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Vision R&D concentrates all of the clinical and pre-clinical knowledge generated by the IOBA. Also, Vision R&D has access to the latest technologies in chemical analysis and other disciplines available in the different laboratories and departments of the University of Valladolid.

As a result of this vast experience, we are able to offer a line of pre-clinical services to evaluate the biocompatibility of ophthalmic medical devices in vitro and/or in vivo.

Our studies are carried out under quality standards (GLP) and maintain absolute confidentiality at all times.

In this way, we offer a unique service in our country, supported by scientific publications and extensive experience in collaboration with companies.

We are able to perform:

1. Evaluation of security (biocompatibility) and/or the tolerance of medical devices using in vitro/in vivo experimental models or in vitro/in vivo eye pathology models, for products that are under development or currently on the market.
2. Evaluation of efficacy of medical devices.
3. Replication or development of experimental models resembling ocular pathologies to meet the needs of our customers.

BECAUSE NOT ONLY PFCLs SHOULD BE TESTED FOR BIOCOMPATIBILITY AND CYTOTOXICITY IN OPHTHALMIC SURGERY

This is the compatibility of any material with living tissue or a living system, by not being toxic, injurious, or physiologically reactive and not causing immunological rejection.

Evaluation of medical devices is crucial to determine their possible clinical applications and to properly establish their biocompatibility grade, in accordance with their mechanical, physical and chemical properties. The application of appropriate methods and evaluation parameters involves a great global concern that has been investigated using specific guidelines (International Organisation for Standardisation (ISO) 10993 Biological evaluation of medical devices). These guidelines are conducted to protocolise various biocompatibility tests including, among others, cytotoxicity, sensitisation, intradermal irritation and acute systemic toxicity tests.

The Medical Device Directive 93/42/EEC defines (art. 1.2a) “medical device” as:

“any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnosis and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:

1. Diagnosis, prevention, monitoring, treatment or alleviation of a disease,
2. Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
3. Investigation, replacement or modification of the anatomy or of a physiological process,
4. Control of conception

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means”.

Using the Medical Device Directive 93/42/EEC (Annex IX), all medical devices are placed into one of the following 4 categories:

• Class I: most non-invasive devices that do not interact with the body or that come into contact with intact skin only. All invasive devices with respect to body orifices, other than surgically invasive devices and which are not intended for connection to an active medical device, if they are intended for transient use. Devices intended for short-term use only if they are used in the oral cavity as far as the pharynx, in the ear canal up to the ear drum or in the nasal cavity. Also, reusable surgical instruments.
• Class IIa: invasive devices that are intended for short-term use or long-term use only if they are used in the oral cavity as far as the pharynx, in the ear canal up to the ear drum or in the nasal cavity, and are not liable to be absorbed by the mucous membrane. Surgically invasive devices for transient or short-term use with exceptions. Also, those that exchange energy with a patient in a therapeutic manner or are used to diagnose or monitor medical conditions. All active devices intend to administer and/or remove medicines, body liquids or other substances to or from the body if it is not hazardous for the patient.
• Class IIb: most implantable and long-term surgically invasive Active devices intend to control or monitor the performance of active therapeutic devices and also to monitor vital physiological parameters. Active therapeutic devices intend to administer or exchange energy to or from the human body in a potentially hazardous way. Also, devices used for contraception or the prevention of the transmission of sexually transmitted diseases, devices for disinfecting invasive devices and those to be used for disinfecting, cleaning, rising or hydrating contact lenses
• Class III: all surgically or implantable devices intended to make contact with the central circulatory system and/or the central nervous system. Devices intended to have a biological effect or to be wholly mainly absorbed, those substance considered a medicinal product incorporated as an integral part and devices manufactured utilising animal tissues or devices rendered non-viable except such devices which are in contact with intact skin only.

Class I devices correspond with the low risk while Class III with the higher risk.

The biocompatibility evaluation is applied to all medical devices that are in contact with the patient in a direct or indirect way.

A structured protocol of biological evaluation must be accomplished and documented by a qualified technician for each medical device and evaluation of the existing literature should be considered.

To evaluate the possible biological risks, it is necessary to consider:

• Short-term effects
  • Severe toxicity
  • Eye, skin and mucous membrane irritation
  • Sensitisation
  • Haemocompatibility
• Long-term effects/toxic specific effects
  • Subchronic and chronic toxicity effects
  • Genotoxicity
  • Carcinogenicity
  • Effects on reproduction

All potential risks have to be considered, but it is not necessary or practical to perform all tests for these risks.

Biological evaluation of a medical device must take into account:

• Exposure conditions to the medical device and its parts:
  • Contact nature: invasive/non-invasive
  • Contact period: time of contact
  • Contact frequency: dose/accumulative dose
• Chemistry composition of the medical device and its parts.

Specific tests have to be selected for each medical device. These tests must be developed by using all of the available information about the device, literature data (valid scientific and medical publications) and pre-clinical and previous clinical data assays.

• It has to be determined whether the assays should be performed in the finished product or in representative samples of the finished product.
• It must be taken into account that it is necessary to carry out re-evaluations if there is any change in the products, their use or if there is a risk of adverse effects.
• Relevant tests corresponding to each product class must be considered.
• Relevant tests for the product class must be considered to individually evaluate each medical device.

Thus, the test to be developed must be based on the final application of the product; it must be sensitive, precise and exact, and be performed under Good Laboratory Practices (GLP) or with GLP accreditation.

Surgical tools and endotamponade agents:

Perfluorocarbon liquids

Vital dyes

Silicone oils

Vicoelastic agents

Intraocular lenses and capsular rings

Orbital implants

Others

In vitro:

Culture techniques:

Line cell culture (obtained from known repositories)

Primary cell culture (human or animal eye cells)

Tissue culture (human or animal ocular tissues)

Monitoring and evaluation techniques:

Cytotoxicity/viability tests (MTT^®, others)

Cytology/Histology/Immunochemistry

In vivo:

Surgical techniques:

Cataract surgery by phacoemulsification

Vitrectomy

Intraocular injections

Evisceration/Enucleation/Exenteration

Monitoring and ophthalmic follow-up:

Biomicroscopy/Slit lamp (anterior pole evaluation)

Ophthalmoscopy (posterior pole evaluation)

Tonometry

Cytology/Histology/Immunochemistry

Advanced instrumental techniques:

• Gas chromatography – mass spectrometry (GC-MS)
• Ultra-high performance liquid chromatography – mass spectrometry (UPLC-MS)
• Spectroscopic techniques: Raman, FTIR

ISO 10993 Biological evaluation of medical devices

Part 2: Animal welfare requirements

Part 5: Tests for in vitro cytotoxicity

Part 6: Tests for local effects after implantation

Part 12: Sample preparation and reference materials

ISO 16672 Ophthalmic implants – Ocular endotamponades

Directive 2010/63/UE of the European Parliament and of the Council of 22 September 2010

Law 32/2007 of 7 November 2007

Royal Decree 178/2004 of 30 January 2004

Order ECC/566/2015 of 20 March 2015