Stem cells and materials technologies Group 16 - Biomaterials and waste treatment Ciência 2009, 29-30th July 2009, Lisbon

Strategic Intent To target clinical needs through the integration of advanced adult stem cell biology and novel biomaterials into innovative therapeutic products for tissue regeneration

History Academic spin-off of the 3B’s Research Group Created in November, 2007 Installed since September 2008 at the European Institute of Excellence for Tissue Engineering and Regenerative Medicine Research, Guimarães, Portugal. Equipped with a future cGMP compliant facility for the processing of human tissue and cells (2003/94/EC Directive): 300 m2 of clean room (classes B, C and D); 250 m2 of R&D and QC laboratories. 1st funding round estimated to be finished by Sept, 2009 Start of operations estimated by Oct, 2009

Team CSO: Rui L. Reis, CEng., MSc., PhD. (n. 1968) – Founder, President and Chief Scientific Officer: is an Associated Professor at the Department of Polymer Engineering and Director 3B’s Research Group. Editor in Chief of the Journal of Tissue Engineering and Regenerative Medicine, John Wiley and Sons Inc. He is author or co-author of more than 900 scientific publications. CEO: Rui A. Sousa, CEng., MBA., PhD. (n. 1974) – Chief Executive Officer: is a senior researcher at the 3B’s Research Group. Possesses business experience in several industrial and consultancy domains. He is author or co- author of more than 90 scientific publications and communications. Dulce Costa Luísa Pereira João Oliveira Adrian Popa

Social Context The WHO estimates that more than 600 million people are aged above 60, being estimated that this number reaches the 2 billion by 2050. Growing impact of degenerative or traumatic conditions due to demographic evolution, more dynamic lifestyles, and increased physical activities.

Regenerative Medicine Overall Market Regenerative Medicine 2 1 3 5 Adaptado de Julian H S George et al http://www.centropede.com/UKSB2006/ePoster 4

Use of stem cells from adipose tissue More than 1.6 billion people are overweight, of which 400 million are considered obese, with treatment costs between 2 and 8% of total health costs. Steep increase in aesthetical surgical procedures, being Europe responsible for about one third of this global market.

Business Portfolio Stemmatters Therapeutics Stemmatters Life Banking Stemmatters Biomedical

Stemmatters Therapeutics

The Market for Cartilage Regeneration Current Markets The Market for Cartilage Regeneration Prevalence of articular cartilage related lesions in Europe Nearly 250.000 traumatic incidents occur; About 7 million cases of treatable arthrosis occur each year. High market potential for cartilage regeneration Among the biggest markets for connective tissues, being estimated between 1 to 5 billion €/year in Europe alone. Very high penetration of traditional treatment approaches Arthroscopic lavage and debridement, microfracture and mosaicplasty rule the treatment of cartilage lesions. Cell based therapies with reasonable track record in this area ACT and MACI procedures are considered market references.

Products Under Development Product Pipeline Products Under Development Types of products currently under development: ATMPs (Advanced Therapy Medicinal Products) G01AT110C | pre-clinical | RECART Hydrogel/Adipose derived adult stem cells G01AT300A | research | Hydrogel/Vascular stromal fraction derived cells MDs (Medical Devices) G01MD210B | research | Injectable filler for soft tissue applications G01MD250B | research | Injectable filler system for maxillofacial applications

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells Combined advanced therapy medicinal product (1394/2007 Regulation, CBMP EMEA guideline) Polysaccharide hydrogel as an active implantable device Exopolysaccharide produced by microbial fermentation: Straight chain of repeating glucose, rhamnose and glucuronic acid units; Potential injectable system for minimally invasive surgeries; Processing under physiogical conditions without any reagents; Used in vivo for human ophthalmic applications and oral veterinary drug delivery. Adipose derived adult stem cells Isolated from harvested adipose tissue: Dedicated or non-dedicated harvest procedure; Subpopulation isolated from the stromal vascular fraction; Good cell yield avoids previous cell expansion.

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells Novel hydrogel system for TE applications J.T. Oliveira et al, Patent Application

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells Good performance upon subcutaneous implantation 1 WEEK 2 WEEKS 3 WEEKS No clear macroscopic change after 3 weeks of implantation. Extremely good integration with the surrounding tissues with a residual and thin fibrotic capsule.

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells 8 WEEKS Human chondrocytes form hyaline-like cartilage in vitro Col1 was not detected after 8 weeks Col2 increased ≈ 400 fold from 2-8 weeks Aggrecan increased ≈ 35 fold from 2-8 weeks Sox9 decreased close to zero from 2-8 weeks house-keeping gene: GAPDH

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells ADIPOSE TISSUE FROM THE INTRASCAPULAR REGION ARTICULAR CARTILAGE FROM THE JOINTS CHONDROGENIC PRE ≠ MEDIUM WITH TGF-Β1 + BMP-2 BASIC MEDIUM WITH NO PRE ≠ PROLIFERATION INDUCING MEDIUM WITH FGF-2

full-thickness defect Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells Implantation site Rabbit articular cartilage Articular cartilage full-thickness defect Subchondral drill (Ø 1 mm) (4 mm x 2-3 mm thickness) Study groups A. Gellan + adipose tissue derived cells with pre differentiation period (ASC + GF*) B. Gellan + adipose tissue derived cells with no pre differentiation period (ASC) C. Gellan + articular chondrocytes (AC) D. Gellan alone (GELLAN) E. Empty defect (EMPTY) + + + *TGF-Β1 + BMP-2 Autologous approach Total implantation time: 8 weeks [Cells]=10x106 cells/ml Characterization Macroscopic observation Histology (H&E for cell morphology and tissue formation and alcian blue for cartilage ECM formation) Histological scoring (Pineda score) Real-time PCR analysis (Sox9, Collagen type I, Collagen type II, and Aggrecan) J.T. Oliveira et al, Patent Application

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells 0 weeks 4 weeks 8 weeks Combination of hydrogel with ASCs is able to regenerate focal cartilage lesions J.T. Oliveira et al, Patent Application Patent Application/Priority date: 01.2008

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells

Product Pipeline Stemmatters Therapeutics | RECART Hydrogel/Adipose derived adult stem cells Advantages of the cartilage repair strategy include: Potential therapeutic performance Minimally invasive system to be administered arthroscopically Avoids the need for a cartilage biopsy Shorter time to therapy (TTT) Competitive cost as compared to traditional ACT and MACI procedures

Competition Tissue Engineering Products Primary cells Progenitor cells Cartilage application Arthro Kinetics, BioTissue Technologies, Cellgenix, co.don, Curasan, Educell, Fidia Advanced Biopolymers, Geistlich Surgery, Genzyme Biosurgery, Histogenics, Interface Biotech, Karocell Tissue Engineering, Orthogen, TIGenix, TETEC, Verigen Transplantation Service International Cartilage: application Stemmatters (Autologous) Bone application Aastrom Biosciences (Autologous), Osiris Therapeutics (Allogeneic) Skin application Organogenesis, BioTissue Technologies, Advanced BioHealing, Inc., Genzyme Biosurgery, Fidia Advanced Biopolymers, Intercytex, Celltran, Forticell Bioscience, Cambrex Primary cells Progenitor cells Cartilage application Osiris Therapeutics (Allogeneic) Several applications: Advanced Cell Technologies, Geron, ES Cell International, Stem Cell Sciences, Aastrom Biosciences, Aldagen, Angioblast Systems, Athersys , BrainStorm Cell Therapeutics, Cardio3, Cellerant Therapeutics, Cognate Therapeutics , Gamida-Cell, Mesoblast , Neuronyx, Osiris Therapeutics, AdiStem, Bioheart, Cellerix, Cognate Therapeutics, Cytori Therapeutics , ReNeuron Group Plc, Tengion, PharmaFrontiers , Tissue Genesis, Inc , Gamida-Cell, Saneron CCEL Therapeutics, ViaCell Cartilage application co.don, Educell, Geistlich Surgery, Genzyme Biosurgery, Interface Biotech, TIGenix, TETEC Other Cell Based Therapies

RECART Hydrogel/Adipose derived adult stem cells Product Pipeline RECART Hydrogel/Adipose derived adult stem cells R&D and non-clinical development Clinical development MA Applic. Marketing Authorization Biomaterial R&D Phase I In vitro testing Phase II Phase III In VivoTesting GMP grade Phase IV 2007-2010 2010-2018 2019 2020

RECART Hydrogel/Adipose derived adult stem cells Product Pipeline RECART Hydrogel/Adipose derived adult stem cells R&D and non-clinical development Clinical development MA Applic. Marketing Authorization Biomaterial R&D Phase I In vitro testing Phase II Phase III In VivoTesting GMP grade Phase IV Stemmatters Life Banking Stem cell isolation and storage services Stemmatters Biomedical Products and services for R&D 2007-2010 2010-2018 2019 2020

Contacts Rui A. Sousa CEO Tel. +351-253-540100 Fax. +351-253-540199 E-mail: rasousa@stemmatters.com

Stemmatters Life Banking

Main application markets for stem cells Current Markets Main application markets for stem cells Current uses of stem cells are made in 3 distinct medical related markets: Cell banking; Therapeutic development; Cell therapies. (source: Frost & Sullivan).

Stemmatters Life Banking | Stem cell isolation and storage services Current Offering Stemmatters Life Banking | Stem cell isolation and storage services Bone marrow (onstem service – B2C); Adipose tissue (adstem service – B2C): The treatment of tissues and biological residues generated in surgical procedures assures a cell banking opportunity not yet addressed. Market potential for the isolation and storage of adipose derived adult stem cells for autologous application is estimated to worth: 75 million €/year for Spain, France, Germany, UK, Italy and Portugal; 120 million €/year for EU15. Assures a polyvalent platform for regenerative technologies; Assures positive cash flow and supports leveraging of R&D pipeline.

Stemmatters Life Banking | Stem cell isolation and storage services Competition Stemmatters Life Banking | Stem cell isolation and storage services Newborns Children Adults Europe Crioestaminal, Bioteca, Bebé Vida, Criovida, Cytothera (Portugal) Celvitae, Vidacord, Secuvita, Vidaplus, Stem Cell, CrioCord, Safetycord (Spain) ActiVision Life (Poland), Babycord (Cyprus), Babycord (Turkey), Biohellenica (Greece), Biophylaxis (Greece), BPK (Slovenia), CopyGene (Denmark), CryoBank (Turkey), Cryo-Save (Belgium), Cryomedica (Russia), Eticur (Germany), Eurocord (Slovakia), Floramed (Russia), Gemabank (Russia), GenKord (Turkey), Hemafund (Ukraine), In Scientia Fides (Italy), Krio (Hungary), Liaison (Greece), LifeBank (Cyprus), Lifecord (Austria), Lifeline (Cyprus), LongaVita (Poland), Polish Stem Cell Bank (Poland), Progenis (Poland), RCB (Switzerland), Seracell (Germany), SmartBank (Italy), StellaCure (Germany), Stemcare (Denmark), Stem-Health Hellas (Greece), VITA34 (Germany), Vitacord (Austria), Yasam Bankasi (Turkey), Cells4Life (UK), Cells Limited (UK), CryoGENESIS (UK), Future Health Technologies (UK), SmartCells (UK), UK Cord Blood Bank (UK), UK Health Solutions (UK), Virgin Health Bank (UK) Bioeden (UK) Stemmatters Cytothera (Portugal) Cryo-Save (Belgium) Cytori Therapeutics Biohellenika (Greece) USA AlphaCord, CordBancUSA, Cord Blood America, Cord Blood Registry, Cord Blood Solutions, Cryobanks International, Cryo-Cell International, DomaniCell, Elie Katz, Family CB Services, Family Link, Genesis Bank, HemaStem, LifebankUSA, LifeLine, LifeSource, MAZE Labs, Neocells, Newborn Blood Banking, New England CB Bank, RMI, Safetycord, Securacell, StemCyte, Stork Medical, Utah Cord Bank, Viacord, Vista Cord, Xytex Bioeden, StemSave, Baby Teeth Cell Bank Cryo-cell Neostem

Stemmatters Life Banking | Stem cell isolation and storage services Current Offering Stemmatters Life Banking | Stem cell isolation and storage services Acquisition Drivers Increased value of the surgical procedure; Potential application in future autologous regenerative therapies; Allows for off the shelf availability of personalized regenerative products; Decreases time for clinical delivery of therapy. Current applications of adipose derived adult stem cells Radiation Necrosis Breast Reconstruction Heart Attack Chronic Heart Disease Crohn’s Disease Tracheal Fistula Healing Calvarial Repair Marrow Transplant Complications Diabetes

Stemmatters Biomedical

Stemmatters Biomedical | Products and services for R&D Current Offering Isolation and processing services of human cells: Human stromal vascular fraction isolated from adipose tissue containing human adipose derived stem cells (all samples are characterized for cell number and viability); Human adipose derived stem cells (all samples are characterized for cell number and viability, as well as multipotent mesenchymal stem cell markers: CD29, CD105, CD34 and CD45); Pre-clinical research in regenerative medicine accounts for a market volume of about 700 million €/year. Cell culturing products; Hydrogel support systems for 3D cell culturing; Very high R&D visibility among the potential buyer community; The global market potential for the commercialization of 3D supports for non-clinical R&D is estimated to worth between 7 and 35 million €/year. Device for dynamic cell seeding and culturing. Stemmatters Biomedical | Products and services for R&D

Corporate Strategy

Corporate Strategy

Financial projections

Financial Projections 2009-2016