Design consideration of a novel polymeric transcatheter heart valve through computational modeling.

Transcatheter heart valve replacement is becoming a more routine procedure, and this is further supported by positive outcomes from studies involving low-risk patients. Nevertheless, the lack of long-term transcatheter heart valve (TAV) durability is still one of the primary concerns. As a result, more research has been focused on improving durability through various methods such as valve design, computational modeling, and material selection. Recent advancements in polymeric valve fabrication showed that linear low-density polyethylene (LLDPE) could be used as leaflet material for transcatheter heart valves. In this paper, a parametric study of computational simulations showed stress distribution on the leaflets of LLDPE-TAV under diastolic load, and the results were used to improve the stent design. The in silico experiment also tested the effect of shock absorbers in terms of valve durability. The results demonstrated that altering specific stent angles can significantly lower peak stress on the leaflets (13.8 vs. 6.07 MPa). Implementing two layers of shock absorbers further reduces the stress value to 4.28 MPa. The pinwheeling index was assessed, which seems to correlate with peak stress. Overall, the parametric study and the computational method can be used to analyze and improve valve durability.

Transcatheter Heart Valves: A Biomaterials Perspective.

Heart valve disease is prevalent throughout the world, and the number of heart valve replacements is expected to increase rapidly in the coming years. Transcatheter heart valve replacement (THVR) provides a safe and minimally invasive means for heart valve replacement in high-risk patients. The latest clinical data demonstrates that THVR is a practical solution for low-risk patients. Despite these promising results, there is no long-term (>20 years) durability data on transcatheter heart valves (THVs), raising concerns about material degeneration and long-term performance. This review presents a detailed account of the materials development for THVRs. It provides a brief overview of THVR, the native valve properties, the criteria for an ideal THV, and how these devices are tested. A comprehensive review of materials and their applications in THVR, including how these materials are fabricated, prepared, and assembled into THVs is presented, followed by a discussion of current and future THVR biomaterial trends. The field of THVR is proliferating, and this review serves as a guide for understanding the development of THVs from a materials science and engineering perspective.

Development and Fabrication of Vapor Cross-Linked Hyaluronan-Polyethylene Interpenetrating Polymer Network as a Biomaterial.

Flexible heart valve leaflets made from hyaluronan-enhanced linear low-density polyethylene interpenetrating polymeric network (HA-LLDPE IPN) films have been shown to provide good hemodynamics, but the resulting surfaces were not consistent; therefore, the present work tries to mitigate this problem by developing a vapor cross-linked HA-LLDPE IPN. Herein, the HA-LLDPE fabrication process is studied, and its parameters are varied to assess their effects on the IPN formation. Thermal analysis and gas chromatography-mass spectrometry were used to quantify the effects of different treatment conditions on material properties. Water contact angle goniometry, infrared spectroscopy, and toluidine blue O (TBO) staining were used to characterize the surface of the HA-LLDPE IPN. The results show that a hydrophilic surface is formed on HA-LLDPE, which is indicative of HA. HA surface density data from TBO staining show consistent HA distribution on the surface. The IPN fabrication process does not affect the tensile properties that make LLDPE an attractive material for use in flexible heart valve leaflets. The 28 day in vitro biological assays show HA-LLDPE to be noncytotoxic and resistant to enzymatic degradation. The HA-LLDPE showed less platelet adhesion and caused less platelet activation than the plain LLDPE or tissue culture polystyrene. All of the results indicate that vapor cross-linked HA-LLDPE IPN is a promising material for use as flexible leaflets for heart valve replacements.

Hyaluronan enhancement of expanded polytetrafluoroethylene cardiovascular grafts.

Heart disease continues to be the leading cause of death in the United States. The demand for cardiovascular bypass procedures increases annually. Expanded polytetrafluoroethylene is a popular material for replacement implants, but it does have drawbacks such as high thrombogenicity and low patency, particularly in small diameter grafts. Hyaluronan, a naturally occurring polysaccharide in the human body, is known for its wound healing and anticoagulant properties. In this work, we demonstrate that treating the luminal surface of expanded polytetrafluoroethylene grafts with hyaluronan improves hemocompatibility without notably changing its mechanical properties and without significant cytotoxic effects. Surface characterization such as ATR-FTIR and contact angle goniometry demonstrates that hyaluronan treatment successfully changes the surface chemistry and increases hydrophilicity. Tensile properties such as elastic modulus, tensile strength, yield stress and ultimate strain are unchanged by hyaluronan enhancement. Durability data from flow loop studies demonstrate that hyaluronan is durable on the expanded polytetrafluoroethylene inner lumen. Hemocompatibility tests reveal that hyaluronan-treated expanded polytetrafluoroethylene reduces blood clotting and platelet activation. Together our results indicate that hyaluronan-enhanced expanded polytetrafluoroethylene is a promising candidate material for cardiovascular grafts.

Hemocompatibility of hyaluronan enhanced linear low density polyethylene for blood contacting applications.

Despite their overall success, different blood-contacting medical devices such as heart valves, stents, and so forth, are still plagued with hemocompatibility issues which often result in the need for subsequent replacement and/or life-long anticoagulation therapy. Consequently, there is a significant interest in developing biomaterials that can address these issues. Polymeric-based materials have been proposed for use in many applications due to their ability to be finely tuned through manufacturing and surface modification to enhance hemocompatibility. In this study, we have developed a novel, hydrophilic biomaterial comprised of an interpenetrating polymer network (IPN) of hyaluronan (HA) and linear low density polyethylene (LLDPE). HA is a highly lubricous, anionic polysaccharide ubiquitously found in the human body. It is currently being investigated for a vast array of biomedical applications including cardiovascular therapies such as hydrogel-based regenerative cell therapies for myocardial infarction, HA-coated stents, and surface modifications of polyurethane and metals for use in blood-contacting implants. The aim of this study was to assess the in vitro thrombogenic response of the hydrophilic polymer surface, HA-LLDPE for future potential use as flexible heart valve leaflets. The results indicate that HA-LLDPE is non-toxic and reduces thromobogenicity as compared to LLDPE surfaces, asserting its feasibility for use as a blood-contacting biomaterial. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1964-1975, 2018.

Characterizing the Cytocompatibility of Various Cross-Linking Chemistries for the Production of Biostable Large-Pore Protein Crystal Materials.

With rapidly growing interest in therapeutic macromolecules, targeted drug delivery, and in vivo biosensing comes the need for new nanostructured biomaterials capable of macromolecule storage and metered release that exhibit robust stability and cytocompatibility. One novel possibility for such a material are engineered large-pore protein crystals (LPCs). Here, various chemically stabilized LPC derived biomaterials were generated using three cross-linking agents: glutaraldehyde, oxaldehyde, and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide. LPC biostability and in vitro mammalian cytocompatibility was subsequently evaluated and compared to similarly cross-linked tetragonal hen egg white lysozyme crystals. This study demonstrates the ability of various cross-linking chemistries to physically stabilize the molecular structure of LPC materials-increasing their tolerance to challenging conditions while exhibiting minimal cytotoxicity. This approach produces LPC-derived biomaterials with promising utility for diverse applications in biotechnology and nanomedicine.

Hemocompatibility and Hemodynamics of Novel Hyaluronan-Polyethylene Materials for Flexible Heart Valve Leaflets.

Polymeric heart valves (PHVs) hold the promise to be more durable than bioprosthetic heart valves and less thrombogenic than mechanical heart valves. We introduce a new framework to manufacture hemocompatible polymeric leaflets for HV (PHV) applications using a novel material comprised of interpenetrating networks (IPNs) of hyaluronan (HA) and linear low density polyethylene (LLDPE). We establish and characterize the feasibility of the material as a substitute leaflet material through basic hemodynamic measurements in a trileaflet configuration, in addition to demonstrating superior platelet response and clotting characteristics. Plain LLDPE sheets were swollen in a solution of silylated-HA, the silylated-HA was then crosslinked to itself before it was reverted back to native HA via hydrolysis. Leaflets were characterized with respect to (1) bending stiffness, (2) hydrophilicity, (3) whole blood clotting, and (4) cell (platelet and leukocyte) adhesion under static conditions using fresh human blood. In vitro hemodynamic testing of prototype HA/LLDPE IPN PHVs was used to assess feasibility as functional HVs. Bending stiffness was not significantly different from natural fresh leaflets. HA/LLDPE IPNs were more hydrophilic than LLDPE controls. HA/LLDPE IPNs caused less whole blood clotting and reduced cell adhesion compared to the plain LLDPE control. Prototype PHVs made with HA/LLDPE IPNs demonstrated an acceptable regurgitation fraction of 4.77 ± 0.42%, and effective orifice area in the range 2.34 ± 0.5 cm2. These results demonstrate strong potential for IPNs between HA and polymers as future hemocompatible HV leaflets. Further studies are necessary to assess durability and calcification resistance.

Comparison of the mechanical behaviors of locked and nonlocked plate/screw fixation applied to experimentally induced rotational osteotomies in canine ilia.

OBJECTIVE: To compare the mechanical behaviors of 2 locked (parallel and diverging screws) and 1 nonlocked (NL) version of triple pelvic osteotomy (TPO) plate/screw fixation. STUDY DESIGN: In vitro biomechanical evaluation. ANIMALS: Cadaveric canine hemipelves. METHODS: Comparison 1-NL screws 20° TPO (NL-20) construct versus locked parallel (LP) screws 20° TPO (LP-20) construct (n = 7). Comparison 2-LP-20 construct versus locked diverging (LD) screws 20° TPO (LD-20) construct (n = 6). Condition 1-Nondestructive loading to determine stiffness. Condition 2-Cyclic loading to determine stiffness, screw loosening, and osteotomy gap displacement. Condition 3-Load to failure (yield load, yield displacement, maximum load, load to failure, failure mode). RESULTS: Stiffness was not significantly different for NL-20 versus LP-20 constructs (P = .48) or for LP-20 versus LD-20 constructs (P = .83). Screw loosening was significantly more frequent for NL-20 versus LP-20 (P = .01) and for LD-20 versus LP-20 constructs (P = .02). The relative risk for screw loosening with NL-20 constructs versus LP-20 constructs was 1.4 (95% CI: 1.1-1.8). The relative risk for screw loosening with LD-20 versus LP-20 was 1.6 (95% CI: 1.1-2.2). Yield load was significantly greater for LP-20 versus NL-20 and LD-20 constructs (P = .04, P = .03), respectively. CONCLUSIONS: No TPO constructs tested maintained complete integrity after cyclic loading; however, screw loosening was significantly reduced and yield loads were significantly larger for LP-20 plate/screw constructs.

Dynamic mechanical analysis and biomineralization of hyaluronan-polyethylene copolymers for potential use in osteochondral defect repair.

Treatment options for damaged articular cartilage are limited due to its lack of vasculature and its unique viscoelastic properties. This study was the first to fabricate a hyaluronan (HA)-polyethylene copolymer for potential use in the replacement of articular cartilage and repair of osteochondral defects. Amphiphilic graft copolymers consisting of HA and high-density polyethylene (HA-co-HDPE) were fabricated with 10, 28 and 50 wt.% HA. Dynamic mechanical analysis was used to assess the effect of varying constituent weight ratios on the viscoelastic properties of HA-co-HDPE materials. The storage moduli of HA-co-HDPE copolymers ranged from 2.4 to 15.0 MPa at physiological loading frequencies. The viscoelastic properties of the HA-co-HDPE materials were significantly affected by varying the wt.% of HA and/or crosslinking of the HA constituent. Cytotoxicity and the ability of the materials to support mineralization were evaluated in the presence of bone marrow stromal cells. HA-co-HDPE materials were non-cytotoxic, and calcium and phosphorus were present on the surface of the HA-co-HDPE materials 2 weeks after osteogenic differentiation of the bone marrow stromal cells. This study is the first to measure the viscoelastic properties and osseocompatibility of HA-co-HDPE for potential use in orthopedic applications.

Synthesis and characterization of a Hyaluronan-polyethylene copolymer for biomedical applications.

Hyaluronan (HA)-based biomaterials are of interest for bone and cartilage tissue engineering because HA plays an important role in orthopedic tissue development, function, and repair. The goal of this project was to develop a biomaterial that incorporated the constituents of both a hydrogel and a hydrophobic polymer for biomedical applications. A series of amphiphilic graft copolymers consisting of HA, a glycosaminoglycan, and high-density polyethylene (HDPE), that is, HA-co-HDPE, were fabricated. The chemical characteristics, physical and viscoelastic properties, and cytocompatibility of novel HA-co-HDPE materials were characterized via Fourier Transform infrared (FTIR) spectroscopy, solid state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), dynamic shear testing, and an in vitro human osteoblast cell study. The esterification reaction between HA and functionalized HDPE resulted in semicrystalline, insoluble powder. The dynamic shear properties of HA-co-HDPE concentrated solutions were more like natural proteoglycans than the HA control. HA-co-HDPE was successfully compression molded into disks that swelled upon hydration. Osteoblasts were viable and expressed the osteoblast phenotype after 7 days of culture on HA-co-HDPE materials. These HA-co-HDPE materials may have several biomaterial applications in saline suspension or molded form, including orthopedic tissue repair.

A novel ultra high molecular weight polyethylene-hyaluronan microcomposite for use in total joint replacements. II. Mechanical and tribological property evaluation.

The mechanical and tribological properties of a new biomaterial, an ultra high molecular weight polyethylene-hyaluronan (UHMWPE-HA) microcomposite, were investigated in this article, which is Part II of a two-part study. Part I presented the synthesis and physical/chemical characterization of the novel microcomposites. The microcomposite was developed for bearing surfaces of total joint replacements and was designed to enhance lubrication and improve wear resistance compared to noncrosslinked UHMWPE. Pin-on-flat wear tests with cross-path motion demonstrated significant decreases for both the wear and wear rate of UHMWPE with the presence of hyaluronan (HA) within and on the microcomposite. Compared to noncrosslinked UHMWPE, a maximum decrease of 56% in wear and a maximum decrease of 31% in wear rate were observed at 1.0 million cycles. Inferior tensile properties were observed for the microcomposites when compared to noncrosslinked UHMWPE, which resulted from poor intermolecular entanglement of the UHMWPE caused by low remolding temperature throughout microcomposite manufacturing. Similar results were observed for the sham control, which was processed in the same way as the microcomposite, except for the addition of HA.

Mechanical characteristics of cortical bone pins designed for fracture fixation.

Pins constructed from cortical bone may provide a reasonable alternative to other fracture-fixation devices by circumventing some of the complications associated with stainless steel and synthetic biodegradable implants. However, it is unknown whether cortical bone pins provide comparable strength compared to conventional pins. Using four-point bending, we compared the mechanical characteristics of 1.2-mm allogeneic cortical bone pins milled from specific regions of human tibiae and femora to commercially available 1.1-mm diameter stainless steel pins and 1.3-mm diameter polydioxanone pins. We used impact testing to identify mechanical differences in cortical bone pins between gender and harvest site. Cortical bone pins had better mechanical properties in four-point bending compared with polydioxanone pins, but not stainless steel pins. Pins milled from the right tibiae of males had the best bending characteristics. The mechanical performance of 1.2-mm cortical bone pins was comparable to those of stainless steel and polydioxanone pins regardless of site, bone, and gender. The clinical investigation of cortical bone pins as an implant for fracture fixation is warranted based on mechanical testing and comparison to commercially available polydioxanone and stainless steel pins.

A novel ultra high molecular weight polyethylene-hyaluronan microcomposite for use in total joint replacements. I. Synthesis and physical/chemical characterization.

A novel microcomposite between ultra high molecular weight polyethylene (UHMWPE) and hyaluronan (HA) was developed to create a hydrophilic and lubricious UHMWPE surface for total joint replacement and other biomedical load-bearing applications. Preforms with interconnected micropores were used as the UHMWPE starting material to form a microcomposite with HA, rather than starting with fully dense, bulk UHMWPE. HA was silylated first to increase its hydrophobicity and compatibility with UHMWPE. The silylated groups were removed through hydrolysis prior to final compression molding. A uniform and enzymatic degradation resistant HA film layer was produced on the microcomposite surface, which quickly hydrated in water, forming a lubricious surface film that was fully wetted by water drops during contact angle measurements. Presence of HA film on the composite surface was also demonstrated through X-ray photoelectron spectroscopy analysis and Toluidine Blue O dye assay. The mechanical and tribological properties evaluation of the novel microcomposites are presented in Part II.

Evaluation of subchondral bone mineral density associated with articular cartilage structure and integrity in healthy equine joints with different functional demands.

OBJECTIVE: To determine and correlate subchondral bone mineral density and overlying cartilage structure and tensile integrity in mature healthy equine stifle (low magnitude loading) and metacarpophalangeal (high magnitude loading) joints. ANIMALS: 8 healthy horses, 2 to 3 years of age. PROCEDURE: Osteochondral samples were acquired from the medial femoral condyle (FC) and medial trochlear ridge (TR) of the stifle joint and from the dorsal (MC3D) and palmar (MC3P) aspects of the distal medial third metacarpal condyles of the metacarpophalangeal joint. Articular cartilage surface fibrillation (evaluated via India ink staining) and tensile biomechanical properties were determined. The volumetric bone mineral density (vBMD) of the underlying subchondral plate was assessed via dual-energy x-ray absorptiometry. RESULTS: Cartilage staining (fibrillation), tensile moduli, tensile strength, and vBMD were greater in the MC3D and MC3P locations, compared with the FC and TR locations, whereas tensile strain at failure was less in MC3D and MC3P locations than FC and TR locations. Cartilage tensile moduli correlated positively with vBMD, whereas cartilage staining and tensile strain at failure correlated negatively with vBMD. CONCLUSIONS AND CLINICAL RELEVANCE: In areas of high joint loading, the subchondral bone had high vBMD and the articular cartilage surface layer had high tensile stiffness but signs of structural wear (fibrillation and low failure strain). The site-dependent variations and relationships in this study support the concept that articular cartilage and subchondral bone normally adapt to physiologic loading in a coordinated way.

Assessing the dog as a model for human total hip replacement: analysis of 38 postmortem-retrieved canine cemented acetabular components.

Thirty-eight cemented acetabular components that had been clinically implanted in client-owned dogs were retrieved postmortem and analyzed for mechanical stability, volumetric wear, and articular surface damage. Comparison of the results from this study with similar studies on autopsy-retrieved human components will provide insight into the adequacy of the dog as a model for human total hip replacement (THR). The canine average volumetric wear rate (6.7 +/- 4.2 mm(3) per year) was an order of magnitude lower than similar studies of human components; however, articular surface damage was considerably different from, and more severe than, that reported in the literature for human acetabular components. The incidence of mechanical loosening of the canine acetabular component was high, with 20 of 38 (52.6%) testing as loose. There was a positive correlation between articular surface damage and mechanical loosening of the acetabular component, but there was no significant correlation between volumetric wear and mechanical loosening, as seen in human retrieval studies. Initial failure events for the canine acetabular component appear to be mechanical in nature. Differences between human and canine acetabular components with regard to wear volume, articular surface damage, and mechanical loosening need to be taken into account when one is designing studies using dogs as the animal model for human THR.

Surface modification of UHMWPE for use in total joint replacements.

To create a hydrophilic, lubricious, more wear-resistant UHMWPE bearing, a novel hyaluronan (HA) derivative and novel UHMWPE-hyaluronan composite were developed. HA was silylated to increase its hydrophobicity and compatibility with UHMWPE. The sily1 HA rapidly diffused into the connected pores of UHMWPE preforms in xylenes solution, and fixed within UHMWPE and on its surface after crosslinking. A micro-composite was obtained after hot-pressing the porous preform. The presence of HA film on the composite surface has been demonstrated through X-Ray photoelectron spectroscopy (XPS) analysis and Toluidine Blue O (TBO) dye assay. The aqueous contact angles of micro-composite samples were significantly lower compared with UHMWPE control samples, and the samples processed with hydrolysis prior to final molding were superior to those processed with hydrolysis after molding.

Novel hyaluronan esters for biomedical applications.

A series of novel hyaluronan (HA) esters with aliphatic chains of different length were synthesized. A silylated complex of HA with cetyltrimethylammonium cations (silyl HA-CTA) was used as the starting material. The reactions were performed in xylenes or no solvent with acid chlorides as the acylation agents. The disappearance of all characteristic FT-IR vibration bands associated with the -OSi(CH3)3 groups and the appearance of the strong ester carbonyl peak at 1753 cm-1 demonstrated the success of esterification. Thermoplasticity was achieved with HA esters of high aliphatic acids. It was found that the longer the ester chain, the lower the melting points, so different melting temperatures can be obtained by adjusting the acid chloride chain length to meet various needs.

Postmortem retrieved canine THR: femoral and acetabular component interaction.

Dogs are the preferred animal model for testing of human total hip replacements (THRs). A postmortem retrieval program for clinical, cemented, canine THR was established to analyze the long-term performance of THRs in dogs and to compare that performance to postmortem retrievals of human THRs. The purpose of the present study was to analyze the interaction between the femoral and acetabular components. Thirty-eight postmortem retrievals from 29 dogs were donated and analyzed. The acetabular components (ACs) were measured for volumetric wear and graded for articulating surface damage. Femoral and acetabular components were mechanically tested for implant stability. Digital image analysis was performed on contact radiographs of transverse femoral slices. Of 14 cases with a firmly implanted femoral component (FC). 6 articulated against loose ACs. Of 24 cases with a loose FC, 16 articulated against loose ACs. Only 4 specimens had both components firmly implanted, and 14 specimens had both components loose. There was a significant positive correlation between AC volumetric wear and FC loosening; however, there was no evidence of osteolysis or wear debris induced osteolysis as seen in human postmortem retrieval studies. There was a significant but weak negative correlation between FC loosening at the cement/bone interface and AC scores reflecting damage to the rim and creep across the entire AC. Although implant-on-implant damage to the AC was expected to positively correlate with FC loosening, this was not found. Researchers need to look at interactions between AC and FC to understand how the failure of one component affects performance of the other.