Tissue Extracellular Matrix (ECM)

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1 Tissue Extracellular Matrix (ECM) ECM Key Facts Present in all tissues and functions as the biological scaffold for cells Contains structural, adhesion and signaling molecules Tissue function and healing are dependent on the ECM The ECM is damaged or missing in wounds The ECM is not a bystander during healing, but actively directs and provides a scaffold for cells Every body has the power to heal

2 TISSUE EXTRACELLULAR MATRIX The essential tissue network The extracellular matrix (ECM) is the material found around and between cells binding them together, and is made up mostly of collagen along with other proteins. 1,2 The ECM provides a structural scaffold to the body s tissues and organs, such as the skin, and is a critical platform for ongoing, dynamic and reciprocal communication and signaling between cells. 1,3 ECM is essential to the health of tissues and to the tissue repair process Epithelial cells Laminin Collagen IV Elastin Blood vessel Collagen I and III GAG s, hyaluronic acid, heparin sulphate Fibronectin Growth factors, chemokines Fibroblast cells Dynamic Reciprocity the interplay between cells and ECM ECM Tension Polarity Differentiation Migration Survival Dynamic Reciprocity Cell Dynamic Reciprocity The ECM is not a silent bystander during the healing process. The ECM and its associated components play key roles in orchestrating communication that directs cells to grow, divide, move and attach. The interplay between cells and the ECM is termed dynamic reciprocity and occurs during all phases of wound healing. 5 Synthesis Degradation

3 Composition The maintenance of healthy tissue and wound repair require a host of different molecules to guide these complex tissue processes. The ECM is a complex mixture of structural adhesion and signaling molecules that interact with cells during the phases of wound repair and tissue maintenance. 4 ECM contains components essential to tissue maintenance and repair Component Class Function Collagen I Structural Provides structure and strength Collagen III Structural Provides delicate scaffold architecture Collagen IV Adhesion Anchors epithelial cells to the matrix Fibronectin Adhesion Enables cell attachment and proliferation during infiltration and remodeling Laminin Adhesion Interconnects scaffold proteins and guides epithelial migration Elastin Structural Provides structural integrity and elasticity Hyaluronic acid Structural Facilitates infiltration via organization of cells and scaffold components Heparin sulphate Adhesion Multifunctional regulator of remodeling GAGs Structural Binds water to maintain scaffold hydration Growth factors and chemokines Signaling Essential communication between cells and between the ECM and cells A damaged or missing ECM requires repair In acute and chronic wounds the ECM is damaged or missing In acute and chronic wounds, the ECM is missing, structurally damaged or unable to function. 3,4 Without functional cues from ECM components, wound healing cannot move forward, and chronicity prevails. 4-6

4 ECMs can provide a scaffold to influence all phases of healing s the wound bed Provides a scaffold for platelet aggregation Recruits cells Balances wound proteases Reduces inflammation Provides a porous scaffold for rapid cell infiltration Recruits cells Stimulates cells Promotes constructive remodeling Undergoes host-mediated biodegradation ECM technologies can augment missing or damaged ECM Technological advances have meant that it is now possible to replace the patient s missing or damaged ECM with a temporary substitute. These ECM technologies act as a provisional ECM to support and guide cell infiltration of the tissue deficit. 7 During the phases of wound healing these ECM technologies augment the patient s own tissue ECM The key considerations for ECM products is the preserved biological accuracy of the ECM scaffold as well the molecular form of its components to maintain functionality. The paperclip analogy demonstrates how loss of structure results in loss of functionality. Preserved Structure and Function for Use Altered Structure and Loss of Function

5 TISSUE EXTRACELLULAR MATRIX Endoform is a unique tissue extracellular matrix Endoform provides a natural porous scaffold that supports rapid epithelial and fibroblast infiltration. Over time the scaffold is completely remodeled as new tissue is laid down. Wound model demonstrating cell infiltration and adhesion (light blue) onto the Endoform scaffold (dark blue) during healing 11 TIME Images show DAPI (a florescent stain, diamidino phenylindole) stained Endoform infiltrated with human fibroblasts cells after 0.5, 5 and 10 days. Images at 20x magnification. 11 Endoform also retains the natural molecular structure of ECM collagen. Preservation of native structure is important in ensuring biological function is not lost. Natural tissue fibers Endoform fibers The composition of Endoform s ECM enables it to interact with patients cells during the phases of healing. Endoform contains 148 secondary molecules, including structural and adhesion proteins, and glycosaminoglycans (GAGs), that are important during healing. 12 Endoform only contains components that are found in tissue ECM. Hyaluronic Acid Facilitates cell infiltration Collagen IV Anchors epithelial cells to the matrix Fibronectin Enables cell attachment GAGs Binds water to maintain scaffold hydration Important Secondary Molecules 15% Adhesion Proteins Heparin Sulfate Regulator of remodeling 85% Collagen I Major structural protein Collagen III Early phase structural protein Laminin Connects scaffold proteins and guides epithelial migration

6 TISSUE EXTRACELLULAR MATRIX Notes References 1. Hynes, R.O., The extracellular matrix: not just pretty fibrils. Science, (5957): p Krafts, K.P., Tissue repair: The hidden drama. Organogenesis, (4): p Schultz, G.S., G.P. Ladwig, and A. Wysocki, Extracellular matrix: review of its roles in acute and chronic wounds. World Wide Wounds, August Schultz, G.S. and A. Wysocki, Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen, (2): p Schultz, G.S., et al., Dynamic reciprocity in the wound microenvironment. Wound Repair Regen, (2): p Clark, R.A., Biology of dermal wound repair. Dermatol Clin, (4): p Badylak, S.F., The extracellular matrix as a biologic scaffold material. Biomaterials, (25): p Badylak, S.F., D.O. Freytes, and T.W. Gilbert, Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomater, (1): p Badylak, S., The extracellular matrix as a scaffold for tissue reconstruction. Seminars in cell & developmental biology, (5): p Bohn, G.A., et al., Proactive and Early Aggressive Wound Management: A Shift in Strategy Developed by a Consensus Panel Examining the Current Science, Prevention, and Management of Acute and Chronic Wounds. Wounds, (11): p. S37-S Lun S, Irvine SM, Johnson KD, et al. A functional extracellular matrix biomaterial derived from ovine forestomach. Biomaterials. 2010;31(16): Dempsey et al (2019). Functional insights from the proteomic inventory of ovine forestomach matrix. J.Proteome Res. DOI: /acs.jproteome.8b RX Only. Prior to use, be sure to read the entire Instructions For Use package insert supplied with the product. For product questions, sampling needs, or detailed clinical questions concerning our products in the US, please call HCPCS are for reference only and subject to change. Endoform is a registered trademark of Aroa Biosurgery Limited. Endoform Dermal Template is marketed in the USA by Appulse. Manufactured for: AROA BIOSURGERY INC 340 Progress Drive, Manchester, CT MKT May 2019