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Dr. Z will be reviewing the basics of host responses to “non-blood contacting” biomaterials. This discussion includes a review of inflammation, biofilms and foreign body giant cell reactions. Dr. Scott will cover infections related to biomaterial-based implants

Central venous catheters –most frequent source of HA bloodstream infections Id.theclinics.com

Host Reactions to Biomaterials  Blood − material interactions  protein adsorption  coagulation  fibrinolysis  platelet activation  complement activation  leukocyte adhesion  hemolysis  Soft tissue/Orthopedics-Modification of normal healing  encapsulation  foreign body reaction  Infection/Biofilm formation  Carcinogenicity  Biomechanical compatibility  Toxicity

 Why is wound healing important when discussing biomaterials-based implants?  How do wounds normally heal?  When wounds do not heal…  Diabetic foot ulcer  Chronic inflammation and the foreign body response  The occurrence of infection  Biofilm formation  The effects of biomaterial implantation

Three predominant layers of skin: Epidermis Dermis Hypodermis Responses to device implantation can be expressed in terms of the generalized healing response of skin

Inflammatory resolution in repair should follow a brief period of acute inflammation

Nature, 2008 Inflammation Acute Chronic New tissue formation Ulceration Remodelling or Scar tissue formation Encapsulation Three stages of wound healing

Initial wound healing responses- injury

Frontiers in Bioscience 9, , January 1, 2004 Normal healing- acute inflammatory response Platelets, neutrophil diapedesis, macrophage activation

Normal healing- new tissue formation Granulation, neoangiogenesis, re-epithelialization Nature.com newly formed blood vessels (mainly capillaries) proliferative fibroblasts residual inflammatory cells endothelial cells

Frontiers in Bioscience 9, , January 1, 2004 Normal healing response- remodeling Dynamic extracellular matrix synthesis and degradation

Frontiers in Bioscience 9, , January 1, 2004 Summary of Steps in Wound Healing

Frontiers in Bioscience 9, , January 1, 2004 Deficient wound healing

Apligraf.com Chronic inflammation and ulceration emedicine.com

Chronic Inflammation and Infection

Timing of Infection

Biofilm-Lifecycle A primary cause of chronic ulceration is the presence of infection Biofilms are responsible for many chronic infections associated with implanted devices 1.7 million hospital acquired infections/year 99,000 deaths Majority caused by biofilm-related infections coe.montana.edu Mooglelifescience.com

Biofilms Hydrophilic coatings HA Hydrogels Heparin How to combat…

Biofilms QS inhibitors and antagonists How to combat…

Disruption of established biofilms Antibiotics Enzymes Nanoparticles Biofilms How to combat…

Frontiers in Bioscience 9, , January 1, 2004 Excessive wound healing

Foreign Body Giant Cell Reactions  Every foreign surface first acquires a protein coat composed of fibrinogen, albumin, fibronectin and other blood and interstitial-fluid proteins.  The edema caused by the surgical procedure of implantation and several chemo-attractants lead to leukocyte emigration from the blood and accumulation in the biomaterial site.  Together with platelets, leukocytes bind on to the protein-coated surface.  Neutrophils have a short lifetime of about 2 days, while macrophages stay in the site for much longer.  Around day 6/7 after implantation of the medical device, small multinucleated Foreign Body Giant Cells (FBGC) appear on the surface of the biomaterial.  These cells can grow to include more than 100 nuclei since they are the result of robust macrophage fusion.

Foreign Body Giant Cell Reactions  Their phagocytic potential far exceeds that of all their component macrophages individually due to their ability to degrade targets extracellularly (extroversion), and they are very similar to osteoclasts which arise from the same cellular precursor in the bone marrow.  Both FBGC and macrophages secrete fibroblast attractants, and the incoming fibroblasts play a key role in creating a dense and organized collagenous matrix around the biomaterial, that has very low vasculature density.  This ECM capsule isolates medical devices from the rest of the interstitial tissue and can also often contract, leading to adverse effects for the medical device function.

Foreign Body Giant Cells FBR and encapsulation openi.nlm.nih.gov Surface Science 500 (2002) 28–60

Regeneration Biomaterials Nature, 2008 The hope

Epicel®-Cultured epidermal autograft Genzyme Biosurgery AlloDerm® is real human tissue that is decellularized to remove the risk of rejection or inflammation. It is then freeze-dried through a patented process that maintains the crucial elements of the tissue structure (collagen, elastin, proteoglycans) and packaged with a shelf life up to two years. AlloDerm® is available in various sizes to increase keratinized gingiva, for soft tissue flap extensions over bone grafts, and for recession defects Life Cell Corporation

INTEGRA® has two layers. The bottom layer (dermal) is made of a fibrous protein material (collagen) from cows and a substance made from shark cartilage. The top layer (epidermal) is made of silicone Integra Life Sciences Corporation