CHAPTER11 Wound Healing and the Presence of Biomaterials 11-1 Introduction: Formation of Granulation Tissue 24 hrs: macrophages and inflammatory cells --- chemoattractants --- migration of fibroblasts and vascular endothelial cells 3-5 days: (1) beginning of granulation tissue formation neovascularization and angiogenesis (2) proliferation of fibroblasts connective tissues and myofibroblasts

11-2 Foreign Body Reaction Foreign body giant cells (FBGCs) --- multinucleated cells (monocytes/macrophage) Relative composition of FBR (1)Surface properties of biomaterial topography (roughness) / surface chemistry (2)Shape of the implants high and low surface area/volume

11-3 Fibrous Encapsulation Granulation tissue maturation (large blood vessels & collagen fiber alignment) Long-term capsule formation (4 weeks post-implantation) (1) Degree of original injury during implantation (2) Amount of subsequent cell death (3) Location of implant site (4) Degradation time of implant Thickness of the capsule (1)Amount & chemical composition of small particulates produced (2) Mechanical factors at implant site (3) Shape of implant (4) Electrical currents 11-4 Chronic Inflammation Between acute and full development of granulation tissue Granulomas Epitheloid cells

11-5 Four Types of Resolution Extrusion / Resolution / Integration / Encapsulation - Failure or success 11-6 Repair vs Regeneration: Wound Healing in Skin - Tissue repair with scar tissue - Tissue regeneration with identical tissue Skin Repair Skin = internal dermal layer + outer epidermal layer Injury --- blood clotting --- fibrin network --- acute inflammation --- influx of fibroblasts into ECM --- beginning of granulation tissue --- Remodeling and scar formation collagen III turnover (1) collagen I (2) GAG ratio 변화 collagen accumulation

Skin Regeneration Erosions: small skin wounds within the epidermal layer Re-epithelialization Defect --- cell flattening --- cell migration --- cell proliferation migration edge in contact with other epithelial cells --- cuboid morphology and re-attach to ECM --- proliferation and matrix production --- restoring the original thickness of tissue

11-7 Techniques: In Vivo Assays for Inflammatory Response Biological response via: (1)Interactions of biological molecules or cells with the implant (2)Interactions with soluble agents leached from the implant (3)Interactions with insoluble particulates (implant degradation) (4)Alterations in load or strain in the area around the implant FDA: in vivo biocompatibility assessment biocompatibility / biocompatibility assessment

Considerations in development of animal models (1) Choice of animals: small vs. large animals (2) Choice of implant site: vascularized area / surrounding cell’s ability (3) Length of study acute / subacute / subchronic / chronic toxicity (4) Biomaterial consideration: dose and administration shape Biocompatibility test to screen novel materials to assess the inflammatory response to the material a. Implant weight and/or bulk size b. Implant surface area c. Implant topography d. # of implants per animal

Direct implantation / Extracts of the material / Cage implant model (5) Inclusion of proper controls a. intact contra-lateral tissue b. an unfilled surgical implant site c. material and device controls Methods of Assessment (1)Histology / Immunohistochemistry (2)Electron microscopy TEM and SEM (3) Biochemical assays colorimetry assay for bioactive molecules immuno-based assay (4) Mechanical testing the implant + surrounding tissue ---- tensile, bending, push-out tests remodeling around the implant integration of the implant