Thrombosis and infection remain long-standing major challenges to the performance and longevity of any blood-contacting medical device. Long-term cardiovascular catheterization, as in the context of hemodialysis and vascular access, presents a significant clinical challenge in this regard. Significantly, thrombus formation and infectious biofilm-based implant infection are frequently inextricably connected, effectively countering resolution with therapeutics, allowing infections and thrombosis to proceed unabated. Many pharmaceutical and materials-based methods addressing biomaterial-associated thrombogenesis have been published. Yet few actively seek combinatorial approaches to address both thrombosis and infection simultaneously while concurrently providing durable mechanical resilience as a biomaterial or coating. These observations frame our overall working hypothesis: a recombinant protein-based polymer containing a cassette for genetically encoding heparin-binding motifs, concatenated with a MaSp2 silk protein backbone, provides a """"""""self- renewing"""""""" heparin-enriched polymer material, yielding both hemocompatibility and antimicrobial properties in a surface coating. This biomaterial construct will be based on known recombinant silk-based protein expression, combined with known heparin-binding mimicry for mammalian proteins to yield a new chimera-based biomaterial that actively binds circulating heparin with high affinity. Fabrication of the proposed medical device coating will proceed according to the following specific aims: 1) Determine the critical density of ARKKAAKA that provides both non-thrombogenic and antimicrobial activity in vitro in plasma-based assays.;2) Determine the critical density of the MaSp2 silk motif, (GGYGPGQQGPGGYGPGQQGPSGPGSAAAAAAAA)n, required to provide a hemodialysis catheter surface coating with appropriate mechanical and antithrombogenic properties under blood flow-induced shear stress;3) Produce a dual cassette biopolymer-based material combining the heparin-binding peptide (ARKKAAKA)n and the MaSp2 silk motif (GGYGPGQQGPGGYGPGQQGPSGPGSAAAAAAAA)n (where n is determined in Specific Aims 1 and 2), in controlled architectures to provide mechanical integrity, hemocompatibility, and microbial resistance. At the conclusion of this proposal, we will have produced and verified the durability and activity of a novel proteinaceous hemocompatible, antimicrobial, mechanically robust blood-contacting surface coating using a combination of rigorous heparin-binding, antimicrobial, and mechanical integrity assays in either plasma, whole blood or another biologically relevant milieu.
Improved performance for blood-contacting and hemodialysis catheters will benefit millions of patients. The approach described in this proposal will seek to address this need by producing: (1) a new biopolymer biomaterial with versatile control and design features, (2) an intrinsic capability to capture circulating heparins from the host, (3) associated blood-contacting performance benefits from renewable heparinized surfaces, (4) assessment of hemodialysis catheter thrombogenic and antimicrobial properties using industry test standards, and (5) known mass production and cost structures from current silk-based biomaterials efforts. Eventually, rapid translation of the new biomaterial to commercial use as an alternative to the array of heparinized coatings in medical device use currently is desired.
| Jones, Clinton F; Campbell, Robert A; Franks, Zechariah et al. (2012) Cationic PAMAM dendrimers disrupt key platelet functions. Mol Pharm 9:1599-611 |
