Description:
Background:
Studies in animals have demonstrated that sterile polymer materials placed intraperitoneally will demonstrate adherent inflammatory cells in a matter of hours and will cause alterations in the surrounding tissue within 24 hours. The initial steps in the reaction involve the irreversible deposition of fibrinogen and other plasma proteins on the polymer surface, followed by the binding of macrophages and other inflammatory cells to epitopes of the protein. In rodents, the local inflammation from intraperitoneal catheters progresses for 1-4 weeks and then gradually subsides, but there is evidence of systemic inflammatory changes in other tissues distant from the foreign body site. Catheter materials placed within blood vessels or within the bladder will likewise incite specific reactions that may cause subsequent dysfunction locally and alterations in distant systems of the body. In addition to inflammatory cells, bacteria form a biofilm on polymer surfaces that is often impenetrable to antibiotic medications and may be the cause of subsequent bacteremia.
Clinical Importance:
Polymer materials are used acutely and chronically in millions of patients each day in healthcare facilities across the U.S. While medical grade silicone is typically less immunogenic than previously used materials (e.g,, polyurethane or polyethylene), there is still a significant foreign body reaction that may directly impact the clinical health of the patient as well as promote the formation of bacterial adherence, biofilm formation, and subsequent infectious complications.
Applications should address all of the following research and development issues:
1. Development of catheter biomaterial(s) and/or biomaterial surface coatings that decrease protein (e.g., fibrinogen and other circulating proteins that bind biopolymers and cells) adsorption and absorption (often termed biofouling) by 99% or more when compared to medical silicone and/or other materials in use today. Testing should include the use of radiolabeled proteins, spectroscopic techniques, electron microscopy, or other applicable measurements to determine the surface area covered by the protein(s).
2. Development of catheter biomaterial(s) and/or surface coatings that decrease inflammatory, bacterial and fungal cell adherence by 99% or more when compared to medical silicone and/or other materials in use today. It is anticipated that standard in vitro procedures will be followed, as described in the US Pharmacopeia, in standards published by the American Society for Testing and Materials (ASTM), the British Standards Institute, and the International Standards Organization (ISO). Close collaboration with the US Food and Drug Administration (FDA) is expected when preparing to bring the biomaterial to market, and documentation verifying communication with the appropriate divisions of FDA should be included in the application. These experiments should include:
Testing with a variety of inflammatory cells: macrophages, T-lymphocytes, polymorphonuclear cells, and fibroblasts (e.g., L-929 fibroblast cell line)
Testing with a variety of bacteria including but not limited to: Staphylococcus epidermidis (e.g., RP62A) and Escherichia Coli.
Testing with a variety of fungal organisms including but not limited to Candida Albicans
Quantitative measurement of cell adherence by appropriate techniques (e.g., electron microscopy or elution with ultrasound followed by counting/fluorescence detection)
3. The following components should be specified or determined in preparation for in vivo assessments:
Material(s) of manufacture
Intended additives, coatings, process contaminants, residues
Leachable substances
Degradation products
Other components and their interaction with the final product
4. In vivo testing of acute (1-7 days) placement of catheter biomaterial(s) in appropriate animal model(s) for local and systemic inflammation and infection in one or all three regions of the body: intravenous, intraperitoneal, or intravesical. Experimental biomaterials should be compared to controls with medical silicone catheters and/or other materials in use today in accordance with applicable FDA guidelines including the FDA Biological Response Test, ISO 10993-1:2009, and the draft guidance on Premarket Notification [510(k)] Submissions for Medical Devices that include Antimicrobial Agents. This should include the following at each time interval:
Immunohistochemical analysis of the tissue surrounding the catheter to include but not be limited to: TNFα, IL-1, TGFβ, VEGF, FGF, αSMA. In the bladder, this would entail the bladder tissue and the urethra. In a vein, this would mean the vein plus the tissue within a minimum of 1000 microns of the vein. In the peritoneal cavity, this would be the following tissues: abdominal wall, liver, small and large intestines, and omentum.
In situ examination with electronmicroscopy of any cell coating/biofilm on the catheter and further immunocytochemical analysis of any cell coating/biofilm (after separation from catheter with ultrasound or another appropriate technique) to determine the cellular makeup of the layer.
5. In vivo testing of chronic (> 7 - 30 days) placement of catheter biomaterial(s) in appropriate animal model(s) for local and systemic inflammation and infection in three regions of the body: intravenous, intraperitoneal, and intravesical. Biomaterials should be compared to controls with medical silicone catheters and/or other materials in use today in accordance with applicable FDA guidelines including the FDA Biological Response Test, ISO 10993-1, and the draft guidance on Premarket Notification [510(k)] Submissions for Medical Devices that include Antimicrobial Agents. This should include the following at each time interval:
Immunohistochemical analysis of the tissue surrounding the catheter to include but not be limited to; TNFα, IL-1, TGFβ, VEGF, FGF, αSMA. In the bladder, this would entail the bladder tissue and the urethra. In a vein, this would mean the vein plus the tissue within 200 microns of the vein. In the peritoneal cavity, this would be the following tissues: abdominal wall, liver, small and large intestines, and omentum.
In situ examination with electron microscopy of any cell coating/biofilm on the catheter and further immunocytochemical analysis of any cell coating/biofilm (after separation from catheter with ultrasound or another appropriate technique) to determine the cellular makeup of the layer.
Immunohistochemical examination and RNA-expression of inflammatory markers in tissues that are not directly in contact with the catheter material. These sites might include heart, liver, spleen, lungs, and brain. The panel of markers should include a broad array of cytokines and chemokines that may indicate systemic inflammation.
