Manufactured by: Tissuemed Ltd.•5 Killingbeck Drive•Leeds•LS14 6UK•United Kingdom www.tissuemed.com•Tel +44(0)1132000500•Fax +44(0)1132407343•©Tissuemed 2009

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__________________________________________ Research and Development History Tissuemed has spent over 20 years at the forefront of technical innovation within medical devices. The company has its origins in the development of tissue-based therapeutic devices including developing the first tissue heart valve to gain regulatory approval in Europe, subsequently developing "living" vascular grafts and collagen patches. The company famously developed light-activated surgical adhesives for which Tissuemed was the Gold Winner of the Medical Design Excellence Award in 2001.

The R&D Department

The R&D group consists of a small, dedicated group of skilled chemists with many years’ of experience in academia and industry. As a small yet highly progressive company Tissuemed relies heavily on innovation and scientific expertise.

The Analytical Group specialises in testing of R&D samples, raw materials and finished goods, and works alongside respected external partners to ensure products conform to specification and are safe to use. These include Sheffield University, Hall Analytical and Wickham Laboratories.

The Development of TissuePatch3 and TissuePatchDural The task of designing a unique surgical sealant began in 2002. Other products on the market, e.g. liquid glues, despite being widely used displayed many disadvantages in both performance and user friendliness. Addressing the weaknesses of existing products was the goal set for our R&D group. This proved to be a highly challenging task! Indeed the solution to the problem took 5 years to develop and refine, during which time several products were developed (and discarded) in the pursuit of the product now in the marketplace, learning the whole time about the real requirement of potential users of the product.

The most challenging aspect of the development was the synthesis: to develop a polymer with greater than 10x the adhesive energy of liquid glues, while ensuring that the material remained user friendly and safe for in vivo use. By discarding the outdated PEG-based technology of our competitors and being truly inventive this has been achieved.

Despite the product having the appearance of a simple plastic film, every single aspect of this unique device had to be designed from scratch. This includes the synthesis of a series of proprietary adhesive polymers, their purification and the perfection of a manufacturing process.

Mode of Action

TissuePatch3 is designed for lung and general surgery (launched 2007) while TissuePatchDural was reformulated for the Neurosurgical market as a Dura Mater sealant (launched 2008). The R&D department are rightly proud of their contribution to the success of this product and Tissuemed as a whole. In fact we welcome visitors to our site who would like to see our technology first hand.

TissuePatchFlex Coming 2009!! Advanced Gastro-intestinal(GI) Sealant Tissuemed intends to shortly CE mark a sealant product for GI surgery. While similar in appearance, TissuePatchFlex has been completely re-engineered, incorporating new iterations of our adhesive polymer to facilitate adhesion to the GI tract. As far as we are aware this is the only material on the market able to adhere to the gut and support wound healing.

Future Direction The Company has invested heavily in R&D over the past 5 years. The aim is to build upon the chemistry of the TissuePatch product range to develop a much broader range of medical products and to remain at the forefront of adhesive/sealant technology. This includes adhesive meshes, anti-cancer drug eluting patches, mucoadhesive patches/sealants to name a few.

ADHESIVE SEALANT BIOMATERIALS Technical Bulletin Ian Thompson PhD, Tissuemed Ltd.

An Introduction to the Science behind TissuePatchTM3/TissuePatchDuralTM

The “sticky stuff”

Manufactured by: Tissuemed Ltd.•5 Killingbeck Drive•Leeds•LS14 6UK•United Kingdom www.tissuemed.com•Tel +44(0)1132000500•Fax +44(0)1132407343•©Tissuemed 2009

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Production

The manufacture of Tissuemed’s raw materials and finished goods is carried out in-house by a team of dedicated and talented chemists and production operators under clean conditions.

Polymer Synthesis Tissuemed synthesises the main raw material for TissuePatch (the adhesive polymer) via what is called a free-radical polymerisation and functionalisation reaction. The polymer is purified several times to ensure that it is free from reaction by-products and is biologically clean.

Clean Room Manufacturing TissuePatch is manufactured in an ISO Class 7 (10,000) clean room. The technologies used to manufacture the product are a closely guarded secret, but, as shown in the diagram below a highly intricate layering structure is created to impart different properties to the film: Non-adhesive upper barrier Core layers designed to give strength Tissue adhesive lower surface The entire film is thinner than a human hair

Large sheets of each film are manufactured and then cut to the desired size. All Tissuemed’s products are gamma irradiated and double packaged to ensure sterility and stability. TP3-01/TD-01 25x50 mm TP3-02/TD-02 50x50 mm TP3-03/TD-03 50x100 mm TP3-04/TD-04 100x100 mm A Cross-Section of TissuePatch

Scale-Up The success of TissuePatch has meant that all aspects of its manufacture are being scaled-up to meet expected demand. This involves new laboratory, production and packaging equipment, glassware and refurbished laboratories/offices. It is the intention to increase capacity to 50,000 units per year. Environmental Consideration: Reducing the use of Solvents

The manufacture and purification of Tissuemed’s adhesive polymers and film products uses a large quantity of solvents. While such solvents are excellent for

purification purposes, they are dangerous to handle/store and are environmentally unfriendly. As part of the scale-up of our manufacturing we are continually striving to switch to more environmentally friendly processes: Switching from flammable solvents to water

for the major polymer purification process will reduce solvent usage by 2000 L/yr. This will also be safer and more environmentally friendly.

Where this is not possible other efficiency

savings will reduce the total usage of solvents.

Recycling of waste paper and other

materials used during the process. Group Photo November 2008 Svetlana, Ian, Diane, Jamie, April, Iain, Jane, Vicki, Jiten

Contacts R&D Manager Ian Thompson (ithompson@tissuemed.com) Production Manager Iain Johnson (ijohnson@tissuemed.com)

Poly(lactide-co-glycolide) barrier Adhesive polymer