TIGR® Matrix Surgical Mesh Launched in the United States

SURGICAL MESH CORPORATE - timeline The history of Novus Scienti c - a journey of innovation

RadiPlast founded Radi Medical Systems AB founded. PressureWire® methodology ‘Fractional Flow Reserve’ (FFR) conceived. on the basis of using Novus Scientific founded. intelligent plastic Radi grows it’s international presence globally with nine regional offices. TIGR® mouldings to avoid RadiPlast becomes RadiPlast sold to to CR Bard. available injuries to children. agent for ACS (Advanced Employees around the world swell to 350. in EU. Catheter Systems). Radi acquired by St Jude Medical Inc. Later the company First PressureWire® sold. TIGR® turns its’ hand to available PressureWire® (Radi Sensor) First FemoStop® sold. First Femoseal® sold. selling catheter kits. in USA. concept conceived. Work starts on TIGR™ project. Polymer research starts in earnest at the Radi research facility in Uppsala.

03 011 1978 2004

1979 2005

1980 2006 RadiPlast 1981 MEDICAL SYSTEMS 2007 1982 2008

1983 2009

1984

1978 1985 Engstrom runs radiology product company 1986RadiPlast AB. 1987

1982 1988 Engstrom secures distribution rights to Advanced Cardiovascular 1989 Systems Inc. (ACS > Guidant Inc). 1990 1988 1991 Engstrom sells RadiPlast AB to CR Bard Inc. and founds Radi Medical Systems 1992 AB. 1993 1988 – 2008 1994 1995

Radi pioneers some of the world’s leading devices for interventional cardiology, hemostasis 1996 management, and radiology. 1999 1997 1998

Engstrom sets up a resorbable biomaterials R&D department in Sweden. 1999 2003 2000 2001

Engstrom invests heavily in clean room production facilities on the island of Phuket. 2002 2004 20 ® Resorbable polymer matrix project group established - 1st patent filed for what would become TIGR Matrix Surgical Mesh. 2005

Engstrom honored at Ernst and Young ’ World Entrepreneur of the Year’ awards.

2008 2010

Radi Medical Systems sold to St Jude. Inc. / Novus Scientific founded and established into 2009. 2 2010 TIGR® Matrix Surgical Mesh launched in the United States. 2011 TIGR® Matrix Surgical Mesh launched in selected European countries. TIGR® Matrix Surgical Mesh - indications for use

for use in reinforcement of soft tissue where weakness exists

In January 2010 the US Food and Drug Administration (FDA) gave the company 510(k) clearance to market TIGR® Matrix Surgical Mesh for use in reinforcement of soft tissue where weakness exists.

In July 2011 Novus Scientific’s Quality Management System was certified by BSI to ISO 13485:2003 for the following scope: Design, control of manufacture and supply of sterile resorbable synthetic surgical mesh for reinforcement of soft tissue.

In August 2011 Novus Scientific received CE Mark approval for TIGR® Matrix Surgical Mesh in Europe.

TIGR® Matrix Surgical Mesh PRODUCT - key features

dual-stage resorption long-term absorbable

% Strength Retention * TIGR® Matrix Surgical Mesh ** Polyglactin 910 100 *** GTMC

* Novus Scienti c, Data on File.

FAST ** Chu, C. C. A comparison of the eect of pH on the biodegradation of two synthetic absorbable sutures. Annals of Surgery 1982;195(1):55-59

*** Katz et al. New synthetic mono lament absorbable suture made from polytrimethylene carbonate. Surgery, Gynecology & Obstetrics 1985;161(3):213-222. 50 SLOW

0 10 20 30 40 50 60 WEEKS

strong when you need it gone when you don’t

wound healing phase remodeling phase

INCREASING MECHANICAL COMPLIANCE

DECREA SING MECHANIC ® AL S TRE NG TH

SURGICAL MESH

100% synthetic increasing mechanical compliance

TIGR® Matrix Surgical Mesh PRODUCT - design

SURGICAL MESH

◆ Unique, patented dual-fiber construction (dual-stage mechanics)

◆ Strong in the acute wound healing phase

◆ Gradually increasing mechanical compliance over time

◆ Pore size of approx. 1mm at time of implantation increasing to approx 1 x 2mm at 4 months

◆ Warp knitted to prevent unravelling

TIGR® Matrix Surgical Mesh PRODUCT - materials

0 days 6 months 3 years Fast-resorbing fiber = copolymer of glycolide, lactide and trimethylene carbonate. strong for 1-2 weeks, gone in 4 months

Slow-resorbing fiber = copolymer of lactide and trimethylene carbonate. strong for 6-9 months, gone in 3 years

TIGR® Matrix Surgical Mesh PRODUCT - strength comparison

Suture retention Burst Strain at Tear resistance, strength, Thickness Product strength 16N/cm parallel/perpendicular parallel/perpendicular (mm) (N/cm) (%) (N) (N) TIGR® 86.5 7.0 45.8 / 59.0 32.0 / 33.3 0.51 Matrix 10 Physiologic 32 15-25 ? - - requirement - Ultrapro™ 35.5 16.2 15.1 / 16.7 10.5 / 5.1 0.50 Parietex Composite 38.9 6.5 28.2 / 36.3 19.7 / 16.2 0.76 ™ C-Qur™ 50.5 13.2 22.3 / 33.8 19.4 / 18.35 0.28 Lite “Small” Proceed™ 52.6 7.25 34.1 / 41.6 19.8 / 20.2 0.57

Gore 97.8 10.2 65.2 / 73.0 30.5 / 41.3 1.20 Dualmesh™

10 Parietex Flat Sheet 112.9 3.5 51.4 / 58.4 32.7 / 28.6 0.52 TEC™ Prolene™ 156.6 5.3 61.2 / 70.5 33.7 / 39.3 0.53

Bard 157.7 10.8 50.8 / 66.8 46.8 / 38.4 0.73 Mesh™

Physiomechanical Properties of Permanent Meshes compared to TIGR® Matrix Physiomechanical Properties of Permanent Meshes compared to TIGR® Matrix Deeken CR, et al. J Am Col Surg. 2011;212:68-79. Deeken CR, et al. J Am Col Surg. 2011;212:68-79. Deeken CR, et al. Surg Endosc. 2011;25:1541-52. Deeken CR, et al. Surg Endosc. 2011;25:1541-52. Data on file: Novus Scientific For six months TIGR® Matrix Surgical Mesh maintains mechanical integrity equivalent to a lightweight polypropylene mesh and initially is twice that strong.

High strength is crucial in the initial wound healing phase. Beyond that the increasing mechanical compliance of TIGR® Matrix is designed to promote remodelling of native tissue.

TIGR® Matrix Surgical Mesh PRODUCT - strength retention comparison

350 % Strength Retention 317 * TIGR® Matrix Surgical Mesh 300 ** Polyglactin 910 100 *** GTMC 253 250 * Novus Scienti c, Data on File.

** Chu, C. C. A comparison of the eect of pH on the biodegradation of two synthetic absorbable sutures. Annals of Surgery 1982;195(1):55-59 200

*** Katz et al. New synthetic mono lament absorbable suture made from polytrimethylene carbonate. Surgery, Gynecology & Obstetrics 1985;161(3):213-222. 50 150 Max Force (N) Force Max

100 89.6

37 50 30 35 23 20 14

0 10 20 30 40 50 60 WEEKS 0 Veritas™ Alloderm™ Permacol™ 0 Months 1-‐12 Months max 1-‐12 Months min

TIGR® Matrix Strength Retention compared to other Resorbable Synthetics Biomechanical Characteristics of Biologic Meshes Deeken CR, et al .J Am Coll Surg 2011;212:880-888

TIGR® Matrix Surgical Mesh retains 50% of its mechanical strength for at least 6 months. TIGR® Matrix Surgical Mesh is stronger for much longer than other synthetic absorbable meshes and is designed to have gradually increasing mechanical compliance. VicrylTM (Polyglactin 910) for example degrades in a matter of 2-3 weeks. The long-term resorption of TIGR® Matrix gives the recipient tissue time to respond to the increasing mechanical load. TIGR® Matrix Surgical Mesh THE CONCEPT of mechanotransduction*

Muscles and tendons become stronger in response to repetitive loading.

“Tendons adapt to changes in mechanical loading, and numerous animal studies show that immobilization of a healing tendon is detrimental to the healing process.”

“collagen networks are mechanosensitive in that they are stabilized by mechanical strain.”

*mechanotransduction is the physiological process where cells sense and respond to mechanical loads Br J Sports Med 2009;43:247-252 doi:10.1136/bjsm.2008.054239

TIGR® Matrix Surgical Mesh PRODUCT - time dependent mechanical characteristics

wound healing phase remodeling phase

required physiological elasticity in vertical stretching (25 ± 7 %)

INCREASING MECHANICAL COMPLIANCE 20 19

16.2 DECREA SING MECHANIC 15 AL S 13.2 TRE NG 10.8

TH Strain at 16N/cm (%) 10.2

(day 0) (day Parietex Composite Parietex

Prolene

(day 277) (day (day 182) (day

7.3

(day 28) (day 7 6.5 Parietex Flat SheetTEC 5.3 3.5

Bard

Gore Dualmesh Proceed

C-Qur Lite Small

Ultrapro

Matrix Matrix ® TIGR

Matrix ® TIGR

Matrix ® TIGR DAY 0

Physiomechanical Properties of Permanent Meshes compared to TIGR® Matrix The increasing mechanical compliance results in a Deeken CR, et al. J Am Col Surg. 2011;212:68-79. gradual transition of load from the mesh to the patient. Deeken CR, et al. Surg Endosc. 2011;25:1541-52. Junge K, et al. Hernia (2001) 5: 113-118. Data on file: Novus Scientific. TIGR® Matrix Surgical Mesh was developed The elasticity of TIGR® Matrix Surgical Mesh based on the hypothesis that soft tissue increases over time, reaching normal positively remodels in response to the physiological levels after 6 months. stimulus of increased mechanical load.

TIGR® Matrix Surgical Mesh PRODUCT - why long-term resorbable /absorbable?

Wound healing is a long-term process. In particular, the time taken to regain 50% of normal tissue strength is typically 3 months, after which about 80% of normal tissue strength is ultimately achieved. The time scale can be significantly longer in some patients.

Approximate times of the different phases of wound healing, with faded intervals marking substantial variation, depending mainly on wound size and healing conditions.

(Image does not include major impairments that cause chronic wounds.)

TIGR® Matrix Surgical Mesh PRODUCT - benefits

0 days 6 months 3 years strong gone when when you you need it don’t for 6 months in 3 years

TIGR® Matrix Surgical Mesh is: 100% resorbable / absorbable 100% synthetic Strong for 6 months, gone in 3 years (dual-stage mechanics) Easy to handle CE marked

TIGR® Matrix Surgical Mesh DEFCET CREATION - 3 year sheep study

This is a summary of the results ® from a 3 year implantation study SURGICAL MESH of TIGR® Matrix Surgical Mesh in the abdominal wall of sheep. TIGR ® Matrix Surgical Mesh

Creation of a 4x4 cm full thickness Mesh repair of the defect performed defect (peritoneum left intact) in the as onlay using TIGR® Matrix Surgical abdominal wall of a sheep. Mesh trimmed to 8x8 cm secured with interrupted permanent sutures.

TIGR® Matrix Surgical Mesh HISTOLOGY GUIDE

Macrophage TIGR® Matrix multifilament bundle

Individual filaments in the Fibroblasts (F) multifilament bundle

Blood vessel (V)

Organized (layered) TIGR® Matrix filament fibroconnective tissue engulfed by giant cell (G) Collagen (C) phagocytosis

Foreign body granuloma Visible signs of TIGR® Matrix fiber degradation Polypropylene fiber (monofilament)

Note: regarding foreign body reaction The foreign body reaction begins as wound healing, including accumulation of exudate at the site of injury, infiltration of inflammatory cells to debride the area, and the formation of granulation tissue.

However, the persistent presence of a biomedical implant, splinter, particulates, or other foreign bodies inhibits full healing. Rather than the resorption and reconstruction that occurs in wound healing, the foreign body reaction is characterized by the formation of foreign body giant cells, encapsulation of the foreign object, and chronic inflammation. TIGR® Matrix Surgical Mesh PRECLINICAL - neovascularization at 4 months

NEOVASCULARIZATION

The formation of new blood vessels can clearly be seen within the connective tissue in the vicinity of the implanted mesh fibers. V

TIGR ® Matrix Surgical Mesh

KEY V - blood vessel

TIGR® Matrix Surgical Mesh PRECLINICAL - 4 & 6 months

mesh fiber bundle

INTEGRATION

Excellent tissue integration of TIGR® Matrix with a well organized, regenerated

fibroconnective tissue at 4 TIGR ® Matrix Surgical Mesh months.

mesh fiber bundle

(bottom left) TISSUE INGROWTH

Connective tissue infiltrating the synthetic filaments of TIGR® Matrix.

(bottom right)

T MACROPOROSITY I G R ®

TIGR® Matrix fibers TIGR ® Matrix Surgical Mesh

t r under plane polarized

S light following 6 months

i implantation. c

M TIGR® Matrix is well

s h integrated into abdominal wall with abundant fibroconnective tissue.

TIGR® Matrix Surgical Mesh PRECLINICAL - 9 months

TYPE I TYPE III

A® B ® TIGR TIGR

TIGR® TIGR® Fibers Fibers

TYPE I

TYPE I TYPE I TYPE III TYPE III PP Fibers PP FIBER C D PP PP

TISSUE GENERATION

Staining for collagen type I (orange) and III (green) in TIGR® Matrix (A-B) and Polypropylene (C-D) meshes following 9 months implantation.

TIGR® Matrix Surgical Mesh PRECLINICAL - 15 months

Control Mesh TIGR® Matrix Surgical Mesh FULL THICKNESS REPAIR

TIGR® Matrix showing excellent tissue integration and thick repair tissue as compared to polypropylene control mesh.

(bottom left) CONTROL

Polypropylene fibers of the control mesh surrounded by granulomas and collagen (the quantity of collagen is lower and typically ingrowth between fibers is not seen to the same extent). G

C TIGR ® Matrix Surgical Mesh (bottom right) V ABUNDANT COLLAGEN

Ordered connective tissue Control Mesh ingrowth (C) between two TIGR® Matrix multifilament bundles.

Collagen is abundant and the KEY KEY V - blood vessel C - collagen inflammatory response is low. G - giant cell TIGR® Matrix Surgical Mesh PRECLINICAL - 24 months

SEM - TIGR® Matrix

TIGR ® Matrix Surgical Mesh ted a ti ss ue connective R egener

Full thickness abdominal wall with TIGR® Matrix well integrated within a thick surrounding fibroconnective tissue.

SEM - POLYPROPYLENE CONTROL

Control Mesh - Fibro ti ss ue a dipo s e

Full thickness abdominal wall with polypropylene fibers integrated within a thin surrounding fibroadipose tissue. TIGR® Matrix Surgical Mesh PRECLINICAL - 24 months

DEGRADATION

TIGR® Matrix filaments surrounded by giant cells which have engulfed G fibers, indicating an ongoing process of degradation.

Collagen fibers are infiltrating the mesh.

Sections of degrading filament

C TISSUE REGENERATED

TIGR ® Matrix Surgical Mesh TIGR® Matrix after two KEY C - collagen years of implantation. G - giant cell Repair tissue is thick and well vascularized. Only the permanent sutures reveal the original location of the mesh and defect.

TIGR® Matrix Surgical Mesh PRECLINICAL - 36 months TIGR ® Matrix Surgical Mesh

TISSUE RESTORED COLLAGEN FORMATION

Three years after the surgery, results TIGR® Matrix is absorbed and replaced by show a nicely restored abdominal wall abundant collagen. without signs of the original defect Few inflammatory cells remaining and no (view from the peritoneal side). foreign body reaction can be seen.

Fibroblasts distributed within well organized connective tissue. TIGR® Matrix Surgical Mesh PRECLINICAL - 36 months

Comparison between TIGR® Matrix & polypropylene as seen in a 3 year sheep model

TIGR® Matrix macroscopically invisible 3 years post Polypropylene mesh encapsulated and implant. Only permanent sutures remain and are visible. delaminated from tissue after 3 years. (clearly visible).

TIGR® Matrix has been completely replaced by At 36 months Polypropylene mesh still elicits an thicker, healthy connective tissue (neo-fascia). inflammatory response.

data on file Novus Scientific

TIGR® Matrix Surgical Mesh TIGR® Matrix - published evidence

A B

Fig. B - Collagen type I/III ratio as a function of time following implantation. (symbols mean values, bars standard deviation). Fig. A - Total collagen content as a function of time following implantation. (symbols mean values, bars standard deviation). As stated in the publication: “As the resorbable test mesh gradually degraded it was replaced by a newly formed collagen matrix with an increasing ratio of collagen type I/III, indicating a continuous remodeling of the collagen towards a strong connective tissue.” Furthermore: “The general connective tissue layer formed was thicker around the test mesh compared to the control.”

Hjort H, Mathisen T, Alves A, et al. (2011) Three-year results from a preclinical implantation study of a long-term resorbable surgical mesh with time-dependent mechanical characteristics. Hernia. doi: 10.1007/s10029-011-0885-y

TIGR® Matrix Surgical Mesh TIGR® Matrix - first in man

INGUINAL HERNIA

World Cup Speedsurfer and TIGR® Matrix recipient (Dec 2009) Martin Lamm was back on his board after 12 weeks and competing within 5 months. Gothenburg, Sweden

◆ 40 patients with primary inguinal hernias. ◆ Enrolled in 2 Swedish hospitals March-Dec 2009. ◆ Clinical outcome assessed 0.5, 1, 3, 6 & 12 months. ◆ Preliminary follow-up presented March 2009, AHS, Orlando. ◆ All patients followed a normal postoperative course. ◆ No serious adverse events and only one recurrence after 12 months. ◆ Three patients experienced mild pain (VAS<10) after 12 months. Only 4 patients could feel the presence of a mesh in their groin after 12 months.

TIGR® Matrix Surgical Mesh TIGR® Matrix - in action

PROCEDURE Endoscopic bilateral component separation enforced with TIGR® Matrix Surgical Mesh

SURGEON HOSPITAL LOCATION BRUCE RAMSHAW, MD, FACS Halifax Health Daytona Beach, FL USA

54 year old male. Necrotizing pancreatitis in 2009. Multiple abdominal operations resulted in open abdomen necessitating skin graft over bowel. Presented one year later with large ventral hernia defect and obvious skin graft deformity.

TIGR® Matrix Surgical Mesh was used as an alternative to permanent synthetic mesh because permanent synthetic mesh can require mesh removal in the setting of a post operative wound infection.

TIGR® Matrix Surgical Mesh performed well with excellent short-term outcomes in a complex patient with high risk of wound complications.

TIGR® Matrix Surgical Mesh TIGR® Matrix - in action

PROCEDURE The use of TIGR® Matrix Surgical Mesh for closure of abdominal donor site following transverse rectus abdominis myocutaneous flap for breast reconstruction. SURGEON HOSPITAL LOCATION YAN LIN YAP, MBBS, FAMS National University Hospital Singapore

In December 2010 a 50 year-old female executive was diagnosed with Primary repair with PDS1 Onlay TIGR® Matrix. left breast carcinoma. She subsequently underwent an elective left skin sparing mastectomy and reconstruction with an ipsilateral transverse rectus abdominis myocutaneous (TRAM) flap.

Following elevation of the TRAM flap, the abdominal donor site is closed primarily with PDS 1 suture. A TIGR® Matrix Surgical Mesh is used as an onlay mesh to reinforce the closure. It is anchored with a PDS 2/0 and 3/0 continuous stitches.

Conclusion:

Being fully resorbable, there is a potential benefit of reduced long term complication associated with permanent implants.

TIGR® Matrix used to reinforce primary repair of rectus sheath

TIGR® Matrix Surgical Mesh TIGR® Matrix - contraindications

◆ Not suitable for reconstruction of cardiovascular defects. ◆ TIGR® Matrix Surgical Mesh must always be separated from the abdominal cavity by peritoneum. ◆ Not for use following planned intra-operative or accidental opening of the gastrointestinal tract. Use in these cases may result in contamination of the mesh, which may lead to infection.

RX ONLY - Read Instructions for Use which accompany the product for indications, contraindications, warnings and precautions.

TIGR® Matrix Surgical Mesh TIGR® Matrix - summary of preclinical testing

Test Standard / Method Conclusion

Cytotoxicity ISO 10993/USP MEM elution method Passed. No evidence of causing cell lysis or toxicity. Grade: 0.

Delayed dermal contact ISO 10993/Maximization method Passed. No delayed sensitization in guinea pig. Grade:0. sensitization

Intracutaneous irritation ISO 10993/Intracutaneous injection in rabbit Passed. The irritation index: 0 for the 0.9% NaCl extract; 0.08 for the sesame oil extract (lower than 1)

Acute systemic toxicity ISO 10993/Injection in mouse Passed. No evidence of significant systemic toxicity or mortality.

Genotoxicity ISO 10993/Ames test Passed. Test article extracts were not toxic or mutagenic.

Genotoxicity ISO 10993/Chromosomal aberrations Passed. Test article extract did not induce chromosomal induction in human cells aberrations in human lymphocytes.

Pyrogenicity USP 30-NF25 Passed. Non-pyrogenic.

Implantation study in rats; ISO 10993 Passed. Good local tolerance. 1, 3 & 6 months follow-up Implantation study in ISO 10993 Passed. Good overall biocompatibility. sheep; 4, 9, 15, 24, & 36 months follow-up

TIGR® Matrix Surgical Mesh RX ONLY – Before using TIGR® Matrix Surgical Mesh read the instructions for use which accompany the product for indications, contraindications, warnings and precautions.

INDICATIONS FOR USE TIGR® Matrix Surgical Mesh is intended for use in reinforcement of soft tissue where weakness exists.

CONTRAINDICATIONS Not suitable for reconstruction of cardiovascular defects. TIGR® Matrix Surgical Mesh must always be separated from the abdominal cavity by peritoneum. Not for use following planned intra-operative or accidental opening of the gastrointestinal tract. Use in these cases may result in contamination of the mesh, which may lead to infection.

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