Medical Device Issues Prof. David Woolfson

Medical Device A device implanted permanently or temporarily in the body for a mechanical/structural purpose. Usually manufactured by extrusion or injection-moulding (polymeric devices) Drug Delivery Device A device intended to deliver a drug for prophylactic or therapeutic purposes. Usually, such devices control the rate at which the drug is made available to the body (controlled release devices Hybrid device A medical device with a primary mechanical/structural function and a secondary drug delivery function, either for device protection or targeted drug delivery. Devices

Insertion pain & tissue trauma Haemocompatibility Device- related problems Insertion pain & tissue trauma Haemocompatibility Device encrustation - morbidity Device-related Infection - mortality >250,000 device-related infections/year in the UK cost >£100million due to longer hospitalisation and more aggressive treatment There is now substantial interest in bioactive medical devices that encompass a drug delivery function

Foley urinary catheter

Surface formation of microbial biofilm, leading to UTI Urinary catheterisation is frequently employed in clinical and domiciliary care of patients. Catheterisation may be short or long-term (indwelling, Foley-type) or intermittent (Nelaton-type) Catheter blockage due to encrustation with complex inorganic salts, resulting in device failure due to obstruction of flow, remains a major problem in longer-term use, as does device-related infection Tissue trauma due to insertion, and also upon removal, is a further problem with most types of catheterisation Surface formation of microbial biofilm, leading to UTI Catheter issues

ET TUBES from ICU PATIENTS at (clockwise) 4h, 8h, 12h Endo- tracheal tube

24h 4h 48h 5d Biofilm formation Surface of endotracheal tube retrieved from an ICU patient 48h 5d 4h 24h

Ureteral stents from GORMAN SP et al BRITISH JOURNAL OF UROLOGY 73 (6): 687-691 1994

Drug-Eluting Stents (stainless steel, nitinol) Cardio- vascular stents angioplasty balloon mounted stent stent in situ Drug-Eluting Stents (stainless steel, nitinol) The drug-eluting stent is basically a bare metal stent that is then coated with a slow-to-moderate-release drug formulation, sometimes embedded in a polymer. It is hoped that this will prevent or at least reduce restenosis, reclosure of the coronary artery, one of the biggest limitations of angioplasty and causes for repeat procedures

The rapid evolution of clinical medicine exerts a continuing demand on manufacturers Manufacturers with a high cost base must add value to their lower-end products by making significant technological advances in order to compete with commodity suppliers, e.g. in continence care, respiratory, cardiovascular sectors Real clinical improvements are needed to demonstrate cost-savings to healthcare systems and justify higher reimbursement costs for healthcare systems Manufacturing and design improvements (e.g smooth device surface) not sufficient - bioactive devices ultimately required Medical Devices - economics

[ ] Medical Devices - polymers poly(vinyl chloride) poly(styrene) plasticised or unplasticised poly(styrene) crystalline or amorphous (tacticity) poly(ethylene) HDPE or LDPE CH2 CH2 [ ] n poly(urethane) HDPE or LDPE silicone repeat unit crosslinked to form an elastomer

Device coatings Device coatings can add lubricity, biocompatibility, and antimicrobial action to device surfaces. Coatings can be used to release drugs or make implanted devices more visible to imaging systems Many device coatings are hydrophilic polymer-based formulations, usually hydrogels Enhanced device lubricity is one major reason for coating, e.g catheters and guidewires can be spray coated with a thin layer of polytetrafluoroethylene (PTFE)

Coatings may be applied to non-polymeric devices fabricated from stainless steel, platinum or nitinol (nickel titanium) Drug delivery coatings that render a device ‘bioactive’ are now of major interest. Typically, a drug in a carrier hydrogel coating is released as the hydrogel imbibes water from surrounding biological fluids and swells Coating technologies presently include dip-coating, spray-coating, co-extrusion and chemical grafting to polymers, whereby the drug is added to the coating mix pre-process Relevant active agents include non-antibiotic antimicrobials, antibiotics and inorganic metallic elements such as silver Bioactive coatings

chemically controlled release mechanisms reservoirs (membranes) matrices (monoliths) diffusion controlled bioerosion/degradation pendant chain chemically controlled osmotic pressure swelling solvent activated externally ‘smart’ controlled e.g. sensor-based

Matrix (monolithic) Reservoir Q Q √t t Diffusion controlled systems Matrix (monolithic) drug uniformly distributed through polymer matrix no danger of drug dumping first-order kinetics Q √t Q t drug core surrounded by non-biodegradable polymer properties of drug and polymer govern diffusion rate ‘drug-dumping’ if membrane ruptures zero-order kinetics from ‘constant activity’ source Reservoir Q t

Effect of bioactive agents released from silicone Bioactive biomaterials Miconazole nitrate Nalidixic acid Gentamicin sulphate Ampicillin 1 2 3 4 5 6 7 Miconazole nitrate Nalidixic acid Gentamicin sulphate Ampicillin 10 15 20 25 30 Zone of Inhibition (mm) 8 Time (days) of Repeated Microbial Challenge

Alteration of surface topologies (nano-engineering) NewLEIF opportunities in bioactive biomaterials Alteration of surface topologies (nano-engineering) Direct implantation on devices surfaces (polymeric, metallic) of inorganic elements with antimicrobial properties, e.g silver , without the need for coating Surface implantation on preformed devices of organic compounds (MW < 500) with antimicrobial activity through generation of highly charged species Laboratory and clinical assessments of efficacy