SBIR-STTR Award

Infection is a serious and potentially fatal complication of surgery to deliver cardiovascular implantable electronic devices (CIEDs) (i.e., pacemakers and implantable cardioverter-defibrillators). Untreated device-related infection is associated with mortality rates as high as 66%. Currently, only one antibiotic-impregnated mesh has been FDA-approved for placement in surgical incisions to reduce infections associated with the implantation of CIEDs. However, staphylococci bacteria, which are commonly found in CIED infections, have well documented resistance to the combination antibiotics used in the mesh. Moreover, the antibacterials can promote the growth of fungii - a source of rare, but highly fatal CIED infections. The use of the current, bulky implantable mesh envelops increase surgical pocket size, which can restrict a patient's physical activities and increase the chance of infection. And the mesh, itself, contributes to the space constraints of the surgical pocket, which reduces the size of the CEIDs that can be accommodated; yet the vast majority of patients would prefer larger devices that last longer. Increasing the length of time between device retrievals and reimplantations would improve the quality of life for patients while decreasing the risk of infections associated with surgery. The objective of this Phase I SBIR proposal is to use 3D printing to fabricate a biodegradable polycaprolactone (PCL)-based antimicrobial envelope, to be fitted outside of cardiac rhythm devices, which will prevent infections after surgical implantation. The hypothesis is that a slow degradation (hydrolysis) of the PCL envelope will gradually release a novel antimicrobial compound (CSA-131, a ceragenin) for antimicrobial and anti-fungal activity. CSA-131 is a synthetic non-peptide compound, with no pre-existing pool of resistance, that mimics the activity of the body's endogenous antimicrobial peptides. The proposed device will be the first to prevent fungal colonization of cardiac devices, while still providing superior and longer lasting inhibition of bacterial growth. Moreover, the customization allowed by 3D printing will also minimize surgical pocket space constraints. To advance this antibiotic mesh technology, a PCL filament for 3D printing applications will be developed that is loaded with the antimicrobial, CSA-131. The elution profiles of the filament will be evaluated and the in vitro efficacy of CSA-131 will be tested. Next, envelopes composed of antibiotic-loaded filament will be fabricated (3D printing), following a design that accommodates a pacemaker. And, finally, the antimicrobial and anti-fungal properties of the PCL envelope will be demonstrated and its cytotoxicity evaluated. It is expected that incorporation of CSA-131 into a 3D printed biodegradable mesh will either prevent or significantly reduce biofilm formation on CIEDs when exposed to daily inocula of Staphylococcus aureus (MRSA) for at least 60 days. This project will pioneer the melding of a novel antimicrobial with a 3D printing, PCL filament, thereby enabling the production of custom-fit envelops for pacemakers and facilitating trouble free surgical implantation. 1

Public Health Relevance Statement:
Narrative Through the development of an antimicrobial envelope for cardiovascular implantable electronic devices (CIEDs), i.e., pacemakers and implantable cardioverter-defibrillators, Saranas will greatly reduce the incidence of infections associated with the implants. Reducing the number of CIED-related infections will also greatly reduce the cost-of-care for these patients, which increase by $50,000 per patient when an infection is acquired.

Project Terms:
Adoption; Antibiotics; Miscellaneous Antibiotic; Antibiotic Drugs; Antibiotic Agents; Combined Antibiotics; Antibiotic Drug Combinations; Antibiotic Combinations; Antifungal Agents; antifungals; anti-fungal drug; anti-fungal agents; anti-fungal; Therapeutic Fungicides; Antifungal Drug; Bacteria; Bacterial Infections; bacterial disease; Cardiovascular system; circulatory system; Heart Vascular; Cardiovascular Organ System; Cardiovascular Body System; Cardiovascular; Complication; Electronics; electronic device; Patient Care; Patient Care Delivery; Growth; ontogeny; Tissue Growth; Generalized Growth; Hydrolysis; In Vitro; Incidence; Infection; Minocycline; mortality; Patients; Printing; Production; Quality of life; QOL; Surgical Replantation; Replantation; Reimplantation; Research; Rifampin; Rimactane; Rifampicin; Rifadin; Benemycin; Risk; Genus staphylococcus; Staphylococcus; Staphylococcus aureus; Staph aureus; S.aureus; S. aureus; S aureus; Surveys; Survey Instrument; Technology; Testing; Time; Microbial Biofilms; biofilm; Catheters; polycaprolactone; Custom; Implantable Cardioverter-Defibrillators; Implantable Defibrillators; base; improved; incision; Otomy; Surgical incisions; Surface; Phase; Evaluation; Physical activity; cardiac rhythm; heart rhythm; antibacterial; anti-bacterial; Antibacterial Agents; Anti-Bacterial Agents; Exposure to; Shapes; Source; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; Infection prevention; Prevent infection; cytotoxicity; Lytotoxicity; novel; member; Devices; Pacemakers; Stimulators, Electrical, Pace; Pace Stimulators; Property; methicillin resistant Staphylococcus aureus; methicillin-resistant S. aureus; Methicillin Resistant S. Aureus; Methicillin Resistant S Aureus; MRSA; Effectiveness; prevent; preventing; Address; Length; Retrieval; Filament; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; urinary; developmental; Development; anti-microbial peptide; antimicrobial peptide; cost; designing; design; resistant; Resistance; anti-microbial; antimicrobial; Implant; implantation; FDA approved; resistance strain; resistant strain; three dimensional printing; 3D printer; 3-D printer; 3-D print; 3D Print; care costs; cardiac implant; cardiodevice; cardiac device

Infections related to the implantation of cardiovascular implantable electronic devices (CIEDs) occur in 20% of the interventions and are associated with a 2-fold increase in mortality rate. While pre-operative antibiotic prophylaxis is currently used in clinical practice, targeting the infectious agents locally is recommended to reduce the risk of antibiotic resistance. The use of an antibacterial envelope (TYRX, Medtronic), made of a polymer mesh coated with two antibacterial agents (minocycline and rifampin), has been shown to reduce by 40% major CIED infections. Despite these positive results, the product has several drawbacks. The envelope has variable effectiveness against coagulase-negative Staphylococci and lacks effectiveness against fungi or biofilms. Moreover, several methicillin-resistant Staphylococcus aureus (MRSA) strains have developed resistance against it. Therefore, an antibacterial and antimycotic resorbable envelope that fully eradicates CIED-related infections remains an unmet clinical need. N8 Medical is developing a new bioresorbable polymeric CIED envelope that incorporates a proprietary ceragenin, a novel class of anti-infective agents that do not engender resistance. The new compound is a synthetic non-peptide compound that mimics the activity of the body's endogenous antimicrobial peptides (AMPs) and it confers efficacy against difficult to eradicate strains, such as MRSA and fungi. N8 Medical's CIED Envelope is the first surgical envelope to prevent fungal colonization of cardiac devices while providing superior inhibition of bacterial growth. Upon implantation of the CIED within the N8 Medical device, the envelope physically secures and stabilizes the implanted pacemaker and releases the ceragenin to eliminate infection-causing pathogens during the period before being fully resorbed by the body within 8-12 weeks. This SBIR Phase II project builds on the results of a Phase I project that provided preliminary validation of the efficacy of the envelope in vitro and in vivo and confirmed its potential broader spectrum of activity compared to TYRX. The goal of this Phase II project is to perform pivotal preclinical studies required to obtain an IDE and FDA device approval through a De Novo application. The project is articulated in three aims over 2 years. First, industrial product development will improve the fabrication method to assure the commercial viability of the envelope (Aim 1). The final design will then be validated in GLP pivotal safety (Aim 2) and efficacy (Aim 3) studies. Comprehensive biocompatibility tests (including cytotoxicity, sensitization, pyrogenicity, and genotoxicity assays), and in vivo acute and sub-chronic and chronic systemic toxicity will be assessed. The high efficacy of N8 Medical's CIED Envelope in eradicating resistant bacterial strains, fungi, and biofilms, will lead to better patient outcomes in terms of morbidity and mortality, reduced infection-related complications, and reduction in the need for additional interventions.

Public Health Relevance Statement:
PROJECT NARRATIVE Infections related to the implantation of cardiovascular implantable electronic devices or CIEDs occur at high frequency (up to ca. 20% of the interventions) and are associated with a 2-fold increase in mortality rate. A solution that delivers a potent anti-infective locally that can eradicate resistant bacterial strains, fungal species, and is efficacious against biofilms is currently missing. N8 Medical is developing a bioresorbable polymeric envelope, that stabilizes the implanted pacemaker and eliminates a broad spectrum of pathogens (including resistant bacteria and fungi) causing CIED infections, through the application of ceragenins, a novel class of anti-infectives designed to mimic naturally occurring antimicrobial peptides.

Project Terms:
Anti-Infective Agents; Anti-Infective Drugs; Anti-Infectives; Anti-infective Preparation; AntiInfective Drugs; AntiInfectives; Antiinfective Agents; communicable disease control agent; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antifungal Agents; Antifungal Drug; Therapeutic Fungicides; anti-fungal; anti-fungal agents; anti-fungal drug; antifungals; Bacteria; Biological Assay; Assay; Bioassay; Biologic Assays; Candida; Monilia; Candida albicans; C albicans; C. albicans; C.albicans; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cephalosporins; Chlorhexidine; Coagulase; Electronics; electronic device; fungus; Gluconates; gluconic acid; Glycolates; glycolic acid; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Health; In Vitro; Infection; Medical Device; Methods; Minocycline; Morbidity - disease rate; Morbidity; mortality; New Zealand; Patients; Permeability; Polymers; Production; Chrysemonas; Flavimonas; Pseudomonas; P aeruginosa; P. aeruginosa; Pseudomonas pyocyanea; Pseudomonas aeruginosa; Public Health; Domestic Rabbit; Rabbits; Rabbits Mammals; Oryctolagus cuniculus; Benemycin; Rifadin; Rifampicin; Rimactane; Rifampin; Risk; Safety; Staphylococcus; Genus staphylococcus; surgical site infection; Surgical Wound Infection; Testing; fabric; Textiles; Time; Vancomycin; Virus; poly(lactide); polylactide; Generations; Microbial Biofilms; biofilm; Antibiotic Resistance; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Medical Care Costs; medical costs; bacterial resistance; Bacteria resistance; Bacteria resistant; Bacterial resistant; resistance to Bacteria; resistance to Bacterial; resistant to Bacteria; resistant to Bacterial; base; Defibrillators; Electric Shock Cardiac Stimulators; Stimulators, Electrical, Cardiac, Shock; Label; improved; Procedures; Surface; Acute; Chronic; Clinical; Phase; Medical; FDA Device Approval; Food and Drug Administration Device Approval; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; Antibiotic Premedication; Antibiotic Prophylaxis; Industrial Product; infectious organism; Infectious Agent; Life; mechanical; Mechanics; Frequencies; Side; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; Prevent infection; Infection prevention; biocompatibility; biomaterial compatibility; Lytotoxicity; cytotoxicity; membrane structure; Membrane; bioresorbable polymer; degradable polymer; biodegradable polymer; genotoxicity; microbial; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; novel; Devices; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Pace Stimulators; Pacemakers; Property; Intervention Strategies; interventional strategy; Intervention; epsilon-caprolactone; caprolactone; Skin; MRSA; Methicillin Resistant S Aureus; Methicillin Resistant S. Aureus; methicillin-resistant S. aureus; methicillin resistant Staphylococcus aureus; Effectiveness; preventing; prevent; Address; Dose; in vivo; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Preparation; Characteristics; safety study; preclinical study; pre-clinical study; antimicrobial peptide; anti-microbial peptide; cost; design; designing; cost effective; Resistance development; Resistant development; developing resistance; pathogen; Resistance; resistant; antimicrobial; anti-microbial; Implant; implantation; prototype; in vitro testing; product development; clinical practice; Sterilization; Secure; liver injury; Injury to Liver; hepatic damage; hepatic injury; liver damage; cardiac resynchronization therapy; systemic toxicity; Electrospinning; efficacy study; in vivo evaluation; in vivo testing; cardiac implant; cardiac device; cardiodevice; renal damage; damage to kidney; kidney damage; 2019-nCoV; 2019 novel corona virus; 2019 novel coronavirus; COVID-19 virus; COVID19 virus; CoV-2; CoV2; SARS corona virus 2; SARS-CO-V2; SARS-COVID-2; SARS-CoV-2; SARS-CoV2; SARS-associated corona virus 2; SARS-associated coronavirus 2; SARS-coronavirus-2; SARS-related corona virus 2; SARS-related coronavirus 2; SARSCoV2; Severe Acute Respiratory Coronavirus 2; Severe Acute Respiratory Distress Syndrome CoV 2; Severe Acute Respiratory Distress Syndrome Corona Virus 2; Severe Acute Respiratory Distress Syndrome Coronavirus 2; Severe Acute Respiratory Syndrome CoV 2; Severe Acute Respiratory Syndrome-associated coronavirus 2; Severe Acute Respiratory Syndrome-related coronavirus 2; Severe acute respiratory syndrome associated corona virus 2; Severe acute respiratory syndrome corona virus 2; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; infection rate; rate of infection; efficacy validation; validate efficacy