------------------------------------------- 40
6 DATE OF THE NEXT CLINICAL EVALUATION -------------------------------------------------------------------------- 41
7 SIGNATURES OF EVALUATORS ------------------------------------------------------------------------------------------- 41
8 QUALIFICATIONS OF THE RESPONSIBLE EVALUATORS ----------------------------------------------------------- 41
9 BIBLIOGRAPHY AND REFERENCES -------------------------------------------------------------------------------------- 42

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1 Summary
This document contains all the activities carried out and the results obtained during the clinical
evaluation of the medical device called "collagen plaque + hyaluronic acid (HA)". The medical
device which is the subject of this document, is a sterile product of which EURORESEARCH
S.r.l. is the manufacturer.
Sterilisation occurs by irradiation with gamma rays, at an irradiated dose of 25 kGy.
The clinical evaluation has the following objectives:
• Find information concerning the safety and efficacy of the medical devices in question
or of the medical devices identified as equivalent.
• Conclude that the data gathered is sufficient to demonstrate compliance with the
Essential Requirements.
• Establish the accuracy of the performance and safety of the medical device as declared
by the Manufacturer.
• Verify the need to perform further clinical investigations on the medical device in
question.
• Confirm that the risks associated with the use of the medical device in question,
identified in the risk analysis and possibly arising from a literature search are
acceptable if compared to the benefits provided to the patient and deriving from use of
the device itself.
The working group that conducted the clinical evaluation is composed of:
Name Title
Adolfo Gasparetto Medical Director
Stefania Gorla Quality assurance
Nicola Schiattarella Regulatory Affairs Manager
The clinical evaluation is based on clinical data produced by the manufacturer supported by
scientific literature data.
The benefit/risk profile was determined on the availability of clinical data (studies carried out
by the manufacturer, scientific literature,) and by the results of the biocompatibility studies. The
composition of the medical devices includes only ingredients that conform with the intended
use. The intended indications for use and precautions established were considered to be
sufficient to prevent the occurrence of side effects. The analysed data support the efficacy of
the product in the intended indications for use. The clinical evaluation report concluded that
the residual risks are acceptable when compared with the expected benefits.

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2 Purpose of the clinical evaluation
2.1 Device identification

The Medical Device is called "collagen plaque + hyaluronic acid (HA)". The internal code
assigned to the medical device is DM 005.
The medical device is marketed under the following trade names:

• HYALO4 REGEN;
• BIONECT PAD;
• HYALOCOL;
• BIONECT HYGEN.
CND Classification M04041002 - Collagen dressings of animal origin with other substances
GMDN code: 33525
2.2 Manufacturer Identification

EURORESEARCH S.r.l.
Registered Office: Viale dei Mille, 20 – 20129, Milan (MI);
Operational Offices: Via Larga 15 – 20122 Milan (MI)
2.3 Reference directive

The medical device described in this report is in conformity with Directive 93/42/EEC as
amended by Directive 2007/47/EC. The medical device is classified as a Class III sterile
medical device on the basis of the classification rule 17 of Appendix IX to Directive 93/42/EEC.
2.4 Device - Description

This is a non-active, sterile and disposable medical device, a bioactive dressing composed of
type I heterologous equine collagen and hyaluronic acid, in the form of spongy plaques which
are sterile lyophilised, easily adaptable to the areas of application; adjuvant in physiological
wound healing processes.
The device presents as a spongy plaque, ivory-white in colour with a characteristic odour.
The composition of the medical device is described below:
Component Quantity (%) Function

Type I Equine Collagen: 97.5 Mechanically facilitates the
anchoring and the orientation
of fibroblasts in tissue repair
processes.
Hyaluronic acid 2.5 Keeps humidity in the micro-
environment of the lesion.
The device is available in different sizes: 1x1, 3x3, 5x5, 5x7, 5x10, 10x10, 10x12, 10x15 cm (±
10%), thickness 0.6 cm (± 0.2 cm).
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The size 5x5 cm is taken as the reference (standard).
The primary packaging consists of a thermoformed rigid PET or PVC blister pack, heat-sealed
in a sheet of aluminium lacquered with polyvalent heat-sealable paint on PET or on PVC for
pharmaceutical use.
Each blister pack contains a collagen plaque (disposable).

The secondary packaging, instead, consists of a medical cardboard box in which the product
is inserted, accompanied by a patient information leaflet with instructions for use.
The device does not contain products of human origin (tissues and blood). The product is
sterile and provides for terminal sterilisation by gamma ray treatment (25 kGy gamma
irradiation dose).
The medical device does not contain medicinal products.
The medical device contains a substance of animal origin, type I equine collagen, extracted
from horse tendons.
2.5 Technologies Used

The production process used for the production of the medical device is a standard process
for the producer, in use for a long time. Therefore, there are no truly innovative aspects in the
production technologies used.
2.6 Device group

The medical device falls into the category of treatments for acute traumatic and chronic injuries,
such as pressure ulcers, vascular ulcers, diabetic foot ulcers, chronic skin ulcers even with
delayed healing, surgical lesions, first and second degree burns. The device can be used as a
local haemostatic in surgical procedures in general and in reconstructive, vascular, carotid,
abdominal and gynaecological vascular surgery, orthopaedic and traumatological surgery,
dentistry and in first aid to control bleeding of the capillaries. This is a series of consolidated
treatments in clinical practice.
2.7 Intended use and indications provided
2.7.1 Intended use

The product is a non-active medical device, composed of type I heterologous equine collagen
and hyaluronic acid, in the form of spongy plaques which are sterile lyophilised, easily
adaptable to the areas of application; for use as a haemostatic and for the treatment of surgical
lesions, traumatic lesions, bedsores, venous ulcers and diabetic ulcers; adjuvant in
physiological wound healing processes.
2.7.2 Indications specified

Acute and chronic lesions from moderately to very exuding.

Treatment of pressure ulcers, vascular ulcers, diabetic foot ulcers, chronic skin ulcers even
with delayed healing, surgical injuries, acute and traumatic injuries; general and specialist

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surgery, traumatology, gynaecology and orthopaedics, dentistry, first and second degree
burns.
Local haemostatic use in surgical procedures in general and in reconstructive, vascular,
carotid, abdominal and gynaecological vascular surgery, orthopaedic and traumatological
surgery, dentistry and in first aid to control bleeding of the capillaries.
Despite its excellent haemostatic properties, it must not replace binding or direct compression
practices in the event of heavy bleeding.
Anticoagulant therapies do not interfere with its activity.
2.7.3 Methods of use

The product should be used immediately after opening the primary packaging.
After opening the blister and if only part of the plaque is used, the remaining parts must not be
reused for subsequent applications.
The product should not be used on infected wounds. In this case, it is necessary to precede
the use of the device with a systemic antibiotic treatment and/or topical antimicrobial treatment
for a few days.
The wound bed must be treated beforehand and cleaned using a damp gauze soaked in a
saline solution, dabbing repeatedly.
After debridement to remove any purulent materials and/or necrotic fragments, the plaque
must be applied to the wound. In the case of light exudate, the plaque must be hydrated with
a saline solution.
The product has a smooth side and a rough side: for the best performance it is suggested to
apply the smooth surface in contact with the wound. You can use one or more plaques
adjoining and overlapping, if necessary, in order to completely cover the wound by ensuring
that the plaque is in full contact with the entire area to be treated. The device must be secured
to the wound with a sterile gauze or with non-adherent dressing. An elastic compression
bandage must be applied later.
It is recommended that an application is carried out every 3-4 days or at shorter intervals,
depending on the exudative state of the lesion.
When the product comes into contact with the exudate, it gels, adapting perfectly to the lesion,
it is absorbed and dissolves over time. The wound must be checked every 2-3 days. To
maintain an ideal humid micro-climate, it is necessary to cover with a more or less absorbent
secondary dressing depending on the level of exudate and secure with a bandage. The product
not yet reabsorbed at the time of a new application must be left in situ.
In the treatment of ulcers, when the product is adhered to the wound bed, it must not be
removed or detached to check the state of the lesion.
If used as a haemostatic, and if the operation is carried out in the uncertainty that it is done in
aseptic conditions, the device must be removed after haemostasis.
2.7.4 Mechanism of action

The matrix of the medical device is composed of collagen, which provides a natural substrate
for cell adhesion, and hyaluronic acid, which reduces viscosity and increases resistance to
compression, without hindering cell mobility.
Collagen and hyaluronic acid are two of the most important structural and biological
components of the body and play a fundamental role in rebuilding the tissue architecture as a
result of wounds.
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Collagen is a structural protein with minimum immunoreactivity covering structural roles in the
skin and in the dermis, giving strength and elasticity. Collagen represents the supporting
structure of the dermis, of which it constitutes 75% of the dry weight and 18 - 30% of the
volume. Collagen gives considerable tensile strength to the dermis, has haemostatic properties
and facilitates healing in damaged tissue. Different types of collagen have been identified and
type I collagen is the most abundant, it is important for cell adhesion and plays a role in
stabilising the structures in formation. This protein performs a mechanical action promoting the
anchoring and orientation of fibroblasts and the formation of new tissue, representing a well-
known adjuvant of tissue repair processes. Fibroblasts are the most abundant cell type in
granulation tissue, a tissue that is physiologically formed during the process of wound healing.
Fibroblasts are also able to produce hyaluronic acid.
Hyaluronic acid is a biological polysaccharide (glycosaminoglycan) distributed in the

extracellular matrix of most tissues, it is strongly hydrophilic and forms a viscous hydrated gel
even at low concentrations. In physiological conditions this molecule helps the skin to maintain
its elasticity, its turgor and its hydration (Pavicic 2011). Hyaluronic acid, thanks to its high
hygroscopicity, is capable of trapping about 1000 times its weight in water which makes
hyaluronic acid important for maintaining the structure and the volume of tissues (Anderegg
2014, 2).
During the wound healing process, hyaluronic acid allows the rapid diffusion of water, solutes,
molecules as well as the migration of cells involved in the activation of the tissue repair
process. Hyaluronic acid controls tissue hydration and keeps the environment moist, also
promoting the ideal conditions for an orderly arrangement of collagen.
The use of a hyaluronic-containing device produces more rapid epithelialisation. There is

growing evidence that the creation of a humid wound environment increases the rate of
epithelialisation which usually begins earlier, reducing the healing time. This is clearly
demonstrated in studies in which only the low molecular weight hyaluronic acid (200 kDa) is
able to accelerate the wound re-epithelialisation process, promoting the proliferation and
migration of basal fibroblasts and keratinocytes (Ghazi et al., 2012; Gariboldi et al., 2008).
The mixing of the equine collagen fibres with hyaluronic acid facilitates wound healing by
reducing the mechanical rigidity of the sole collagen plaque, acting more efficiently as an
anchoring substrate for the migration of different cell types involved in the tissue repair process
and improving the reshaping capacity of newly synthesised collagen fibres.
In particular, in contact with exudates, the collagen plaque immediately gels, ensuring the
maintenance of a humid micro-environment that promotes the healing of acute and chronic
skin lesions with different aetiologies, while at the same time ensuring a barrier effect against
micro-organisms and a reduction of pain perception. The wound repair process is faster than
that obtained with conventional dressings, with a reduced number of applications that can help
to reduce the incidence of wound dehiscence and local signs of inflammation. It also provides
a natural substrate for cell adhesion which increases the resistance to compression, without
hindering cell mobility in a manner similar to fat in the healthy tissue.
On the basis of the above, it is possible to conclude that the main components of the medical
device, type I equine collagen and hyaluronic acid, exert their expected mechanisms of action
and that the medical device enables the activities described in the claims.

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2.7.5 Warnings and Precautions
The product should not be administered to patients with a proven family history of
anaphylactoid reactions or of individual hypersensitivity to the components. The device is non-
toxic, does not give rise to bolus formation, does not swell if it absorbs moisture and therefore
does not pose a risk of suffocation.
The product must be kept out of the sight and reach of children.
The device is disposable. Leftover plaque remnants must not be reused.
The device is sterile. Do not use if the package is damaged.
The product should not be used after the expiration date.
2.7.6 Contraindications and Side Effects

The device is biocompatible and bioresorbable.
The product is not harmful nor toxic or irritating. There are no known cases of irritant or
sensitising effects or adverse effects arising from the use of the collagen plaques, even in the
event of prolonged use of the product. No sensitisation or side effects or undesired effects
have been found or reported.
The device does not affect the ability to drive and use machines.
There are no known contraindications for use during pregnancy or breastfeeding; however, in
the absence of specific data, its use is not recommended unless under the direct control of a
doctor.
2.7.7 Storage
The product must be kept in a cool, dry place away from sources of heat.
The sterile collagen plaque, individually packaged inside a blister, is stable with a product shelf-
life of 60 months (5 years), when properly stored.
Transport at temperatures not exceeding 30°C, avoiding direct exposure to sunlight.
2.8 Device status

The medical device obtained CE marking on 11/09/2012 (certificate number CTP-0943-14,
issued by the Istituto Superiore di Sanità). The procedures for the five-year renewal of the CE
marking are currently under way.

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3 Clinical Background, current knowledge, state of the art
3.1 Summary of the research strategy

The manufacturer manages the clinical evaluation as per internal procedure. The aim of the
research was to retrieve data on the use of the medical device and its main components in the
intended indication of use in order to demonstrate the efficacy and safety of the medical device
when used according to the intended indications of use. Details on the type of data retrieved
and analysed are reported in the following sections of the document
3.2 Applicable standards and guidance documents

• Council Directive 93/42/EEC as amended by Directive 2007/47/EC
• MEDDEV 2.7/1 revision 4
• MEDDEV 2.12/2 revision 2
• ISO 14155-1: Clinical investigation of medical devices for human subjects - Good
clinical practice. 2011
• ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing
within a risk management process
• IEC62366 Medical devices - Application of usability engineering to medical devices
3.3 Clinical condition to be treated

The medical device subject to clinical evaluation is used for the treatment and management of
acute and chronic lesions, from moderately to very exuding, and can also be used as a local
haemostatic during surgical procedures of various kinds.
Wound healing represents the body's ability to repair damaged tissue: in physiological
conditions, when tissue receives damage that damages its integrity, the instinct of the tissues
and the body is to evolve toward the repair process.
The wounds can undergo healing in three different ways:
• By primary intention, where healing is promoted by the proximity of the wound edges
and the possible joining and suturing of skin flaps, in order to reduce the space between
the wound margins and to accelerate healing (e.g. surgical wounds and sharp injuries);
• By secondary intention, where the tissue necessary for healing begins to form on the
bottom of the wound progressively moving upwards until it reaches the surface (e.g.
burns, ulcers of various kinds);
• By tertiary intention, when the wound is infected and must be cleansed, freed from
organic residues and necrotic areas and regulated in the edges which are then
saturated; it is also possible that the wound is left open so as to allow healing by
secondary intention.

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Irrespective of the mode, wound healing is a well-organised process governed by sequential
but overlapping steps, known as haemostasis, inflammation, proliferation and reshaping.
Haemostasis protects the body from excessive blood loss and from increased exposure to
bacterial contamination. This phase is distinguished by vasoconstriction, vasodilatation and
increased capillary permeability for leukocytes and platelets and for the formation of a blood
clot consisting of a fibrin network containing red blood cells, white blood cells, platelets and
other blood components.
The inflammation phase prepares the wound bed for healing through the physiological
mechanism of autolysis. It is characterised by the disintegration or liquefaction of tissues or
cells due to the action of leukocytes and enzymes. In this phase, macrophages and
mononuclear cells with phagocytic capacity appear and are therefore active in "cleaning" the
lesion of the fibrin and from the cell residues and debris that may be deposited.
With the proliferation phase, the wound bed is filled and closed. This phase is characterised
by the creation of a network of capillaries and arterioles (neoangiogenesis), by the production
of connective tissue (granulation) and by the reduction in the size of the lesion by the
contraction of the edges of the lesion itself. The tissue that appears takes the name of
granulation tissue and consists mainly of fibroblasts that originate from connective tissue, they
penetrate into the wound along the filaments that make up the fibrin network, replacing them
with fibres with high contractile capacity, the myofibrils. At the same time, the production of
vascular and lymphatic drafts begins which stretch gradually toward the centre of the wound.
In this phase, the wound appears swollen and reddened due to the richness of the newly
formed vascular tissue.
The re-epithelialisation phase consists in the neo-epithelium covering of the lesion and in the
closure of the lesion itself. This process of re-epithelialisation is followed by the proliferation of
keratinocytes on the edge of the wound, thus restoring the stratified epidermis. The integrity of
the epithelial barrier is then restored and the reshaping of the underlying matrix resumes
(Demidova-Rice TN, 2012; Lindley LE, 2016). Over time the number and the activity of
fibroblasts decreases, blood capillaries are reduced and at the same time collagen fibres are
increased. Thus, the transformation of granulation tissue in scar tissue occurs, the
characteristics of which are poor elasticity, reduced blood supply and innervation, modest
epithelialisation, and the absence of skin appendages.
The final stage is the reshaping of the wound. This process leads to the formation of a solid
scar in about two weeks. Subsequently further transformations take place that will cause it, in
a few months, to flatten and change its colour assuming the final appearance.
In physiological conditions in a healthy individual, the cutaneous epidermal repair process

described above is highly efficient and performed through communication between the various
local skin compartments. However, when this process is blocked in pathological conditions,
the tissue fails to regain structural and functional integrity with consequent genesis of chronic
wounds (Linsey E et al., 2016, Werdin F, 2009). In a similar manner, deep or very large wounds
may require long healing times, which in a condition of severe stress to the tissue or non-
optimal patient conditions, lead to the lesion becoming chronic.
The main aspects of the lesions that can be treated with the medical device subject to clinical
evaluation are described below. The main acute and chronic lesions are described below.
Decubitus ulcers

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Decubitus ulcers are areas of tissue damage in the skin and/or underlying tissues caused
mainly by pressure, stretching or friction. This type of damage (also called a pressure ulcer,
sore, ulcer or bedsores), although largely preventable, is an important phenomenon in
hospitalisation wards and in the territory, both due to the number of patients involved and the
time and resources required for the treatment of the problem.
Whereas pressure lesions develop in hospitalised patients with a prevalence ranging from 18%
to 29% (A.I.S.Le.C. 2010), in the home-assisted population it is difficult to find large and well-
conducted studies.
In populations of high-risk hospitalised patients, the prevalence of decubitus sores is even
higher, with studies citing incidence rates of 38%. One study found that even with the use of a
pressure-reducing bed and early nutritional support, 3% of patients in a surgical intensive care
unit who were in the study developed pressure ulcers. The annual risk of pressure ulcers in
patients with neurological impairment is 5-8%, with a life risk of approximately 85% and a
mortality rate of 8% (A.I.S.Le.C. 2010).
Vascular ulcers
Vascular lesions of the lower limbs are defined as cutaneous wounds with venous, arterial
and/or mixed vascular aetiology, that localise below the knee up to the foot and that occur with
a duration equal to or greater than eight or ten weeks.
Chronic leg ulcers are a very common pathology in the western world, which mainly affects the
elderly, thus resulting in a high social cost.
Predisposing factors for venous hypertension include a history of deep vein thrombosis (DVT),
thrombophlebitis, trauma to the legs, arthritis, obesity, pregnancy and a sedentary lifestyle.
These factors can cause damage to the valves in the veins of the legs causing a pathological
blood flow which leads to venous hypertension. This causes distension of the veins in the legs,
oedema (swelling due to the accumulated fluid) of the lower limb and loss of circulatory fluids
from the capillaries into the surrounding tissues. This in turn induces irritation and increased
fragility of the epidermis (the outer layer of the skin) which leads to ulceration (Doughty 2007).
The duration of venous leg ulceration varies from weeks to over 10 years and some people
never heal (Moffatt 1995; Ruckley 1998; Vowden 2009a).
The more advanced age of the patient, the longer presence of the wound and the size of the
ulcer, were reported as independent risk factors for delayed ulcer healing (Gohel 2005;
Margolis 2004).
The prevalence data of vascular lesions fall within a range from 1.8 to 3.05 per thousand, with
an increasing prevalence with the increasing of age. In Western countries it has been
calculated that 10 in one thousand of the adult population has been affected at least once in
their life by an ulcer in the lower limbs.
Diabetic ulcers
A diabetic ulcer is a continuous lesion that is difficult to heal spontaneously, that can affect, in
relation to its importance and severity, the subcutaneous skin and bone tissues. Its most
common district location is in the foot involving distally/proximally the apical regions of the
fingers, articular interphalangeal joint, the metatarsal heads (the plantar region), the heel, the
bone protrusions of the tibio-peroneal talus mortar (ankle), and the leg. Approximately 1 to 4
% of patients suffering from diabetes develops ulcers particularly affecting the foot (Abbot
2002, Kumar 1994).
The involvement of the foot is very dangerous due to the continuation of the pathology as there
are often implications for subcutaneous and bone tissues with infections and fistulas that can
grow septic necrosis and relative amputation of the region concerned; a serious risk of
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complication of a diabetic foot is in fact the likely onset of infection, which often constitutes the
true cause that can determine the amputation.
World Health Organization forecasts have estimated that the number of diabetics in 2025 will
be over 300 million compared to 120 million calculated in 1996, from which we can easily guess
the scale of this issue. In fact, estimates of this disease show that approximately 15% of
diabetic patients will encounter a foot ulcer that will require medical care.
Surgical wounds
A surgical wound is a lack of tissue continuity produced by a mechanical agent. In clinical
practice, it is possible to fall into 2 main types of surgical wounds:
• Wounds that heal by primary intention in which the edges have been joined by the
application of a suture. They repair quickly, generally developing a linear scar that is
often scarcely visible;
• Wounds that heal by secondary intention in which the edges are not joined often due
to an infection. Healing is slow and the scar that forms can assume varying sizes.
The dehiscence of the surgical wound indicates a post-operative complication represented by

the spontaneous reopening of a previously sutured wound. It may be partial and therefore
affect one or more stitches or complete.
A very serious form is that which concerns laparotomic wounds, in which the complete opening
of all the layers of the wall leads to the release of the mobile viscera on the outside of the
abdominal cavity or evisceration.
Burns
A burn is a lesion of the integument tissues caused by exposure of the tissue itself to heat
sources, chemical substances (chemical burn), electrical sources or radiation. Burns that affect
only the first layer of skin are called "superficial burns" or "first-degree"; when the damage
penetrates some of the underlying layers, the lesion is called "partial thickness burn" or
"second degree"; if, on the other hand, the alteration involves all the layers of the skin, it is
classified as "full thickness burn" or "third degree"; a "fourth degree" burn involves lesions to
deeper tissues, such as muscle or bones.
Worldwide, about 11 million people per year require medical care and 300,000 die from burns.
In the United States, about 4% of people hospitalised in a major burns centre do not survive.
The long-term prognosis is mainly linked to the size of the burns and to the age of the person
affected, since the younger generations have a greater hope of healing than more elderly
subjects.
3.4 Alternative therapies

The effective treatment of wounds firstly requires the assessment of the injury, i.e. the
assessment of the size and the depth of tissue involvement, the appearance of the surface of
the wound, the quantity and characteristics of wound exudate, and the state of the perilesional
tissues (e.g., pigmented, healed-over cuts, atrophic, cellulitic). The creation of a humid
environment in the area of the lesion is one of the essential requirements to support the
regeneration process of the damaged tissues.

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A humid environment prevents eschar formation and stimulates growth factors, fibroblasts,
keratinocytes and inflammatory and phagocytic activity (Junker JPE, 2013). Fibroblasts also
have the ability to secrete hyaluronic acid, an active component in the formation of collagen
fibres and the healing process.
Although lesions of different severity and nature require different approaches, generally
medical practice involves the use of dressings used with the aim of protecting the wound,
preventing its contamination and promoting its healing. Dressings are defined as primary when
the dressing material is placed in direct contact with the tissues affected, secondary when the
dressing material serves to further fill a cavity or performs the function of fixing the primary
dressing. According to the British National Formulary, the ideal conditions required for wound
healing in terms of application of the dressing is the maintenance of a humid environment
without risk of maceration, exclusion in the dressings of chemical elements, fibre particles in
the dressing material which may interfere with the healing process, minimising the number of
dressing changes, maintaining an optimal pH (BNF 2015).
The dressings used in the treatment of lesions therefore have these basic characteristics:
• they allow the absorption of exudate;

• they promote sterility maintenance and wound cleaning;
• they do not release particulate contaminants on the wound;
• they provide thermal insulation to the injured tissue;
• they are permeable to water and ensure a moist micro-environment;
• they allow the atraumatic removal of the dressing itself;
• they provide relief from pain and comfort.
Dressings of this type are used alone or in addition to other therapies, depending on the
severity and type of lesion.
With regard to the treatment of pressure ulcers or decubitus sores, the main strategy is to
reduce the pressure, typically using specialist decompression support (McInnes 2011)
alongside the management of the wound environment with specific dressings. Other general
strategies include patient education, pain management, optimisation of the circulation and
perfusion, the optimisation of nutrition, surgical solutions for wound closure and treatment of
possible infection (AWMA 2012; EPUAP-NPUAP 2009).
In venous ulcers, compression therapy (bandages or socks) is considered to be the critical

intervention factor in the treatment of venous leg ulcers (Moffatt 2007; O'Meara 2012) and
dressings in direct contact with the lesion are generally applied together with compression
devices. A series of other interventions used in conjunction with compression, include lesion
debridement agents (Davies 2005), vasoactive drugs (Robson 2006), fibrinolytics (Robson
2006), and physical therapies (Cullum 2010; Aziz 2015).
The use of wound dressings is a practice used for the treatment of diabetic foot ulcers (Bergin
2006; Dumville 2011a; Dumville 2011b). In general, the treatment of diabetic foot ulcers
includes, in addition to the dressing, relief from the pressure (discharge) by supporting the foot
or wearing special shoes or plantar (or both), the removal of dead cell material from the wound
surface (debridement or desloughing) (Edwards 2010) and infection control (Storm-Versloot
2007). Other general strategies in the treatment of diabetic foot ulcers include patient education
(Dorresteijn 2010; Dorrestein 2001), the optimisation of blood glucose control, correction
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(where possible) of arterial insufficiency and surgical interventions (drainage of pus,
revascularisation, amputation).
The specific treatment of burns depends on their severity, but the use of specific covering
dressings is frequent. Superficial alterations can be managed with simple painkillers, while
large burns require prolonged treatment in specialised centres and the use of dressings. In
general, cooling with water can help alleviate the pain and decrease damage. Burns over the
whole thickness usually require surgical treatments, such as skin grafts; extensive burns also
often require the administration of large quantities of intravenous fluids, since the subsequent
inflammatory response involves the formation of oedema and significant losses of capillary
fluid.
The use of dressings is also common for the treatment of surgical wounds where the correct
preparation of the patient's skin is followed by local wound care through dressing.
Among the various types of dressings available, several authors have highlighted how the
simultaneous application of collagen and hyaluronic acid preparations (HA) on chronic and
acute lesions of different aetiology, can accelerate healing, through the maintenance of a
micro-humid environment suitable to help cell migration (e.g. fibroblasts and endothelial cells)
useful in containing a phase of excessive inflammation and promoting a granulation phase in
acute wounds (Anilkumar 2011, Chen 1999). Other authors have also suggested that HA can
reduce scarring, fibrosis and improve angiogenesis (Dicker 2014, Knudson 1993, Zhu 2006).
In light of what has been discussed, the medical device in Pad form developed by
Euroresearch is configured as a dressing that reflects the main factors mentioned above, by
exploiting the properties of type I collagen, widely used as a dressing for the treatment of acute
and chronic cutaneous lesions, promoting the healing and repair of damaged tissues and the
presence of hyaluronic acid, a polysaccharide polymer ubiquitously present in human tissues
and in the dermis-epidermis, equipped with large absorbent and moisturising capacity.
The medical device subject to clinical evaluation therefore fits into in a framework of
consolidated topical treatments for the pathologies described above.
3.5 Analysis of the components of the medical device

The medical device consists of 97.5% type I equine collagen, extracted from horse tendon,
and 2.5% hyaluronic acid.
Equine collagen is BSE-free and TSE-free.

Collagen is hypo-allergenic, phthalate-free and latex-free and there are no known adverse
events attributable to it.
The hyaluronic acid used for the production of the medical device in the form of sodium salt is
obtained by fermentation, without the use of tissues of animal origin.
4 Device in evaluation

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4.1 Type of evaluation:
The medical device subject to clinical evaluation falls into the category of treatments for the
treatment and management of acute and chronic lesions, treatments widely consolidated in
clinical practice.
The clinical evaluation is based on the analysis of the clinical data generated by the
manufacturer, supported by the scientific literature data currently available on the components
of the medical device, on similar products and on the treatment of the diseases of interest for
the medical device.
The risk analysis performed on the device in question did not identify significant residual risks
for the patient, connected to the use of the medical device in the proposed indications, to be
taken into consideration in performing this clinical assessment.
For the evaluation of the efficacy and safety of the medical device, the following data are
considered:
a) Results of pre-clinical studies

b) Clinical data obtained by the manufacturer
c) Analysis of the scientific literature found with bibliographic research and scientific
literature already in possession of the manufacturer
4.2 Demonstration of equivalence

There are no equivalent medical devices, with the term "medical device equivalent" meaning
a product whose equivalence has been demonstrated under the guideline MEDDEV 2.7.1 Rev
4 from the:
• Technical point of view (Use under the same conditions of application, same
specifications and technical characteristics, similar design, similar operating methods).
• Clinical point of view (Use for the same indications of use and for the same clinical
conditions, use on the same parts of the body, use on the same type of patients).
• Biological point of view (Use of the same materials in contact with the same tissues or
body fluids).
However, similar products are available on the market in terms of composition, indications and
methods of use for the medical device subject to clinical evaluation, as summarised in the
following table
Product Components Indications

PURACOL PLUS Hyaluronic acid Diabetic ulcers, venous
ulcers, decubitus ulcers, first

and second degree burns,
chronic ulcerations,
traumatic lesions that heal by
secondary intention
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Hyalofill-F
Hyaluronic acid Acute and chronic exuding
Hyalomatrix wounds such as: venous
ulcers, donor sites, decubitus
ulcers (Stage II - IV), surgical
wounds, traumatic wounds
PURACOL PLUS AG Hyaluronic Acid and Silver Diabetic ulcers, venous
ulcers, decubitus ulcers, first
and second degree burns,
chronic ulcerations,
traumatic lesions that heal by
secondary intention
ANTEMA Equine Collagen acute and chronic cutaneous
ulcerative lesions of a
vascular nature (arterial and
venous), traumatic,
metabolic (diabetic) or
pressure (decubitus)
Prisma Matrix Cellulose, Collagen and Diabetic ulcers, vascular
Silver ulcers, decubitus ulcers,
abrasions, traumatic lesions
that heal by secondary
intention, chronic and
acute ulcerations,
bleeding surface wounds
PROMOGRAN PRISMA
Cellulose, Collagen and Diabetic ulcers, vascular
Silver ulcers, decubitus ulcers,
abrasions, traumatic lesions
that heal by secondary
intention, chronic and
acute ulcerations,
bleeding surface wounds
Also available on the market are products containing hyaluronic acid or collagen used for
indications of use or modes of administration different to those of the medical device subject
to clinical evaluation.
Overall this information can be regarded as supportive of the safe use of the components of
the medical device.
4.3 Clinical data generated and stored by the manufacturer

Prior to the collection of clinical data, the manufacturer in accordance with ISO 10993 - 1
"Biological Evaluation of medical devices - Part 1: Evaluation and Testing" has conducted
biocompatibility tests as summarised below:
• Delayed hypersensitisation test

• Skin irritation test
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• Cytotoxicity tests for elution
Tests have shown that the product is not cytotoxic, is not sensitising nor irritating to the skin.
The medical device has been tested in different clinical centres and hospitals in Italy, on a vast
medical population and in various areas (venous ulcers, diabetic foot ulcers, surgical
dehiscence, etc.), particular and challenging environments given the complex profile of
patients involved and the rather high risk of relapses.
This data was collected from the manufacturer and summarised in the present clinical
evaluation.
1. "Bionect Pad in diabetic foot ulcers: clinical experiences"

Congress of the European Wound Management Association (EWMA), 3-5 May 2017
Carlo Caravaggi: Orthopaedics and Endocrinology, University Vita Salute San
Raffaele, Milan
2. "Surgical Dehiscence: how and when to use a bioactive dressing - results of a

spontaneous multi-centre observational study"
XIV National Congress of the Italian Association of Skin Ulcers (AIUC), 4-7 October
2017
Silvio Abatangelo: Department of Plastic Surgery and Hand Surgery Centre - Hospital
"G. Fornaroli Magenta", Milan
Guido Ciprandi: Dept. of surgery, UOC of Plastic and Maxillofacial Surgery, Paediatric
Hospital "Bambino Gesù", Rome
Alessandro Scalise: Clinic of Plastic and Reconstructive Surgery, Dept. of Experimental
and Clinical Medicine, Polytechnic University of Marche, Ancona
Grazia Strazzeri: Nurse U.O.C. Vascular Surgery A.O.U. Policlinico Vittorio Emanuele,
Catania
3. "Abdominal Dehiscence: evaluation of a biologically active preparation, clinical

observation of the action of a collagen and hyaluronic acid dressing product"
2017
Baglioni Elisabetta Adelaide: S.C. Plastic and Reconstructive Surgery, A.O.U. Città
della Salute e della Scienza Presidio Molinette, Turin
Russo Agata, Carbone Pierangela Fassero, Elisa, Bernocco Laura, A. Scarmozzino:
S.C. Medical Direction, A.O.U. Città della Salute e della Scienza Presidio Molinette,
Turin
4. "Observational Study on the reparative capacity of a new heterologous equine collagen

and hyaluronic acid dressing"

2017

18/44
Grazia M.A. Strazzeri, Maddalena Calì, Lorenzo Russo: Departmental Surgical Clinics
- Vittorio Emanuele Polyclinic Company - Catania
5. "Observational Study on the reparative capacity of a new heterologous equine collagen

and hyaluronic acid dressing"
2017
Grazia M.A. Strazzeri, Maddalena Calì, Lorenzo Russo: Departmental Surgical Clinics
- Vittorio Emanuele Polyclinic Company - Catania
6. "Evaluation of the efficacy of a collagen and hyaluronic acid dressing in patients

suffering from chronic venous ulcers of the lower limbs that do not tend towards healing,
in respect of standard venous ulcer therapy"
Spontaneous observation of 21 May 2012
Marco Romanelli: Department of Surgery, Dermatology University, Cutaneous Tissue
Repair Section, Dermatological Clinic
7. "Peristomal skin changes: what treatment should be adopted? Results of an

observational multi-centre study”
WCET journal, Volume 38 Number 1 2 January/March 2018
Mario Antonini: San Giuseppe Hospital, Empoli
Raimondo Arena: AO ARNAS Garibaldi, Catania
Simona Mancini: Santa Maria Annunziata Hospital, Florence
Silvia Manfredda: Ospedale Infermi, Rimini
Gaetano Militello: Santo Stefano Hospital, Prato
Raffaella Tantulli Bartoli: Ospedale Santa Maria Annunziata, Firenze
Stefano Veraldi: Institute of Dermatology, University of Milan
Stefano Gasperini: Medical Advisor, Pisa
8. Safety and Efficacy Report on a hyaluronic acid and collagen Dressing pad (trade name
Hyalo4 Regen/Bionect Pad)"
16 May 2018
Carlo Maria F. Caravaggi: Diabetic Foot Care Centre, IRCCS Sesto San Giovanni;
Diabetic Foot Centre, San Giuseppe Multimedica Hospital, Milan
9. Reporting on rehabilitation supply product in pad form with a hyaluronic acid and
collagen base (Bionect pad)
17 May 2018
Michele Riccio: S.O.D. of reconstructive surgery and Hand Surgery-Ospedali Riuniti of
Ancona
Clinical reference 1

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A pilot study was conducted on the use of Bionect pad (equine collagen + hyaluronic acid) on
28 patients with diabetic foot ulcers, a serious complication of diabetes that often precedes
amputation of the lower limb. In the study, the time and percentage of healing and the rate of
reduction of the ulcer area were assessed.
The inclusion criteria included type I or II diabetes, the presence of dorsal or plantar ulcer with
bone exposure, no local or systemic signs of infection and TcPO 2 > 30 mmHg before and after
revascularisation procedures (when necessary), as well as good patient compliance. The
treatment protocol consisted of surgical debridement and revascularisation procedures, as
stipulated in the guidelines. During surgical debridement, callus and non-vital tissue removal
was performed which involved the bleeding of the wound bed, an indispensable condition for
the correct use of the medical device being studied.
After debridement, the wounds were rinsed with H2O2 followed by sterile saline, haemostasis,
application of the medical device being studied, coating with medicated gauze and an inert
secondary dressing.
In the follow-up period, post-surgical shoes with no load were prescribed in the case of plantar
ulcers, together with a change of dressing every four days. An aspect to be highlighted is that
the edges of the wounds were clean, without slough.
Analysing the results of the entire pilot study, the average treatment period for patients was 68
days (± 70). Complete healing was observed in 6 out of 28 patients (21%), which may be
defined as a high cure rate if you consider the severity of the injuries taken into examined. The
average reduction of the surface of the wounds was 69% (± 25).
The efficacy of the medical device was evaluated in a spontaneous, observational, multi-centre
study, promoted by the SACS 2.0 study group. The study involved 14 centres in Italy, including
departments of various specialisations such as plastic surgery, vascular surgery, general
surgery, nursing/medical and oncology clinics and the cardiology rehabilitation and paediatric
surgery.
The aim of the study was to evaluate the efficacy of the medical device in the dehiscence of
wounds, one of the major complications following surgical interventions, both within hospital
and outpatient departments, which has a significant impact on the patient's morbidity and
mortality.
The parameters studied for the evaluation of the treatment with the medical device were the
reduction in the lesion volume after 4 weeks, the pain (VAS), the state of the perilesional area,
the level of exudate and the average change rate of the dressing.
The enrolled patients presented localised lesions in different anatomical sites, attributable to
complications following surgical interventions of various kinds (heart surgery, orthopaedic
abdominal, etc.).
From the findings in the various areas in which the medical device was used, more than
positive data emerged. In particular, of the 55 patients involved in the study, 28 completely
healed cases were observed, 22 patients with wound reduction between 80% and 95%, 4
patients with wound reduction between 50% and 80% and 1 non-responder patient.
With regard to the parameters considered, the VAS decreased in all cases starting from the
second week, the perilesional skin remained undamaged and improvements were observed
within the second week, finally the exudate progressively decreased in the first three weeks.
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The study aimed to evaluate the efficacy of the type I equine collagen bioactive dressing at
97.5% and hyaluronic acid at 2.5% in terms of reduction of the lesion surface area and the
quality of the tissue repair of surgical dehiscence, in terms of trophism, pain and scar quality.
The recruitment criteria were as follows: tissue damage involving the muscle fascia, wound
healing phase: granulation and a clean wound bottom, the absence of clinical signs of critical
colonisation/infection, with average/poor exudate. A total of six patients were enrolled.
The study involved the clinical observation of surgical wound dehiscence with healing by
secondary intention and the application of the medical device. The first evaluation was
performed at time zero (T0) with 4 subsequent revaluations (every 7 days). The treatment
involved the use of specific company protocols: in the granulation phase the collagen in use
was replaced with the medical device being studied, in association with a gel with PHMB, in
order to ensure control of the bacterial load, disintegration of the biofilm and maintenance of
the moist environment.
In terms of effectiveness, a reduction in the surface area (15% in 7 days, 50% in 30 days) and
volume (between 85% and 97% the fourth week) was observed. There was also a reduction
in pain in the first week (VAS 1 in all patients), a normalisation of the appearance of perilesional
skin and the edges as early as the first revaluation, a reduction in the level of exudate within
the second week (moisture balance), with soft and elastic scar tissue.
Eleven patients were enlisted from April 2017 to June 2017 with an average age of 48 years
(minimum 2 months, up to 76 years) with various diagnoses, having in common a closable
dehiscence in secondary intention. Each patient was monitored weekly for four weeks and the
following parameters were reported on the appropriate form: volumetric measurements of the
lesion, VAS, level of exudate, perilesional aspect.
Each lesion was treated, on average, every 4 days (examinations T1, T2, T3, T4), using the
medical device.
Of the 11 patients enrolled, 3 did not complete the study due to transfer to another hospital, 1
was cured at T1, 2 were cured at T2, 3 were cured at T3, 1 was cured at T4, one patient
reduced the volume of their lesion > 80% at T4.
The VAS was reduced in all patients by T2, the level of exudate was obviously reduced in all
patients with a reduction in the volume of the lesion, while the peri-lesion had already changed
at T1.
For descriptive purposes only, 2 of the 11 patients seemed worthy of sharing: the first a 20-
year-old patient, suffering from sacrococcygeal fistula open since 2015 in the presence of
hidradenitis suppurativa (see Reference below); the second a 78-year-old patient, suffering
from purulent peritonitis on which a dehiscence manifested (patient healed at T5, during
treatment an occlusion of the common bile duct was found with metabolic repercussions on
the affected subject, 42Kg).
A 20-year-old patient suffering from fistula sacrococcygeal fistula (SCF), open since 2015, in
the presence of hidradenitis suppurativa, who in the course of the last two years had performed
daily dressings without any particular outcome, presented at T0 a SCF depth of 5 cm with the
presence of medium/abundant exudate.

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After only one week of applying the medical device, the SCF depth was completely filled. Over
the course of the next two months, application was continued of non-stick dressings that
promote re-epithelialisation and with a specific treatment for hidradenitis suppurativa.
Compliance was excellent and thanks to the almost complete healing of the lesion the patient
returned to having a normal quality of life.
There were 20 patients included in the observational study (13 females and 7 males) aged
between 64 and 78 years (average age: 71 years), who presented with a chronic ulcerative
lesion of the lower limbs with clinical signs of venous insufficiency and instrumental
confirmation tests (ABPI Doppler Examination). The lesions included were present for at least
six months and had not shown signs of healing in the last six weeks despite standard therapy.
The average size of the lesions was at the time of inclusion 84 ± 12 cm 2, the lesion bottom
presented granulation tissue on 75% of the affected area, there were no clinical signs of
infection.
Patients were randomised into two groups (10 + 10) according to a random computer-
processed list. Group A received therapy with collagen and hyaluronic acid plaques + interface
+ compression. Group B received therapy with interface + compression.
The interface dressing consisted of a non-adherent rayon-viscose dressing. The dressing was
applied every 3 days by doctors/nurses experienced in wound care. The bandage was applied
with a two-layer technique for a total of 30 mmHg of resting pressure.
The study continued for a 6-week observation according to the data on prognostic indicators
of international literature on venous ulcers. During the study, patients participated with frequent
follow-up visits.
At the end of the observation period, group A had average sized lesions of 54±4 cm 2, with
granulation tissue on 95% of the affected area, while group B presented average sized lesions
of 64±6 cm 2 with granulation tissue on 80% of the affected area.
No particular difficulties emerged in the management of local therapy. There have been no
reported side effects or adverse events related to the dressing under examination. Patients
were free from clinical signs of infection throughout the observation period. The final evaluation
of the data obtained show that group A showed a significant reduction of the lesion site and an
increase in granulation tissue with respect to group B.
The purpose of this spontaneous multi-centre observational study was to evaluate whether
some topical preparations available on the market had a significant impact on healing times
with respect to peristomal skin lesions.
The study lasted a total of two years from 1 January 2014 to 31 December 2015.
The object of this study was the verification of a strict therapeutic protocol that included the
use of some topical preparations in each according to the SACS 2.0 classification, checking
the progress in terms of tissue repair of the lesions analysed during the 12 weeks of treatment.
Specifically, the treatments were as follows: 0.2% hyaluronic acid + collagenase, 0.2%
hyaluronic acid + 2% metallic micronised silver, 0.2% hyaluronic acid, 2.5% hyaluronic acid +
97.5% equine collagen.
Verification and follow-up were carried out with the use of a form at T0 (registration), T1 (after
4 weeks), T2 (after 8 weeks) and T3 (after 12 weeks), while during outpatient examinations

22/44
normal clinical practice was followed, which provided for a replacement of the dressing every
3 days.
Additional parameters were monitored simultaneously, on the basis of the same programme,
as possible indicators and, in particular, itching, burning, pain, bleeding during removal and
digital imaging.
During the two-year study 331 patients (178 males and 153 females, average age 62.68 years,
age range 22-100 years) were enrolled. These subjects had an abdominal stoma with
peristomal skin changes.
Treatment with 0.2% hyaluronic acid + 2% metallic micronised silver resolved the
erythematous condition within 4 weeks from the treatment of L1 lesions and exercised an
adjuvant action in all other cases.
Treatment with 0.2% hyaluronic acid + collagenase and 0.2% hyaluronic acid, although
theoretically indicated for lesions L2, L4 and LX, did not present significant results due to its
cream or pomade-based formulation, respectively.
Treatment with 2.5% hyaluronic acid + 97.5% equine collagen was used in 37% of the patients
studied, demonstrating a very high level of performance. The treatment was able to heal 100%
of cases with L4 and L5 lesions at 8 weeks after the beginning of treatment relatively and 98%
of cases with L3 lesions after 12 weeks. In particular, in L5 lesions, rare but certainly not easy
to manage, the dressing presented the most encouraging data and may therefore be regarded
as the first choice in this type of situation.
Thirty-eight patients with an average age of 72 years (31 males and 7 females) suffering from
foot skin ulcers were evaluated.
The treatment consisted of a surgical debridement performed to obtain a cleansed and bloody
bottom of the ulcerative lesion, the correction of any peripheral arterial disease (surgical or
endoluminal revascularisation), the discharge of the plantar ulcerative lesion with a rigid
fibreglass support or a dressing shoe for dorsal ulcerative lesions and medical treatment.
The medicative treatment with the medical device being studied consisted of surgical
debridement followed by cleansing with saline and intralesional dressing with the medical
device plaque, with medicated gauze covering. The dressing was renewed every 5 days, when
the area of the lesions was measured.
The study was interrupted in case of infection and side effects and systemic effects.
The study showed a very high percentage of healing of both dorsal and plantar ulcerative
lesions in a short treatment period if compared with the literature data.
The total percentage of healing (46%) and the reduction of the ulcer area (78%) at week 12
are extremely interesting compared to the data reported in the literature. Throughout the
observation period, no side effects of differing severity or infection of the treated wounds were
observed.
Reference 9
The medical device in question has been used since 2014 in the field of the treatment of difficult
wounds, chronic skin lesions (vascular ulcers, of autoimmune origin, etc.), diabetic foot ulcers.
The product was also used in acute lesions and traumatic injuries, where it was necessary to
protect noble structures (e.g. tendons, muscles, nerves and blood vessels) from damage
caused by dehydration by covering them quickly.
23/44
Since the beginning of its use, approximately 200 patients have been treated, generally in
treatment/outpatient management regimes and/or home care.
In normal practice, the investigators have found that the presence of hyaluronic acid
contributes significantly to accelerating healing by reconstituting the deepest layers and
superficial re-epithelialisation of the lesion, both in the case of chronic wounds (where it is
obviously possible to adequately control the underlying pathology) and in the case of acute
wounds.
The investigators also report that patient compliance has always been excellent, thanks to the
fact that the product, in addition to being effective, does not pose management problems to
the operator, in fact the level of self-degradation within the application site occurs in
approximately 3-7 days (depending on the state of exudation of the lesion itself) by releasing
the basic components (hyaluronic acid and collagen) in the surrounding environment.
Other clinical studies have also been conducted on similar medical devices from the same
manufacturer, based on equine collagen, that are reported below as clinical data to support
the efficacy and safety of equine collagen:
a) "Evaluation of a dressing based on an equine collagen and silver spray in "partial

thickness lesions" - 2006
Prof. Marco Romanelli: Department of Dermatology, Cutaneous Tissue Repair Section,
Pisana University Hospital
b) Evaluation of the effectiveness of heterologous collagen in wound healing"

National Congress of the Italian Association of Skin Ulcers (AIUC), 2006
M Romanelli, V Dini, MS Bertone, S Barbanera, C Brilli: Cutaneous Tissue Repair
Section - Dermatological Clinic - University of Pisa
c) "Use of spray collagen in the control of exudate in chronic venous ulcers"

National Congress of the Italian Association of Skin Ulcers (AIUC), 2006
V Dini, MS Bertone, G Brilli, M Romanelli: Cutaneous Tissue Repair Section -
Dermatological Clinic - University of Pisa
d) "Evaluation of the efficacy and tolerability of collagen spray (BIOSPRAY Euroresearch)

in the treatment of acute and chronic skin lesions"
Spontaneous Observation Romanelli - University of Pisa the clinical trial is appended
Marco Romanelli, Antonio Magliaro, Diego Mastronicola, Rosa Maria Semeraro,
Salvatore Siani: Dermatological Clinic, University of Pisa
e) "Conservative treatment of leg ulcers of different aetiology. Clinical comparison

between heterologous lyophilised collagen and hydrocolloid" - 2012
L. Cangiotti, A. Vinco, C. Codignola, A. Coniglio, P. Mujesan, G.A.Tiberio: General

surgical clinic and surgical therapy - University of Brescia
E. Teta: Clinical Research Department Istituto Gentili, Pisa

24/44
Reference a
The aim of the study was to investigate the clinical efficacy, general and local tolerability and
the safety of use of a type I equine collagen and silver spray device in the treatment of acute
and chronic partial thickness cutaneous lesions, through a series of clinical cases with acute
and chronic partial thickness lesions and altered perilesional skin, without clinical signs of
infection. In particular, 10 patients (5 males and 5 females) aged between 39 and 75 years
participated in the study.
Periodic checks were carried out before admission (T0), after two weeks of therapy (T1) and
after four weeks of therapy (T2).
After cleansing the lesion with a saline solution, the lesion was then covered with a non-
adherent dressing. Patients were instructed to change the dressing daily or if necessary, more
frequently and to record every change in a clinical diary.
The efficacy of the product concerned manifested with considerable efficacy in the perilesional
skin, with a marked reduction of erythema. The action was rapid, immediately after the first few
applications and was maintained during the observation period. In superficial lesions complete
healing was also achieved despite the short observation period. This data confirms the role of
collagen in promoting the extracellular matrix during tissue repair.
There have been no reported adverse events particularly worthy of note throughout the
duration of the study.
Reference b
In this study the effects of treatment were monitored with a dressing in heterologous collagen
dressings tablets on the healing of chronic venous ulcers.
Twenty patients participated in this study with a median age of 58.9 years, who presented with
chronic venous ulcers of the lower limbs, between 5 and 75 cm2 in diameter, without any
obvious signs of scarring after 8 weeks of conventional therapy. The dressing was changed
twice a week for a total of 4 weeks.
Efficacy end-points included the size of the ulcers and the increase of granulation tissue. For
each patient, two measurements were performed, at week 0 and after 4 weeks. After 4 weeks
of therapy, a significant increase in granulation tissue was observed. Furthermore, a significant
reduction in the size of the ulcers was found.
The results of this study show that treatment with the medical device being studied is effective
in the healing of chronic venous ulcers of the lower limbs. In particular, the device has proved
effective in promoting and stabilising granulation tissue.
Reference c
This study was conducted to evaluate the efficacy of heterologous collagen spray in the control
of exudate in chronic venous ulcers.
Fifteen patients participated in this study (10 females and 5 males) with an average age of 76
years, who presented with chronic venous ulcers in the lower limbs with an average size of 22
cm 2 and an average duration of 3 years.
The heterologous collagen dressings spray device was applied to the lesion bed as a primary
dressing, on alternate days for 4 weeks.
The medical device has proved to be useful in the management of exudate in these patients
with chronic venous ulcers of the lower limbs. After 4 weeks, a substantial reduction in trans-
epidermal water loss (TEWL, Trans Epidermal Water Loss) was observed and consequently,
25/44
maceration at the perilesional skin level. This effect is particularly remarkable, since the
maceration of the perilesional skin may represent an important obstacle to the healing of
chronic venous ulcers of the lower limbs.
Reference d
In this clinical study, performed according to a randomised model, the clinical efficacy, general
and local tolerability and safety of a medical device containing heterologous type I collagen of
equine origin, administered to 20 patients with acute and chronic wounds, were evaluated
The device was administered daily with a topical spray application on the lesion. Periodic
checks were carried out before enrolment (T0), after a treatment of two weeks (T1) and after
a treatment of four weeks (T2).
The device proved to be excellent in promoting tissue repair of acute and chronic wounds. The
collagen spray has proven to be beneficial, particularly due to the reduced healing time and
better pain control. The absence of side effects confirms the safety of heterologous equine
collagen.
Reference e
The study analyses the differences in terms of efficacy and safety in the treatment of vascular
ulcers between lyophilised collagen (Condress) and a hydrocolloid preparation. A total of 18
patients were involved (8 men and 10 women, with an average age of 63 years). Patients were
evaluated at T=0 and at 7,14,28,56 and 90 days after the start of treatment. The results showed
that collagen has a better impact with respect to the hydrocolloids in terms of decreasing the
ulcer diameter. In particular, collagen was statistically more effective in the treatment of ulcers
of venous origin. At the end of treatment both ulcers treated with collagen and those treated
with hydrocolloids were healed or improved but the collagen allowed faster healing times or
improvement of the wound.
4.4 Clinical data from the literature

The bibliographic research was conducted according to internal procedure. Conducting
bibliographic research according to company practices by assessing each bibliographic
reference that emerged from the research itself in such a way that no data concerning the
safety or the efficacy remains excluded. The articles retrieved are evaluated for their relevance
and evaluated.
The purpose of the research was to find safety and efficacy data relating to the functional
substances of the device considering the intended use of the product to further support the
clinical data generated by the manufacturer and described in the previous section. Data on
products similar to the medical device being evaluated were also analysed.
The bibliographic research was conducted on PubMed using the following search terms:
"collagen and sodium hyaluronate, study, wound"

Filter: Clinical Trial, Species: Humans
The results obtained from the research are reported in the table

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Results Relevance Information Retrieved
1. Gocmen G, Gonul O, Oktay NS, Yarat A, Goker K.
The antioxidant and anti-inflammatory efficiency of hyaluronic acid after third No
//
molar extraction. - J Craniomaxillo fac Surg. 2015 Sep;43(7):1033-7. doi: Other indications for use:
10.1016/j.jcms.2015.04.022. Epub 2015 May 6.
2. Pak CS, Lee J, Lee H, Jeong J, Kim EH, Jeong J, Choi H, Kim B, Oh S, Kim I,
Heo CY.
A phase III, randomised, double-blind, matched-pairs, active-controlled
clinical trial and preclinical animal study to compare the durability, efficacy No
//
and safety between polynucleotide filler and hyaluronic acid filler in the Other indications for use:
correction of crow's feet: a new concept of regenerative filler. - J Korean Med
Sci. 2014 Nov;29 Suppl 3: S201-9. doi: 10.3346/jkms.2014.29. S3 S201 Epub 2014
Nov 21. Retraction in: J Korean Med Sci. 2016 Feb;31(2):330.
3. Catalfamo L, Belli E, Nava C, Mici E, Calvo A, D'Alessandro B, De Ponte FS. Safety and efficacy data
Bioengineering in the oral cavity: our experience. - Int J Nanomedicine. 2013; Yes on collagen and on
8:3883-6. doi: 10.2147/IJN.S47697. Epub 2013 Oct 9. hyaluronic acid
4. Potocká D, Kevická D, Koller J.
Safety and efficacy data
Clinical trial of the temporary biosynthetic dermal skin substitute based on a
Yes on collagen and on
collagen and hyaluronic acid named Coladerm H/HM, first part. - Acta Chir Plast.
hyaluronic acid
2012;54(2):31-8.
5. Colella G, Cannavale R, Vicidomini A, Rinaldi G, Compilato D, Campisi G.
Efficacy of a spray compound containing a pool of collagen precursor
No
synthetic aminoacids (l-proline, l-leucine, l-lysine and glycine) combined
Other indications for use; //
with sodium hyaluronate to manage chemo/radiotherapy-induced oral
different components
mucositis: preliminary data of an open trial. - Int J Immunopathol Pharmacol.

2010 Jan-Mar;23(1):143-51.
6. Giannini S, Buda R, Vannini F, Cavallo M, Grigolo B.
No
One-step bone marrow-derived cell transplantation in talar osteochondral
lesions. - Clin Orthop Relat Res. 2009 Dec;467(12):3307-20. doi: 10.1007/s11999-
009-0885-8. Epub 2009 May 16.
Share capital € 90,000.00 fully paid-in Tax identification n. and VAT registration n. 06901450152 Trade Register of Milan Economic and administrative index n. 1123845
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7. Yamada N, Uchinuma E, Matsumoto Y, Kuroyanagi Y.
Comparative evaluation of re-epithelialisation promoted by fresh or No
//
cryopreserved cultured dermal substitute. - J Artif Organs. 2008;11(4):221-4. doi: Different Components
10.1007/s10047-008-0428-1. Epub 2008 Dec 17.
8. Hantash BM, Ubeid AA, Chang H, Kafi R, Renton B.
No
Bipolar fractional radiofrequency treatment induces neoelastogenesis and //
Topic not relevant
neocollagenesis. - Lasers Surg Med. 2009 Jan;41(1):1-9. doi: 10.1002/lsm.20731.
9. Favia G, Mariggio MA, Maiorano F, Cassano A, Capodiferro S, Ribatti D.
Accelerated wound healing of oral soft tissues and angiogenic effect induced Efficacy data on
SI
by a pool of aminoacids combined to sodium hyaluronate (AMINOGAM). - J hyaluronic acid
Biol Regul Homeost Agents. 2008 Apr-Jun;22(2):109-16.
10. Yonezawa M, Tanizaki H, Inoguchi N, Ishida M, Katoh M, Tachibana T,
No
Miyachi Y, Kubo K, Kuroyanagi Y.
Clinical study with allogeneic cultured dermal substitutes for chronic leg
ulcers. - Int J Dermatol. 2007 Jan;46(1):36-42.
11. Kashiwa N, Ito O, Ueda T, Kubo K, Matsui H, Kuroyanagi Y.
Treatment of full-thickness skin defect with concomitant grafting of 6-fold No
//
extended mesh auto-skin and allogeneic cultured dermal substitute. - Artif Different components
Organs. 2004 May;28(5):444-50.
12. Jones S, Holmes CJ, Krediet RT, Mackenzie R, Faict D, Tranaeus A, Williams
JD, Coles GA, Topley N - Bicarbonate/lactate-based peritoneal dialysis solution No
//
increases cancer antigen 125 and decreases hyaluronic acid levels. - Kidney Topic not relevant
Int. 2001 Apr;59(4):1529-38.
13. Di Mauro C, Ossino AM, Trefiletti M, Polosa P, Beghè F.
The safety and efficacy
Lyophilised collagen in the treatment of diabetic ulcers. - Drugs Exp Clin Res. SI
data on collagen
1991;17(7):371-3.

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Articles considered relevant are summarised below:
Reference 3
The article refers to two dressings, Promogran and Hyalomatrix, whose main components are
collagen and hyaluronic acid respectively.
The authors evaluated the safety and efficacy of the two products used for the treatment of
lesions and wounds of the oral cavity resulting from trauma, inflammatory processes and
tumours. 80 patients (52 women and 28 men) with an average age of 67 were involved. The
average size of the lesions was approximately 2 cm. The patients were divided into two groups
of 40 people. The first group was treated with conventional dressings (hydrogen peroxide,
povidone-iodine and gauzes with iodoform); the second group was treated with collagen or
hyaluronic acid dressings (depending on the type of lesion and its position). The collagen
dressing was replaced twice a day, the hyaluronic acid dressing every two weeks. The patients
were monitored up to complete remission of the disease. The results showed that the patients
of the second group achieved complete healing in times statistically faster than those of the
first group (2-20 days, against 45 days). None of the patients in either group had problems
during and after treatment. According to the authors, the reasons for the faster healing with the
collagen or hyaluronic acid dressings are to be found in several factors. With regards to
collagen, this provides a mechanical support for cell growth, stimulates fibroblast migration and
promotes the metabolic activity of granulation tissue. Hyaluronic acid has a structural role that
promotes the colonisation of fibroblasts and its hygroscopic properties retain a hydrated
cellular micro-environment; hyaluronic acid also has positive effects on epithelial tissue and
acts as an antioxidant against free radicals, by lowering the level of inflammatory stress. The
authors conclude by recommending the use of these dressings in clinical practice because
they accelerate wound healing, promote sterility maintenance and improve the patient's quality
of life.
Reference 4
This article presents the results of a clinical study where the performance and safety of a
collagen and hyaluronic acid (Coladerm H / HM) dressing were evaluated as a dermo-
cutaneous biosynthetic substitute. In particular, the dressing was applied to patients donating
skin grafts on the graft donation site. The study was carried out at the hospital of Brastislava
and involved 20 patients aged between 18 and 65 years, without problems relating to diabetes,
renal complications, arteriosclerosis, severe allergic conditions and immune problems. The
results showed that the collagen and hyaluronic acid dressing do not affect epithelial formation
over the long term, while the influence is very positive over the short term, thereby helping to
minimise the risk of complications. Wound secretions were reduced after the application of the
product and the colour of the treated area showed significant improvements. With regard to
the effect on pain reduction, doctors have estimated the effect as good in 70% of cases;
patients (95% of those treated) stated that they felt only slight pain at the time of application.
No adverse events were recorded except for one patient who complained of itching which then
resolved spontaneously. Only one patient had a positive bacteriological finding on the lesion.
The authors conclude by stating the effect of the dressing in the treatment of the lesion as
positive.
Reference 13

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This article examines the role of collagen in the treatment of diabetic foot ulcers, studying the
ulcers of 20 patients (12 men and 8 women) aged between 60 and 78 years. All patients
presented with an altered metabolic balance with high blood glucose and were subject to a
strict diet and insulin therapy. The patients were randomised into two groups of 10. The ulcers
of the patients of both groups were subject to debreeding. Group 1 then received a treatment
based on type I collagen of lyophilised bovine origin applied directly on the surface of the lesion
and covered with a gauze; Group 2 received a treatment with a gauze soaked in hyaluronic
acid. The dressings were replaced every two days. The results showed better results in terms
of efficacy in the group treated with collagen compared to the group treated with hyaluronic
acid (complete wound healing time 32.4 ± 8.6 days against 49.0 ± 11.0 days). In the group
treated with collagen, granulation tissue appeared more quickly and in addition, patients
treated with collagen did not need antibiotic therapy, while some patients of the other group
had to take antibiotics systemically. No safety issue was found in the two groups. According to
the authors, the best results of the treatment with collagen are to be found in a greater capacity
of collagen to promote the migration of epithelial cells from the edges of the wound.
4.4.1 Other literature evaluated

In addition to the bibliographic research illustrated previously and conducted in accordance
with the internal procedures, this section contains additional scientific articles already in the
possession of the manufacturer and the result of research carried out on other products owned
by the manufacturer. The additional articles presented and analysed in this section provide
supporting and in-depth data about the components of the medical device.
The following table lists the additional articles evaluated.
Source
14) Karl E. Kadler, David F. Holmes, John A. Trotter. And John A. Chapman
Collagen fibril formation - Biochem. J. (1996) 316, 1-11
15) Lutz Weber, Emily Kirsch, Peter Moller and Thomas Krieg
Collagen Type Distribution and Macromolecular Organization of Connective Tissue in
Different Layers of Human Skin – The journal of investigative dermatology
16) Chi H. Lee, Anuj Singla a, Yugyung Lee
Biomedical application of collagen - International Journal of Pharmaceutics 221 (2001) 1–
22
17) Robert F. Diegelmann and Melissa C. Evans
Wound Healing: An Overview of Acute, Fibrotic and Delayed Healing -Frontiers in
Bioscience 9, 283-289, January 1, 2004
18) Kari Haukipuro, Jukka Melkko, Leila Risteli, Matti Kairaluoma and Juha Risteli
Synthesis of Type I Collagen in Healing Wounds in Humans - Ann. Surg. January 1991
19) Carolina Weller, Geoff Sussman
Wound Dressings Update - Journal of Pharmacy Practice and Research 318 Volume 36,
No. 4, 2006
20) G. Nebbioso, F. Petrella, E. Caprarella
The role of hyaluronic acid in non-responder chronic skin lesions - Acta Vulnol 2010;8
21) Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.
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Systematic reviews of wound care management: (2) Dressings and topical agents used in
the healing of chronic wounds - Health Technol Assess 1999;3(17 Pt 2).
22) O’Meara S, Cullum N, Majid M, Sheldon T.
Systematic reviews of wound care management: (3) antimicrobial agents for chronic
wounds; (4) diabetic foot ulceration - Health Technol Assess 2000;4(21).
23) Purpura V, Bondioli E, Graziano A, Trovato L, Melandri D, Ghetti M, Marchesini A,
Cusella De Angelis MG, Benedetti L, Ceccarelli G, Riccio
Tissue Characterization after a New Disaggregation Method for Skin Micro- Grafts
Generation. M.J Vis Exp. 2016 Mar 4;(109).
Listed below are the reports of the scientific articles analysed
Reference 14
The article examines the role of collagen and its formation in normal tissue physiology. With
regard to the clinical evaluation context, the article reiterates how type I collagen is localised
in all types of tissues, with the exception of cartilage where type II collagen is found. The article
also underlines that type I collagen is normally synthesised by the body in response to injury
and damage and that a detailed understanding of the molecular mechanisms that regulate the
formation of collagen may be of interest to developing better clinical strategies for the treatment
of lesions.
Reference 15
In this article, the authors study the distribution of the various types of collagen in human skin
using biochemical analysis. With regard to type I collagen, experiments conducted both in vivo
and ex vivo, have shown that type I collagen is present in all tissues together with type III
collagen. The ratio between the two types of collagen was found to be in favour of type III
collagen in the papillary layer and in the subcutaneous fat, while type I collagen was more
abundant in the reticular layer of the skin.
Reference 16
In this review, the different uses of collagen in the biomedical field are discussed. The article
highlights how collagen plays an important role in the normal formation of tissues and organs;
this aspect together with the biodegradability, the greater biocompatibility compared to other
natural polymers such as albumin and gelatine and to the poor antigenicity has made the use
of collagen in the biomedical field grow rapidly. With regard to the use of collagen in the
treatment of lesions, the authors highlight how collagen has good haemostatic abilities, is
effectively used in the healing of the skin, particularly type I collagen for the treatment of burns.
Collagen is also used in the context of surgical lesions. The authors consider the safety profile
to be excellent, defining rare allergic reactions to collagen and citing only two cases of severe
allergic reactions due to bovine collagen. Currently, collagen is also used in drug-delivery
systems and to create skin and bone substitutes.
Reference 17
Diegelmann and collaborators in this review address the issue of wound healing of chronic and
acute wounds with a special focus on the role of collagen. The authors show how collagen is
a very abundant protein (about 30% of human proteins) and how, in healthy tissues, collagen
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is responsible for the strength, integrity and the structure of the tissue. In fact, when tissues
are damaged, it is the collagen which acts to repair the damage and restore the correct
anatomical structure and the deposition of collagen in the injured site is a fundamental step. In
particular, type I collagen is the most present in the skin and involved in skin repair processes.
Reference 18
In this article, the collagen content in serum and wound fluids collected from 20 patients
operated on for colorectal cancer at the "Oulu University Central" hospital was analysed. The
authors searched in the samples for the concentration of Procollagen type I carboxy-terminal
propeptide (PICP) which is considered to be an indirect measurement of the type I collagen
synthesis. The PICP always seemed to be present in serum at overall constant concentrations,
while its concentration in wound fluids was initially double that of the serum and subsequently
up to 1,000 times higher, indicating a synthesis of type I collagen in the damaged tissues.
Reference 19
In this review different types of wound dressing available are reviewed. The authors emphasise
the usefulness of dressings in the treatment of pressure ulcers, venous ulcers and diabetic foot
ulcers. By focusing on the use of collagen, the article, in addition to highlighting the role of
natural collagen in wound healing, cites some products similar to the medical device subject
to clinical evaluation that contain collagen and which are used in medical practice. These
products are: Promogran, a matrix based on collagen and cellulose recommended for the
treatment of wounds free from necrotic tissue and not infected; Integra, a scaffold composed
of collagen and chondroitin-6-sulfate used in skin regeneration processes; Apligraf, a double
layer given by live fibroblasts and type I collagen extracted from bovine, particularly indicated
for the treatment of venous ulcers.
Reference 20
The article examines the involvement of hyaluronic acid in the ulcer healing process, taking
into consideration 14 patients (10 men and 4 women) suffering from chronic ulcers of different
aetiology and difficult to resolve, i.e. not healed despite adequate preparation of the bottom of
the lesion and the use of advanced dressings. Patients were treated with a dressing consisting
of esters of hyaluronic acid. Over a period of 6 months, 7 patients have complete healing, 5
found an improvement in the state of the wound and a reduction in the size of the ulcer and 2
stopped treatment. The authors conclude by saying that hyaluronic acid generates an optimal
micro-environment capable of stimulating the proliferation and migration of fibroblasts,
endothelial cells, keratinocytes, promotes neoangiogenesis and has a positive effect on the
inflammatory response; moreover the hyaluronic acid inhibits the formation of the scar
obtaining a better aesthetic result.
Reference 21
In this article, the authors collected literature data on clinical studies where patients suffering
from venous ulcers and decubitus ulcers were treated with topical preparations. With regard
to the use of collagen and hyaluronic acid, the authors report that collagen sponges used for
the treatment of leg ulcers have been found to be effective in two clinical studies published
and that in a study where they evaluated the sterility and cleanliness of the wound, by
comparing the application of collagen with an antiseptic, the collagen dressing gave better
results. Two clinical studies have compared the hyaluronic acid dressings with standard

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dressings and in one of the two studies the hyaluronic acid promoted more healing. In general,
the authors state that the use of hyaluronic acid and collagen benefits the patient.
Reference 22
In this article, the authors collected literature data on clinical studies where patients suffering
from diabetic foot ulcers were treated with topical preparations, with particular attention to
antimicrobial function. With regard to the use of collagen, the authors have shown that in
studies where benzoyl peroxide was compared with collagen, benzoyl peroxide had minor
results. In particular, a comparison study between collagen gel and 20% benzoyl peroxide, on
20 patients, has highlighted how after 12 weeks of treatment the wound area was much less
extensive in patients receiving treatment with collagen.
Reference 23
In this study the collagen pad was used as a three-dimensional structure to transmit to the
lesion site and promote the engraftment of dermal micro-grafts in the treatment of large losses
of cutaneous substance as a result of severe trauma. Forty-five patients were involved with an
average age of 69.7 ± 8.64 years, of which 16 were male and 29 female. The pad has proved
to be superior in clinical performance compared to similar products/scaffolds tested in the past
in the same facility /department, highlighting reduced healing times, high scar quality, excellent
patient compliance.
There were no signs of recurrence in the following six months. Scar quality was good in all
subjects during the healing period and did not deteriorate at the six-month follow-up. No patient
complained of skin problems.
4.5 Summary and evaluation of clinical data

Preclinical data
The manufacturer has collected pre-clinical biocompatibility data with skin irritation, cytotoxicity
and delayed hypersensitivity tests according to ISO 10993.
Clinical data on the medical device
Overall, 8 experiments and clinical observations involving almost 700 patients worldwide were
conducted. In particular, a study was conducted on 28 patients with diabetic foot ulcers, two
studies on patients with surgical dehiscence (55 and 6 patients, respectively), a study of 11
patients with closable dehiscence in secondary intention, a study of 20 patients who presented
with chronic ulcerative lesions of the lower limbs, a study on 331 patients with abdominal stoma
and a study on 38 patients suffering from skin ulcers of the foot. Finally, the medical device
has been used on approximately 200 patients with difficult wounds, chronic skin lesions and
diabetic foot ulcers.
Clinical support data on similar medical devices

An equivalent product has not been identified pursuant to the MEDDEV 2.7 / 1 Rev.4 guideline,
but similar products have been identified in terms of composition, directions and method of
use.

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There are 5 supporting clinical studies available to demonstrate the safety and efficacy of
collagen, obtained as a result of clinical trials with a medical device owned by the manufacturer
and similar to the one that is the subject of the present clinical evaluation.
Scientific literature data
Bibliographical references relating to clinical data on similar medical devices were analysed.
The literature data derive both from a bibliographic research (13 articles found, 3 relevant),
and from articles already in the possession of the manufacturer and deriving from studies and
evaluations made by the manufacturer itself on other medical devices which it owns (23
articles). The literature data provided supporting data regarding the safety and efficacy of the
components of the medical device in the proposed indications for use.
PMCF (post-marketing clinical follow-up)
The manufacturer has prepared a PMS with related Post Marketing Clinical Follow up (PMCF)
for the medical device.
The PMCF plan provides, in addition to the active collection of information from the market, a
monocentric clinical study randomised into two groups with the proposed title "a prospective,
randomized, clinical trial to evaluate the safety and efficacy of collagen pad+HA compared to
standard care in the management of superficial cutaneous lesions".
The study will involve 30 patients suffering from skin ulcers; patients will be treated with the
medical device subject to clinical evaluation and it will be held at the University Hospital
"Ospedali Riunti di Ancona". Patients will be observed for 28 days. The study will be subject to
the prior assessment of the Ethics Committee.
The clinical data of the follow-up study will be used to support efficacy and safety at the next
clinical evaluation.
The clinical data is discussed in detail in the subsequent sections of this document.
4.6 Analysis of clinical data
4.6.1 Safety Requirement

Data on the components of the medical device and pre-clinical studies
The components of the medical device, collagen and hyaluronic acid, are natural substances
physiologically present in human tissues, which ensures an excellent level of biocompatibility
and poor immunoreactivity. The use of the components of the medical device, alone or in
combination with other substances, is consolidated in medical practice and in support of this
there are products available on the market containing collagen or hyaluronic acid that are
considered similar in terms of composition, method of application and indications to the medical
device subject to clinical evaluation. The technological form of the device in question is also
widely used; in fact there are solid matrices on the market to be deposited on the lesion which
undergo integration in the biological fluids of the lesion itself.
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As further confirmation of the safe use of these components, there are products on the market
containing hyaluronic acid and collagen used in indications for use and with different routes of
administration compared to those of the medical device subject to clinical evaluation. The use
of hyaluronic acid is also common in cosmetics.
Overall, this data supports the safe use of collagen and hyaluronic acid.
Collagen used by Euroresearch is extracted from horse tendons. This collagen is certified as
BSE-free and TSE-free and supporting documentation is available to the manufacturer. In
addition, the collagen used is hypo-allergenic and latex-free, which further reduces the risks of
use.
According to ISO 10993 – 1 "Biological evaluation of medical devices - Part 1: Evaluation and
Testing" the manufacturer has conducted biocompatibility tests as summarised below:
• Delayed hypersensitisation test

• Skin irritation test
• Cytotoxicity tests for elution
Tests have shown that the product is not cytotoxic, is not sensitising nor irritating to the skin,
thus providing preliminary indications on its safety for the patient.
Literature data
The literature data analysed confirms the safety of the medical device and of its components
when the product is used according to the indications provided, as explained below.
In a review of Chi e collaboratori (Chi 2001) on the medical use of collagen, the authors judged
the safety profile of the molecule as excellent, defining rare allergic reactions to collagen and
citing only two cases of severe allergic reactions due to bovine collagen, while in the medical
device subject to clinical evaluation equine type collagen is used. The authors also state that
collagen is more biocompatible than many other natural polymers used in the medical field.
Bradley and O'Meara have produced reviews on the clinical data available in the literature on
topical treatments for venous decubitus and diabetic ulcers and reported no safety problems
for collagen and hyaluronic acid, either alone or in combination with other substances (Bradley
1999; O'Meara 2000). In a study on patients treated with collagen pads to promote the rooting
of dermal grafts, no patient complained of problems or no adverse events occurred (Purpura
2016).
In a study involving 80 patients treated with products containing hyaluronic acid or collagen for
the healing of oral cavity lesions, none of the patients had problems during and after treatment,
with the patients being observed until complete healing (Catalfamo 2015).
Potocká and collaborators have shown that in donor patients of cutaneous appendages treated
with collagen and hyaluronic acid dressings, the only negative effect was slight pain at the time
of application. No adverse events were recorded except for one patient who complained of
itching which then resolved spontaneously (Potocká 2012).

In the use of components on diabetic foot ulcers of 20 patients, no safety problems were found
(Mauro 1991).

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Clinical data generated by the manufacturer
The manufacturer has collected data from experiments and clinical observations with the
collagen and hyaluronic acid pad which involved about 700 patients treated for the resolution
of various types of lesions (diabetic ulcers, surgical lesions, venous ulcers, stomas etc.).
In no case, irrespective of the duration of treatment, the type and severity of lesion, were
problems found regarding the safety profile. In addition, it should be pointed out that good
patient compliance of the patient to the treatment was generally found and all patients who
began treatment completed it; the only exception were 3 patients enrolled for the study on the
surgical dehiscence presented by Strazzeri and collaborators who left due only to a transfer to
another clinical facility. The very low percentage of interruption and high compliance with the
treatment are indirect indications of the safety of the product.
With regard to the information returned from the market, Euroresearch has never received
complaints of quality or safety from end users of the product. Likewise, no incident reports
have ever been received.
Conclusions
The working group evaluated all the clinical data collected. The working group also evaluated
and verified the conformity of the medical device with the safety requirements described in the
essential requirements in point 1.
The conclusion of the analysis was that the device is safe for its intended use:
• There are no design features that require special attention to safety.
• A complete risk analysis on the device has been carried out and literature information
was considered. The risk analysis report is in the technical dossier.
• All hazards and the other relevant information have been appropriately identified: the
warnings section of the Instructions for Use (leaflet) covers all the possible residual
risks identified in the risk analysis.
• The device is easy-to-use and the use of similar devices is common. The Instructions
for Use supplied are clear and adequate for the intended use. The working group
concludes that there is no need for a particular end-user training or other precautions
different from those already included in the instructions.
• The analysis of the scientific literature, technical information on the components of the
device (MSDS) and on the biocompatibility data is consistent with the risk analysis
process and its results.
• Clinical studies have shown the safety of the medical device.
• The marketing history of this device proves its safety, as no incidents have ever been
reported.
4.6.2 Requirements related to the acceptability of the benefit/risk ratio

The working group has evaluated the benefit/risk profile of the medical device. The evaluation
has considered the result of the risk analysis and the evaluation of the efficacy (see 4.6.3,
below). The residual risks identified appear to be under control if the device is used for its
36/44
intended purpose and in accordance with the instructions given and the warnings indicated.
The warnings provided allow users to prevent improper use of the product and incorrect
handling.
The benefit is proven by the evidence presented, therefore the benefit/risk profile is acceptable.
As further confirmation, the experience of marketing the device supports the considerations on
the benefit/risk ratio.
4.6.3 Performance Requirement

Literature data
The collected literature data shows the excellent performance of the components of the
medical device or products similar to it in the treatment of various types of lesions on a varied
and heterogeneous medical population, as detailed below.
In its review on the medical use of collagen, Chi e collaboratori (Chi 2001) state that collagen
can be effectively used in the healing of skin, for surgical wounds and, in particular, type I
collagen for the treatment of burns. Similarly, Diegelmann states that collagen deposition in
the injured site is a fundamental step in wound healing (Diegelmann 2004). Collagen is also
commonly used for the treatment of pressure ulcers, diabetic foot ulcers and venous ulcers
(Weller 2006). In particular for vascular ulcers, collagen sponges have been found to be
effective in two clinical studies published, while in a study where they evaluated the sterility
and cleanliness of the wound, by comparing the application of collagen with an antiseptic, the
collagen dressing gave the best results ( Bradley 1999). The efficacy of collagen was also
evaluated from the point of view of sterility maintenance by comparing it with benzoyl peroxide
on diabetic foot ulcers; collagen gave more satisfactory results (O’Meara 2000).
With regard to the use of hyaluronic acid, this substance used for 6 months on 14 patients
suffering from various types of ulcerations allowed complete healing in 7 patients and an
improvement in the state of the wound and a reduction in the size of the ulcer in 5 patients.
For the authors, the positive effect is to be found in the maintenance of an optimal micro-
environment that stimulates the proliferation and migration of fibroblasts, endothelial cells and
keratinocytes. (Nebbioso 2010). According to Bradley (Bradley 1999), the use of hyaluronic
acid on leg ulcers and on bed sores provides benefits to the patient.
Catalfamo presents a study on 80 patients (52 women and 28 men) with an average age of
67, with oral lesions resulting from trauma, inflammatory processes and tumours treated with
collagen or hyaluronic acid dressings. Starting from an average lesion size of 2 cm, the results
showed that patients achieved complete healing in statistically faster times than in control
patients (2-20 days, against 45 days). The authors attributed the efficacy of the treatment to
the mechanical support provided by collagen to fibroblasts or to the hygroscopic action of
hyaluronic acid and concluded by suggesting the use of similar dressings because they
accelerate wound healing, promote sterility maintenance and improve the patient's quality of
life (Catalfamo 2013).

37/44
The efficacy of a hyaluronic acid or collagen dressing was also verified on 20 donors of skin
appendages, applying the dressing on the donation site. Wound secretions were reduced after
the product was applied, the colour of the treated area showed significant improvements and
doctors estimated the effect on pain reduction as good in 70% of cases (Potocká 2012).
Evidence on the efficacy of collagen and hyaluronic acid in the treatment of ulcers of the
diabetic foot was also found. Twenty patients (12 men and 8 women) aged between 60 and
78 years randomised to receive treatment with collagen or with gauze soaked in hyaluronic
acid showed faster complete healing of the wound in the group treated with collagen compared
to the group treated with hyaluronic acid (32.4 ± 8.6 days against 49.0 ± 11.0 days) (Di Mauro
1991).
Clinical data generated by the manufacturer

The manufacturer has evaluated the efficacy of the medical device from the data from
spontaneous experiments and observations that involved approximately 700 patients suffering
from ulcers and lesions of various type and severity. The medical device was used with good
results for the treatment of chronic cutaneous lesions, acute lesions and traumatic injuries,
where it was necessary to protect noble structures (e.g. tendons, muscles, nerves and blood
vessels) from damage caused by dehydration by covering them quickly. In general, the studies
conducted with the medical device showed that the device allows a more rapid resolution of
many types of skin lesions, creating the ideal conditions for the treatment of injuries due to the
complementary and synergistic action of the two components, hyaluronic acid and type I
equine collagen, and determining the acceleration of the skin repair process. The synergy of
the two molecules involved optimises the wound healing process, improving the times and the
results: reconstitution of the deepest layers and superficial re-epithelialisation of the lesion,
more compact granulation tissue, softer and more elastic scar tissue, significant reduction of
pain, since it maintains an excellent level of hydration of the granulation tissue and re-
epithelialisation Another important aspect is that the medical device was easily applicable and
adaptable on the wound bed. In addition, as it is fully resorbable (the level of self-degradation
within the application site occurs in about 3-7 days, depending on the state of exudation of the
lesion itself) patient management was facilitated.
In detail, in the case of diabetic foot ulcers of 28 patients treated for approximately 68 days,
complete healing was observed in 6 of 28 patients (21%) with an average reduction in the
wound surface area of 69 % (± 25). These results are to be considered excellent and the
healing rate can be defined as high if you consider the severity of the wounds examined, as
only patients with bone exposure were included in the study.
Efficacy was also tested on surgical dehiscence in 55 patients in 14 clinical centres in Italy.
Efficacy was also tested on surgical dehiscence in 55 patients in 14 Italian clinical centres. Of
the 55 patients involved in the study, 28 completely healed cases were observed, 22 patients
with wound reduction between 80% and 95%, 4 patients with wound reduction between 50%
and 80% and 1 non-responder patient It was noted in all patients that there was decreased
pain, progressive decrease of exudate within 3 weeks and an improvement in the state of the
perilesional skin after 2 weeks of treatment. A second study involved 6 patients with tissue
injury affecting as far as the muscle fascia. The patients were observed every 7 days for a total
of 4 observation points. All patients reported a decrease in pain and a reduction in the surface
area (15% in 7 days, 50% in 30 days) and the volume of the lesion (between 85% and 97%
38/44
the fourth week) was observed. The exudate began to decrease in the second week of
treatment. A third study involved 11 patients (average age of 48 years) treated for the healing
of dehiscence closable only by secondary intention. Of the 11 patients enrolled, 3 did not
complete the study due to transfer to another hospital, 7 were healed and one patient reduced
the volume of the lesion > 80%. Also, in this case the pain decreased in all patients, perilesional
skin improved as well as the production of exudate. Worthy of note is the specific case of a 20-
year-old patient suffering from sacrococcygeal fistula (SCF) that had been open for two years;
after only one week from application of the medical device, the depth of the FSC was filled.
The bioactive dressing with the medical device also provided a very encouraging result in a
particular case in which the patient was a non-responder to other types of treatment.
A study on 331 patients (178 males and 153 females, average age of 62.68 years, age range
22-100 years) with abdominal stomia, peristomal skin changes, evaluated the effects of various
topical preparations on the healing time of the lesions. Treatment with hyaluronic acid + equine
collagen was used in 37% of the patients studied, demonstrating a very high level of
performance. The treatment was able to heal 100% of cases with lesions at 8 weeks from the
start of the treatment and 98% of cases with lesions after 12 weeks.
An observational study involved 20 patients (13 females and 7 males) aged between 64 and
78 years (average age: 71 years), who presented with a chronic ulcerative lesion of the lower
limbs, randomised into two groups (treatment: collagen and hyaluronic acid plaques + interface
+ compression; control interface: + compression). After 6 weeks of treatment, the treated group
showed a significant reduction of the lesion site and an increase in granulation tissue compared
to the control group.
Still in the context of ulcers of the lower limbs, particularly the foot, 38 patients with an average
age of (31 males and 7 females) were evaluated who showed a 46% healing rate after 12
weeks, with a reduction of 78% of the ulcerated area.
From what has been noted, it is possible to state that the medical device is intended to fill a
technological void in the panorama of bioactive dressings, used for the treatment of lesions.
It should also be considered that the clinical support data obtained by the manufacturer with
its other MD collagen dressings confirms the efficacy of this substance.
Conclusions
The working group analysed all the clinical data and verified the correspondence with the
essential requirements of the legislation.
The conclusion of the analysis was that the device is effective in its intended use:
• There are no design features that require special attention in order to improve its
efficacy.
• A complete risk analysis on the device was carried out and literature information was
considered. The risk analysis report is in the technical dossier.

• The benefit/risk ratio is considered acceptable.

39/44
• The device is easy-to-use and the use of similar devices is common. The use of the
components of the medical device in the indications proposed is consolidated in
medical practice.
• Clinical studies have demonstrated the efficacy of the medical device in the intended
indications of use and on a heterogeneous medical population.
• The marketing history of this device proves its safety, as no incidents have ever been
reported, and no complaints have been reported in terms of its efficacy.
4.6.4 Requirement on the acceptability of side effects

The information available in the literature and the data of the retrospective clinical observation
show the safety and tolerability of the medical device and in general of dressings containing
the functional ingredients of the MD.
The available data is considered sufficient to consider any side effects acceptable.
The Instructions for Use contains detailed information regarding warnings and to possible side
effects.
Warnings and Precautions

The product should not be administered to patients with a proven family history of
anaphylactoid reactions or of individual hypersensitivity to the components.
The device is non-toxic, does not give rise to bolus formation, does not swell if it absorbs
moisture and therefore does not pose a risk of suffocation.
KEEP OUT OF THE SIGHT AND REACH OF CHILDREN.
The device is disposable. Do not reuse any plaque remnants.
The device is sterile. Do not use if the package is damaged.
Do not use after the expiration date. The expiration date refers to an intact and properly stored
package.
Contraindications/Side effects
The device is biocompatible and bioresorbable. No sensitisation or side effects or undesired
effects have been found or reported.
The device does not affect the ability to drive and use machines.
There are no known contraindications for use during pregnancy or breastfeeding; however, in
the absence of specific data, its use is not recommended unless under the direct control of a
doctor.
5 Conclusions
The medical device covered by this clinical evaluation is in compliance with the essential
requirements imposed by this Directive. The essential requirements are analysed in the
technical dossier.
The current knowledge of the risk associated with the individual components and the
information on additional risks due to their combination which were acquired with the
40/44
biocompatibility studies have allowed the working group to evaluate an acceptable risk / benefit
profile.
The instructions for use are adequate to ensure safe use and to reduce the residual risk to
acceptable levels particularly with the presence of specific warnings on the methods of use.
The device is suitable for use: The design is easy-to-use for users. The instructions are
complete and clear. No discrepancy was found.
The claims established by the manufacturer are supported by clinical studies and by the
bibliographic data on similar medical devices; the PMS developed for the medical device
provides a PMCF with clinical study managed by the Manufacturer: the clinical data generated
will support the efficacy and safety for the next review of the clinical evaluation.
Printed materials (label, carton, leaflet) are consistent with the claims described in the technical
dossier and with the results of this clinical evaluation. No discrepancy was found.
All of the above is consistent with current scientific knowledge. The residual risk is well covered
by the warnings and instructions included. The manufacturer will check during the commercial
life of the device with an adequate surveillance and monitoring programme, as detailed in the
relevant quality system procedures.
6 Date of the next clinical evaluation

The clinical evaluation is managed in accordance with the internal procedure that provides for
the periodic updating of the clinical evaluation.
7 Signatures of evaluators
Signatures of evaluators
Responsibility* Date Signature
Medical Director
ADOLFO GASPARETTO 24.07.2018
Regulatory Affairs
NICOLA SCHIATTARELLA 24.07.2018
Quality Assurance
STEFANIA GORLA 24.07.2018
*By signing this document, the evaluators endorse the contents of the report.
8 Qualifications of the responsible evaluators

The CV of the expert clinician is set out in the Appendix.

Proof of the evaluator's qualifications is given in the corresponding appendix of the reference
STED.
41/44
9 Bibliography and References
Abatangelo Silvio, Ciprandi Guido, Scalise Alessandro, Strazzeri Grazia: Surgical

dehiscence: how and when to use a bioactive dressing - results of a spontaneous multi-
centre observational study, XIV National Congress of the Italian Association of Skin Ulcers
(AIUC), 4-7 October 2017
Antonini Mario, Arena Raimondo, Mancini Simona, Manfredda Silvia, Militello Gaetano,
Tantulli Bartoli Raffaella, Veraldi Stefano, Gasperini Stefano: Peristomal skin changes: what
treatment should be adopted? Results of an observational multi-centre study, WCET journal,
Volume 38 Number 1 2 January/March 2018
Baglioni Elisabetta Adelaide, Russo Agata, Carbone Pierangela, Fassero Elisa, Bernocco
Laura, A. Scarmozzino: Abdominal dehiscence: evaluation of a biologically active
preparation, clinical observation of the action of a collagen and hyaluronic acid dressing
product, XIV National Congress of the Italian Association of Skin Ulcers (AIUC), 4-7 October
2017
Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.: Systematic reviews
of wound care management: (2) Dressings and topical agents used in the healing of chronic
wounds - Health Technol Assess 1999;3(17 Pt 2).
Cangiotti L., Vinco A., Codignola C., Coniglio A., Mujesan P., Tiberio G.A., Teta E.:
Conservative treatment of leg ulcers of different etiology. Clinical comparison between
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Caravaggi Carlo Maria F.: Safety And Efficacy Report on a hyaluronic acid and collagen
dressing pad (trade name Hyalo4 Regen/Bionect Pad), 16 May 2018
Caravaggi Carlo: Bionect pad in diabetic foot ulcers: clinical experience, Congress of the
European Wound Management Association (EWMA), 3-5 May 2017
Catalfamo L, Belli E, Nava C, Mici E, Calvo A, D'Alessandro B, De Ponte FS.: Bioengineering
in the oral cavity: our experience. - Int J Nanomedicine. 2013; 8:3883-6. doi:
10.2147/IJN.S47697. Epub 2013 Oct 9.
Chi H. Lee, Anuj Singla a, Yugyung Lee: Biomedical application of collagen - International
Journal of Pharmaceutics 221 (2001) 1–22
Colella G, Cannavale R, Vicidomini A, Rinaldi G, Compilato D, Campisi G.: Efficacy of a
spray compound containing a pool of collagen precursor synthetic aminoacids (l-proline, l-
leucine, l-lysine and glycine) combined with sodium hyaluronate to manage
chemo/radiotherapy-induced oral mucositis: preliminary data of an open trial. - Int J
Immunopathol Pharmacol. 2010 Jan-Mar;23(1):143-51.
Di Mauro C, Ossino AM, Trefiletti M, Polosa P, Beghè F.: Lyophilized collagen in the
treatment of diabetic ulcers. - Drugs Exp Clin Res. 1991;17(7):371-3.
Dini V, Bertone MS, Brilli G, Romanelli M: Use of collagen spray in the control of exudate in
chronic venous ulcers, National Congress of the Italian Association of Skin Ulcers (AIUC),
2006
Favia G, Mariggio MA, Maiorano F, Cassano A, Capodiferro S, Ribatti D.: Accelerated
wound healing of oral soft tissues and angiogenic effect induced by a pool of aminoacids
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combined to sodium hyaluronate (AMINOGAM). - J Biol Regul Homeost Agents. 2008 Apr-
Jun;22(2):109-16.
Giannini S, Buda R, Vannini F, Cavallo M, Grigolo B.: One-step bone marrow-derived cell
transplantation in talar osteochondral lesions. - Clin Orthop Relat Res. 2009
Dec;467(12):3307-20. doi: 10.1007/s11999-009-0885-8. Epub 2009 May 16.
Gocmen G, Gonul O, Oktay NS, Yarat A, Goker K.: The antioxidant and anti-inflammatory
efficiency of hyaluronic acid after third molar extraction. - J Craniomaxillo fac Surg. 2015
Sep;43(7):1033-7. doi: 10.2147/IJN.S47697. Epub 2009 May 16.
Hantash BM, Ubeid AA, Chang H, Kafi R, Renton B.: Bipolar fractional radiofrequency
treatment induces neoelastogenesis and neocollagenesis. - Lasers Surg Med. 2009
Jan;41(1):1-9. doi: 10.2147/IJN.S47697.
Haukipuro Kari, Melkko Jukka, Risteli Leila, Kairaluoma Matti and Risteli Juha: Synthesis of
Type I Collagen in Healing Wounds in Humans - Ann. Surg. January 1991
Jones S, Holmes CJ, Krediet RT, Mackenzie R, Faict D, Tranaeus A, Williams JD, Coles
GA, Topley N: Bicarbonate/lactate-based peritoneal dialysis solution increases cancer
antigen 125 and decreases hyaluronic acid levels. - Kidney Int. 2001 Apr;59(4):1529-38.
Karl E. Kadler, David F. Holmes, John A. Trotter. And John A. Chapman: Collagen fibril
formation - Biochem. J. (1996) 316, 1-11
Kashiwa N, Ito O, Ueda T, Kubo K, Matsui H, Kuroyanagi Y.: Treatment of full-thickness skin
defect with concomitant grafting of 6-fold extended mesh auto-skin and allogeneic cultured
dermal substitute. - Artif Organs. 2004 May;28(5):444-50.
Nebbioso G., Petrella F., Caprarella E.: The role of hyaluronic acid in non-responder chronic
skin lesions - Acta Vulnol 2010;8
O’Meara S, Cullum N, Majid M, Sheldon T.: Systematic reviews of wound care management:
(3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration - Health Technol
Assess 2000;4(21).
Pak CS, Lee J, Lee H, Jeong J, Kim EH, Jeong J, Choi H, Kim B, Oh S, Kim I, Heo CY.: A
phase III, randomized, double-blind, matched-pairs, active-controlled clinical trial and
preclinical animal study to compare the durability, efficacy and safety between
polynucleotide filler and hyaluronic acid filler in the correction of crow's feet: a new concept
of regenerative filler. - J Korean Med Sci. 2014 Nov;29 Suppl 3: S201-9. doi:
10.3346/jkms.2014.29. S3 S201 Epub 2014 Nov 21. Retraction in: J Korean Med Sci. 2016
Feb;31(2):330.
Potocká D, Kevická D, Koller J.: Clinical trial of the temporary biosynthetic dermal skin
substitute based on a collagen and hyaluronic acid named Coladerm H/HM, first part. - Acta
Chir Plast. 2012;54(2):31-8.
Purpura V, Bondioli E, Graziano A, Trovato L, Melandri D, Ghetti M, Marchesini A, Cusella
De Angelis MG, Benedetti L, Ceccarelli G, Riccio: Tissue Characterization after a New
Disaggregation Method for Skin Micro- Grafts Generation. M.J Vis Exp. 2016 Mar 4;(109)”
Riccio Michele: Reporting on rehabilitation supply product in pad form with a hyaluronic acid
and collagen base (Bionect pad) 17 May 2018
Robert F. Diegelmann and Melissa C. Evans: Wound Healing: An Overview of Acute,
Fibrotic and Delayed Healing -Frontiers in Bioscience 9, 283-289, January 1, 2004

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Romanelli M, Dini V, Bertone MS, Barbanera S, Brilli C: Evaluation of the efficacy of
heterologous collagen in wound healing, National Congress of the Italian Association of Skin
Ulcers (AIUC), 2006
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Salvatore: "Evaluation of the efficacy and tolerability of collagen spray (BIOSPRAY
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patients suffering from chronic venous ulcers of the lower limbs that do not tend towards
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Strazzeri Grazia M.A., Calì Maddalena, Russo Lorenzo: Observational Study on the
reparative capacity of a new heterologous equine collagen and hyaluronic acid dressing,
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Macromolecular Organization of Connective Tissue in Different Layers of Human Skin – The
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Clinical Evaluation Report

Review Of the Reason for Check Approval

EURORESEARCH s.r.l. Sole-shareholder company

2.2 MANUFACTURER IDENTIFICATION -------------------------------------------------------------------------------------------- 5

2.3 REFERENCE DIRECTIVE --------------------------------------------------------------------------------------------------------- 5

2.4 DEVICE - DESCRIPTION -------------------------------------------------------------------------------------------------------- 5

2.5 TECHNOLOGIES USED --------------------------------------------------------------------------------------------------------- 6

2.6 DEVICE GROUP ----------------------------------------------------------------------------------------------------------------- 6

2.7 INTENDED USE AND INDICATIONS PROVIDED --------------------------------------------------------------------------------- 6

2.7.1 Intended use --------------------------------------------------------------------------------------------------------- 6

2.7.2 Indications specified ----------------------------------------------------------------------------------------------- 6

2.7.3 Methods of use ----------------------------------------------------------------------------------------------------- 7

2.7.4 Mechanism of action ---------------------------------------------------------------------------------------------- 7

2.7.5 Warnings and Precautions --------------------------------------------------------------------------------------- 9

2.7.6 Contraindications and Side Effects ---------------------------------------------------------------------------- 9

2.7.7 Storage ---------------------------------------------------------------------------------------------------------------- 9

2.8 DEVICE STATUS ---------------------------------------------------------------------------------------------------------------- 9

3 CLINICAL BACKGROUND, CURRENT KNOWLEDGE, STATE OF THE ART -------------------------------------- 10

3.2 APPLICABLE STANDARDS AND GUIDANCE DOCUMENTS--------------------------------------------------------------------- 10

3.3 CLINICAL CONDITION TO BE TREATED ---------------------------------------------------------------------------------------- 10

3.4 ALTERNATIVE THERAPIES ----------------------------------------------------------------------------------------------------- 13

3.5 ANALYSIS OF THE COMPONENTS OF THE MEDICAL DEVICE ----------------------------------------------------------------- 15

4 DEVICE IN EVALUATION --------------------------------------------------------------------------------------------------- 15

4.3 CLINICAL DATA GENERATED AND STORED BY THE MANUFACTURER -------------------------------------------------------- 17

4.4 CLINICAL DATA FROM THE LITERATURE -------------------------------------------------------------------------------------- 26

4.4.1 Other literature evaluated -------------------------------------------------------------------------------------- 30

4.5 SUMMARY AND EVALUATION OF CLINICAL DATA ---------------------------------------------------------------------------- 33

4.6 ANALYSIS OF CLINICAL DATA ------------------------------------------------------------------------------------------------- 34

4.6.1 Safety Requirement -------------------------------------------------------------------------------------------- 34

4.6.2 Requirements related to the acceptability of the benefit/risk ratio --------------------------- 36

4.6.3 Performance Requirement ---------------------------------------------------------------------------------- 37

4.6.4 Requirement on the acceptability of side effects --------------------------------------------------- 40

EURORESEARCH s.r.l. Sole-shareholder company

The clinical evaluation has the following objectives:

EURORESEARCH s.r.l. Sole-shareholder company

2.1 Device identification

The medical device is marketed under the following trade names:

2.2 Manufacturer Identification

2.3 Reference directive

2.4 Device - Description

The composition of the medical device is described below:

Component Quantity (%) Function

Each blister pack contains a collagen plaque (disposable).

2.5 Technologies Used

2.6 Device group

2.7 Intended use and indications provided

2.7.1 Intended use

2.7.2 Indications specified

Acute and chronic lesions from moderately to very exuding.

EURORESEARCH s.r.l. Sole-shareholder company

2.7.3 Methods of use

2.7.4 Mechanism of action

compression, without hindering cell mobility.

Hyaluronic acid is a biological polysaccharide (glycosaminoglycan) distributed in the

The use of a hyaluronic-containing device produces more rapid epithelialisation. There is

EURORESEARCH s.r.l. Sole-shareholder company

2.7.6 Contraindications and Side Effects

Transport at temperatures not exceeding 30°C, avoiding direct exposure to sunlight.

2.8 Device status

EURORESEARCH s.r.l. Sole-shareholder company

3.1 Summary of the research strategy

3.2 Applicable standards and guidance documents

3.3 Clinical condition to be treated

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