Regulatory Positioning of an Innovative Biomaterial

for Regenerative Medicine: TissYou Project

Gwenaël Rolin

1,2 a

, Kenny Pinot

and Marilys Blanchy

INSERM CIC-1431, CHU Besançon, F-25000 Besançon, France

Univ. Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/ Ingénierie Cellulaire et

Génique, F-25000, Besançon, France

Rescoll

, Pessac, France

Keywords: Biomaterial, Electrospining, Implantable Device, European Regulation.

Abstract: New technologies make it possible to industrialize objects that can reconstruct in-vivo like extracellular

matrices. Actually, these scaffolds exhibit properties mimicking physiological tissue. The project presented

here aims at the industrial production of a new bicomposite biomaterial for skin regeneration. This “TissYou”

matrix is produced by electrospining two polymers, silk fibroin and polycaproclactone, using an innovative

process. The state of progress of the project leads us today to have in our hands a functional prototype on the

way to becoming a finished product. In order to ensure the transition of this product from R&D to a possible

medical device, the regulatory roadmap that awaits the future product should be prepared as soon as possible.

Consequently, and relying on the European regulation and its annexes, our main objective is to demonstrate

that the product meets the definition of a medical device, to precisely define the class to which it belongs, to

start a risk analysis process and definition of the standards that should be applied in the subsequent

qualification of the product. In order to stabilize the perimeter of the future indication of the product, we will

also present a questionnaire deployed among professionals in order to collect their user needs.

1 INTRODUCTION

The TissYou project aims to the industrial production

of an innovative bicomposite biomaterial intended for

skin regeneration. This biomaterial is produced by

electrospining, with two polymers, silk fibroin

(natural) and polycaproclactone (synthetic), thanks to

an innovative process.

The electrospinning technique is a technology

allowing the production of polymeric fibers with

controlled dimension in terms of composition, size,

diameter and orientation in the three dimensions (Liu

et al. 2021). This technology is the result of a process

developed at the end of the 19th century (Boys et al.

1887). Today, researchers have more than a hundred

years of experience on this technology, which is

experiencing enormous interest; in the wild field of

biomaterials (Wang et al. 2019). The basic

electrospining technique (Aidana et al. 2021) is based

on the use of a system (Figure 1) consisting of a

syringe containing a polymer or a mixture of

polymers in solution in a solvent (A) and a needle (B)

https://orcid.org/0000-0002-6234-869X

Figure 1: Electrospining technique (from Liu et al., 2021).

(A) Polymers solubilised in a syringe. (B) Needle. (C)

Collector. (D) Electric field. (E) Biomaterial.

allowing the exit of the polymer towards a collecting

surface (C). An electric field is applied between the

needle and the collector (D) and induces the

Rolin, G., Pinot, K. and Blanchy, M.

Regulatory Positioning of an Innovative Biomaterial for Regenerative Medicine: TissYou Project.

DOI: 10.5220/0011926300003414

In Proceedings of the 16th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2023) - Volume 1: BIODEVICES, pages 243-249

ISBN: 978-989-758-631-6; ISSN: 2184-4305

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

243

Figure 2: Concept of TissYou product composed of an epidermal and a dermal side to mimic human skin architecture.

formation of "solid" fiber from the raw material in

solution contained in the syringe.

The electrospining technique (which can be

difficult to master technically) offers the advantage of

being extremely versatile. Indeed, each of the bricks

of the system (A, B, C, D) can be considered as a

variable on which to play to modify the final

characteristics of the biomaterial obtained. Thus, the

system input parameters can be adjusted: type,

molecular weight, viscosity, conductivity, surface

tension of the polymer(s), voltage, flow rate at the

syringe outlet, distance between the collector and the

syringe, environmental parameters of the process

(humidity, temperature). Adjusting these parameters

makes researchers control the morphology of the

obtained material, such as the orientation, the

diameter of the fibers obtained and the porosity (Zhao

et al., 2021; Wang et al., 2020). Faced with such

possibilities, electrospining is clearly considered as

one of the gold standard to produce material that can

faithfully mimic an extracellular matrix for

applications in Regenerative Medicine (Phang et al.,

2022).

Building on the interest of electrospinning for the

production of material used in the composition of

medical devices, our preclinical and clinical research

teams (Inserm UMR 1098 and Inserm CIC 1431)

have been working together for several years on R&D

phases, which have now resulted in the production of

an innovative biomaterial. We currently characterize

in vitro the scaffold that seems to reproduce the

architecture, composition and physical properties of

human skin. Grafted on the patient, should boost

tissue regeneration. Thanks to its particular

properties, this biomaterial could also be used as

artificial skin for in vitro tests and thus replace animal

models. This biomaterial is called TissYou. It is also

the name of the European project which was financed

(Eurostars, 2021-2024) and which allows the

continuation of work on a European scale. Indeed, to

allow future patients to benefit from the results of this

research, pre-clinical and clinical studies will still

have to validate the safety and efficacy of this

innovation in Regenerative Medicine. The state of

progress of the project leads us today to have in our

hands a functional prototype on the way to becoming

a finished product (Figure 2).

The objective of the work presented here was first

of all to describe the context of the progress of the

project and the short-term objectives from a

regulatory point of view. Indeed, and to ensure the

transition of this product from R&D to a possible

medical device, it is necessary to prepare as much as

possible a precise regulatory roadmap that drives the

future product development. Consequently, and

relying on the European regulation and its annexes,

the main objective of this paper was to demonstrate

that the product meets the definition of a biomaterial,

a medical device, to precisely define the class to

which it belongs, and to start a risk analysis process.

In order to stabilize the perimeter of the future

indication of the product and feed the future risk

analysis, we also worked on a questionnaire deployed

among professionals in order to collect their user

needs.

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Table 1: Justification for medical device classification.

2 METHODOLOGY

In order to position the TissYou product in the right

regulatory context, and to place our object on the

regulatory roadmap that awaits it in its regulatory

journey as a medical device, we will rely in particular

on the European regulation and its annexes to

demonstrate that the product meets the definition of a

biomaterial, and that of a medical device. Then we

will precisely define the class to which it belongs, and

will start a process of defining the standards that will

be appropriate to apply in the continuation of the

qualification of the product. In order to stabilize the

perimeter of the future indication of the device, we

will also present a questionnaire deployed among

professionals in order to collect their user needs and

the results that we have already been able to obtain.

3 ANALYSIS

3.1 Regulatory Position

3.1.1 Is our Product a Biomaterial?

According to the definition of the European Society

for Biomaterials (European Society for Biomaterials),

a biomaterial is defined as a : “Material intended to

be in interaction with a biological system with the aim

of evaluating, treating, increasing or replace a tissue,

organ or function of the human body”. TissYou is a

material intended to interact with the human body, the

skin in particular, with the aim of supplementing skin

healing. The notions of interaction, replacement and

supplementation of a function of the organism are

very present. The TissYou product can therefore be

qualified as a biomaterial.

3.1.2 Is our Biomaterial a Medical Device?

According to European regulation MDR

2017/745/EU which entered into force on May 26,

2021, a medical device meets the following

definition. Is considered as a “medical device”:

Any instrument, device, equipment, software,

implant, reagent, material or other article, intended by

the manufacturer to be used, alone or in combination,

in humans for one or more of the following specific

medical purposes:

• Diagnosis, prevention, control, prediction,

prognosis, treatment or alleviation of a disease,

• Diagnosis, control, treatment, mitigation of

injury or disability or compensation thereof,

• Investigation, replacement or modification of

an anatomical structure or function or of a

physiological or pathological process or state,

• Communication of information by means of in

vitro examination of samples from the human

Article - UE 2017/745 Justification

Article 2 Section 1

Medical device

The biomaterial is a material, intended for use in humans, with the aim of treating

traumatic wounds with extensive loss of substance, by replacing by replacing or

modifying the physiological process of healing. The biomaterial meets the

definition of a “medical device”.

Article 2 Section 2

Accessory

The biomaterial is a “medical device” and is therefore not a “accessory”.

Article 2 Section 3

Custom-made device

The device is not expressly manufactured according to a prescription and intended

for a single patient. It is not a “custom-made device”

Article 2 Section 4

Active device

The operation of the device does not depend on a source of energy other than that

generated by the human body for this purpose or by gravity. It is not an “active

device”.

Article 2 Section 5

Implantable device

The device aims to replace the skin on an injured surface. It is an “implantable

device”.

Article 2 Section 6

Invasive device

The device is applied to the surface of a wound or damaged skin and penetrates the

body through its surface. It is an “invasive device”.

Annexe VIII 2,2 –

Invasive device, surgical type

The device is an invasive device but is not an “invasive surgical-type device”.

Regulatory Positioning of an Innovative Biomaterial for Regenerative Medicine: TissYou Project

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body, including organ, blood and tissue

donations,

and whose principal intended action in or on the

human body is not obtained by pharmacological or

immunological means or by metabolism, but whose

function can be assisted by such means.»

With the help of the European regulation and the

articles that make it up, we have chosen as a strategy

for determining membership in the category of

medical devices the creation of a checklist in order to

answer point by point the questions that must be

asked (Table I). In the light of the answers provided

according to the characteristics noted, the TissYou

biomaterial can be considered as a medical device. It

is not an accessory of DM nor of a custom-made or

active DM. On the other hand, TissYou is an

implantable MD, invasive but not of the surgical type.

3.1.3 What Class of Risk for TissYou ?

MD classification, as defined by European

legislation, is a risk-based system that takes into

account the vulnerability of the human body and the

potential risks associated with the devices.

This approach uses a set of criteria that can be

combined in various ways to determine classification,

such as duration of body contact, degree of

invasiveness, local vs systemic effect, potential

toxicity, body part affected by use of the device and

whether the device depends on an energy source.

The "classification rules" set out in Annex VIII of

Regulation (EU) 2017/745 relating to medical

devices (MDR) were used and transcribed in the form

of a checklist (Table II) in order to determine the class

of membership of our medical device “TissYou”.

Thus, for each of the 22 stated rules, the notion of

applicability has been defined and justified with

regard to our product. In accordance with the

answers provided, the TissYou medical device can

be classified as a class III medical device, the class

with the highest level of risk. Indeed, the device is an

implantable device, absorbed in whole or in large

part, and is intended to undergo a physico-chemical

transformation in and by the body. Furthermore, the

device is composed of combinations of substances

intended to be introduced into the human body by

application to damaged skin and absorbed by the

human body or dispersed locally therein. The

substances in question, or the products of their

metabolism, are systemically absorbed by the human

body in accordance with the intended purpose of the

Device.

3.1.4 What Intended Use for TissYou?

The skin is an essential organ for maintaining the

homeostasis of the human body as a whole. However,

being the first barrier against the external

environment, skin tissue can be easily damaged,

leading to the formation of an injury. The severity of

these injuries is variable and depends on the layers of

skin affected.

Figure 3: Example of clinical indication addressed by

TissYou. From left to right: leg ulcer, burn, and skin cancer.

In response to this injury, a physiological repair

process takes place: healing. Healing is an extremely

complex and regulated phenomenon that can be

summarized in 4 major phases: hemostasis,

inflammatory phase, proliferative phase, and

remodeling phase. During serious injuries, the dermis

is no longer able to regenerate properly. One of the

therapeutic management strategies may then consist

of the use of equivalent dermis / regeneration matrix.

Three main clinical indications (Figure 3) have been

considered in terms of application of our future

medical device TissYou: chronic wounds, burns,

reconstructive surgery after surgical resection.

Depending on the intended indication, the

properties of the biomaterial may not be the same.

From a regulatory point of view, the risk analysis,

which will have to be carried out to feed the

documentation relating to our medical device in order

to converge towards its CE marking, will also greatly

depend on the clinical indication. In the current state

of development of the TissYou biomaterial, a firm

indication has not yet been chosen. Nevertheless, for

the reasons mentioned above, and in order not to slow

down the progress of the translational project, this

choice must be made quickly.

Today the project team working around TissYou

does not include a committee of clinical experts. As

part of the work presented here, we then wrote and

distributed a questionnaire intended for future users /

endusers of our biomaterial. This questionnaire

(Figure 4) aimed to achieve several objectives:

• Define the best indication for TissYou

according to user needs,

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Table 2: Justification of the risk class assigned to the device (for full definition: 2017/745:

http://data.europa.eu/eli/reg/2017/745/oj).

Classification rules

(Appendix VIII)

Applicability Justification

1 to 4: Non-invasive device Non applicable The device is an invasive device.

5: Invasive devices with

respect to bod

orifices

Non applicable The device is unrelated to body orifices and is not a surgical

pe invasive device.

6 et 7: Transcient/ shor-

term use

Non applicable The device is intended for long-term use (more than 30

days) because, the scaffold will be graft on the skin and will

be biodegraded by the organism over time (> degradation

rate > 30 da

s).

8: Implantable device

classification?

Applicable

Classe III

The device is an implantable device, absorbed in whole or

in large part and is intended to undergo chemical

transformation in the bod

9 to 13: Active device Non applicable The device is not an active device.

14: Drug incorporation Non applicable The device does not incorporate any substance that could be

considered a dru

15: Contraception or STD

revention

Non applicable The device is not used for contraception or to prevent the

transmission of STDs.

16: Desinfection or

sterilization

Non applicable The device is not intended to disinfect, clean, rinse or

moisturize contact lenses or Class IIa devices.

17: X-ray radiation Non applicable The device is not intended to record diagnostic images

enerated b

X-ra

irradiation.

18: Tissue or cell origin Non applicable The device is not manufactured from tissues or cells of

human or animal ori

in or their derivatives.

19: Nanomaterial

incorporation

Non applicable The device does not incorporate nanomaterials and does not

consist of them.

20: Medicinal product

inhalation

Non applicable The device is not related to the body orifices and are not

intended to administer medicinal product.

21: Human body absorption Applicable

Classe III

The device is composed of combinations of substances

intended to be introduced into the human body by

application to damaged skin and absorbed by the human

body or dispersed locally in it. The substances in question,

or the products of their metabolism, are systemically

absorbed by the human body in accordance with the

intended purpose of the device.

22: Active device Non applicable The device is not an active device.

• Collect information on user expectations

vs competitiors,

• Obtain data allowing us to develop our

biomaterial in order to meet closely their needs,

• Propose to clinicians to join us as an

expert,

• Propose to the clinicians contacted to be

those who will participate in the first clinical and

usability trials,

• Obtaining other user contacts with a

“close by close” strategy, with clinicians sending

us the contact details of potentially interested

colleagues.

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To date, our questionnaire was distributed to 12

clinicians (Dermatologists and Plastic surgeons)

working at the Besançon University Hospital or at the

Nord Franche-Comté Hospital in Trevennans

(France). It was sent in Word format as well as in

Googleform to facilitate data extraction.

Among the responding clinicians, 1/3 have

already used dermal substitutes and 2/3 have never

experienced such device. The dermal substitutes

usually used are Integra® and Matriderm®. The

indications leading to the use of a dermal substitute

are: preparation for thin skin grafts and resurfacing.

The complications encountered were superinfection,

lack of integration of the biomaterial and detachment

of the basement. Regarding the manipulation of the

dermal substitute, the surgeon is not the only user.

Nurses and interns may also be required to handle it.

The reasons that hinder practitioners from using

dermal substitutes are the lack of easy availability of

such medical devices, the lack of habit of use on this

subject, their cost and the difficult match with the

topography of deep wounds. The reasons that could

lead clinicians to use more dermal substitutes are: a

shortening of the healing time, better functional and

aesthetic results, the management of wounds, an

effective and permanent discharge of chronic

wounds, the treatment of a superficial wound, the fact

that the device is available, ergonomic and at a low

cost. Clinicians would also prefer the device to be

ready-to-use and not sutured.

4 CONCLUSION

TissYou is a bicomposite biomaterial produced by an

optimized electrospinning technique. The material is

said to be bicomposite because it is composed of two

polymers: a natural and a synthetic one. In order to

ensure the transition of this product from R&D to a

possible medical device, the regulatory roadmap that

awaits the future product should be prepared as much

as possible.

To achieve this objective, we have shown here

that our product meets the definition of a biomaterial

and more specifically that of a medical device within

the meaning of European Regulation 2017/745.

Appendix VIII and the positioning of our product

have enabled us to show that our product consists of

a class III, invasive and implantable medical device.

Nevertheless, there remains uncertainty about the

positioning of medical devices as an invasive product

and about the proposed definition of invasiveness.

Interpretation of the definition may not be as clear as

expected with respect to the use of the device on

injured skin and the interface with the inside and

outside of the body. To contribute to progress on this

subject, a study of the competition has been initiated

in order to compile the information available, in

particular via the ANSM's documentary base to

parallelize us with the devices of the same type

already on the market.

Still based on the regulations, and thanks to

appendix II (section 6.1 and 6.2), we will also list the

verification and validation elements to be provided in

the technical documentation of our future MD. Thus,

the output data from appendix II will allow us to

orient ourselves towards the standards that will have

to be followed and respected within the framework of

our work, in particular standard 10993 devoted to the

biological evaluation of medical devices. Other

standards have also been identified which would also

be applicable to the future DM TissYou (data not

shown). This non-exhaustive list will be completed,

in particular in parallel with the performance of a risk

analysis. This analysis may begin as soon as the

indication for use of the TissYou device is fixed.

Indeed, for the time being, the indication for use is not

defined. Several avenues have been suggested

(chronic wounds, burns, reconstructive surgery) as

shown previously.

In order to converge towards a choice based on the

desire to respond strongly to an unmet clinical need,

we decided during this work to build and distribute a

questionnaire to health professionals with several

objectives: to collect information to develop our

biomaterial, better meet their needs, choose the right

indication, create a network of experts. The data

collection is not finished but already many relevant

answers and comments allow us today to validate

some of our technical choices (thickness and

mechanical properties), to rule out indications not

favorable to the use of our product (chronic wound),

to identify possible indications. The choice of an

indication, and therefore of specific claims, will help

define what preclinical steps will be taken and which

remain ahead of us, namely the trials in small and

large animals that we will have to conduct soon.

In conclusion, the work presented has triggered a

regulatory switch in the way the TissYou project is

viewed until today. Indeed, the available prototype,

and soon to become a finished product, only has a

chance of becoming a medical device with a place on

the market if it meets a strong clinical need. This is

the challenge of positioning our product quickly in

front of a precise indication. We will thus be able to

take a further step on the regulatory roadmap which

will lead us to carry out work contributing to meeting

the requirements of the regulations, to demonstrating

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the safety and then the effectiveness of our class III

medical device and to being able to file medium term

a CE marking dossier.

ACKNOWLEDGEMENTS

TissYou Project “Industrial production of a

biomimetic matrix for cutaneous regenerative

medicine and in vitro research (n°E!115719)” is

funded by Eurostars-2 from European union (Horizon

2020) and BPI France.

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