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Wound Healing and the Presence of Biomaterials Topics: • Formation of Granulation Tissue • Wound Healing and the Presence of Biomaterials Topics: • Formation of Granulation Tissue • Foreign Body Reaction • Fibrous Encapsulation • Chronic Inflammation • Types of Implant Resolution • Repair vs. Regeneration • In Vivo Assays for Inflammatory Response MSE-536

Responses following injury: 1. Blood clotting and formation of fibrin network 2. Acute inflammation: Responses following injury: 1. Blood clotting and formation of fibrin network 2. Acute inflammation: • activation of neutrophils • phagocytosis of foreign bodies • release of hyaluronic acid and glycosaminoglycan (chemoattractants) into ECM. 3. Inflammatory response: influx of fibroblasts into ECM beginnings of granulation tissue formation generation of new blood vessels deposition of type III collagen fibers (thin and randomly oriented) fibrin clot is dissolved, enzymes released and phagocytosis continues 4. Remodeling and scar formation: • Type III collagen replaced by type I collagen: collagen bundles are larger and oriented with principal lines of stress in tissue • Increased amounts of chemicals such as chrondroitin and dermatan sulfate • Scar tissue continues to form for several months • Blood vessels that are unattached are resorbed • Scar becomes pale and avascular MSE-536

Definition: Granulation Tissue: characterized by a pebbly, granular appearance caused by the creation of Definition: Granulation Tissue: characterized by a pebbly, granular appearance caused by the creation of many vascular buds sprouting from existing blood vessels. This process is called neovascularization or angiogenesis. Fibroblasts: committed cell type found in many tissues. Fibroblasts synthesize and maintain connective tissues by producing and extracellular matrix (ECM) rich in collagen and proteoglycans. Fibroblasts with features of smooth muscle cells are called myofibroblasts and are responsible for wound contraction. MSE-536

Formation of Granulation Tissue Wound-healing response of the body after injury or biomaterial implantation Formation of Granulation Tissue Wound-healing response of the body after injury or biomaterial implantation Granulation tissue formation at the tissue/material interface. (G) zone of granulation tissue separates the spleen (S) from the polymer implant (I) MSE-536

Foreign Body Reaction Definition: Foreign Body Giant Cells (FBGCs): multinucleated cells formed by fusion Foreign Body Reaction Definition: Foreign Body Giant Cells (FBGCs): multinucleated cells formed by fusion of monocytes/macrophages in an attempt to phagocytose biomaterials much larger than a single cell. Factors affecting Foreign Body Composition: 1. Topography 2. Surface Chemistry Factors affecting Foreign Body Reaction: Large cells: FGGCs Small Cells: macrophages Bright particles: polypropylene 1. Shape 2. Surface/Volume Ratio MSE-536

(a) Foreign body reaction to embedded PMMA. Arrow points to macrophages in tissue (b) (a) Foreign body reaction to embedded PMMA. Arrow points to macrophages in tissue (b) Foreign body reaction to large particles of UHMWPE showing macrophages and FBGCs MSE-536

Fibrous Encapsulation In vivo response to a biodegradable, polymeric biomaterial implanted in a rat Fibrous Encapsulation In vivo response to a biodegradable, polymeric biomaterial implanted in a rat for 12 weeks. (a) 4 days (b) 3 weeks (c) 12 weeks. P indicates polymer, or space left by polymer; N: neutrophils, FC: fibrous capsule, M: macrophages, PF: polymer fragments embedded in fibrous capsule. Infiltration of neutrophils into implantation area is seen within a few days, followed by slower development of fibrous capsule surrounding implant. Because material is biodegradable, polymer fragmentation is present at later times. MSE-536

Fibrous Encapsulation, cont. Final stage of healing for implants made of nondegradable materials. Steps Fibrous Encapsulation, cont. Final stage of healing for implants made of nondegradable materials. Steps in granulation tissue maturation: • Presence of larger blood vessels • Alignment of collagen fibers in response to local mechanical forces • Collapse of capsule surrounding implant and formation of a scar Factors affecting capsule formation: • Degree of original injury during implantation • Amount of subsequent cell death • Location of implant site • Degradation time of implant Factors affecting capsule thickness: • Amount and composition of small particulates produced • Mechanical factors at implant site • Shape of implant • Electrical currents MSE-536

Chronic Inflammation Characterized by the presence of mononuclear cells, including lymphocytes and plasma cells Chronic Inflammation Characterized by the presence of mononuclear cells, including lymphocytes and plasma cells Can include presence of granulomas – a layered structure comprised of a nonphagocytosable particle surrounded by a layer of FBGCs, a layer of modified macrophages called Epithelioid cells, and surrounded by a layer of lymphocytes Subcutaneous model showing: • Polymer hydrogel implant (h) • Macrophages (right arrow) • Lymphocytes (left arrow) • C: beginning of fibrous capsule MSE-536

Four types of implant response resolution: 1. Extrusion: material forced out of the body Four types of implant response resolution: 1. Extrusion: material forced out of the body (e. g. splinter) 2. Resorption: material biodegrades, no fibrous capsule forms 3. Integration: implant and host tissue grow together (e. g. porous titanium implant in bone) 4. Encapsulation: implant surrounded by fibrous tissue MSE-536

Repair vs. Regeneration Wound healing in Skin Repair involves healing of the internal dermal Repair vs. Regeneration Wound healing in Skin Repair involves healing of the internal dermal layer Regeneration is regrowth of thin outer epidermal layer MSE-536

Skin Regeneration In the epidermis, this process is called reepithelilization. Cells at edge of Skin Regeneration In the epidermis, this process is called reepithelilization. Cells at edge of wound flatten to cover more of the wound, releasing attachment to ECM to migrate across wound Epithelial cells gradually cover the entire wound site ECM attachments are reestablished, and cells recover original shape MSE-536

In vivo Assays for Inflammatory Response Items in the table at right may cause In vivo Assays for Inflammatory Response Items in the table at right may cause biological response through: • Interactions of biomolecules (e. g. proteins and ions) or cells with implant • Interactions of biomolecules or cells with soluble agents leached from implant • Interactions of biomolecules or cells with insoluble particulates • Alterations in load or strain in the area around the implant MSE-536

Biocompatibility: the ability of a medical device to perform with an appropriate host response Biocompatibility: the ability of a medical device to perform with an appropriate host response in a specific application. Biocompatible assessment: a measurement of the magnitude and duration of the adverse alterations in homeostatic mechanisms that determine the host response. Evaluation of biocompatibility usually involves exposing a small animal to the selected biomaterial or its extract through injection or implantation. Two primary reasons to carry out biocompatibility tests: 1. Screen novel materials to learn degree & type of inflammation response 2. Assess inflammation response to the material in a form very similar to that which will be implanted MSE-536

Choice of Animal: • Select on similarity of physiology and healing response to that Choice of Animal: • Select on similarity of physiology and healing response to that of humans in a given application • Start with a small animal (e. g. , rat, rabbit) and scale up as warranted Choice of Implant Site: • As close as possible to that used in final application • Use accessible site (subcutaneous pouch) to check for inflammation response. • Identify parameters that may affect degree of inflammation Length of Study: Dose: should be same shape as • Subacute toxicity: 14 -28 days final product. • Acute toxicity: up to 24 hours • Subchronic toxicity: up to first 90 days • Chronic: > 90 days MSE-536

Factors that can affect dose in addition to shape in direct implants 1. Implant Factors that can affect dose in addition to shape in direct implants 1. Implant weight/bulk size 2. Implant surface area 3. Implant roughness 4. Number of implants per animal Biomaterials may be introduced via: 1. Direct implantation 2. Injection of soluble products 3. Placing in a “cage” to isolate biomaterial – cage may affect inflammatory response. l Stainless steel cage implant model. This allows investigators to examine inflammatory response without direct contact between biomaterial and surrounding tissue. MSE-536

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