A novel approach for reducing ischemic mitral regurgitation by injection of a polymer to reverse remodel and reposition displaced papillary muscles.

BACKGROUND: Ischemic mitral regurgitation (MR) relates to displacement of the papillary muscles from ischemic ventricular distortion. We tested the hypothesis that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) polymer, a biologically inert biomaterial that has been specially formulated to produce an encapsulated, stable, resilient gel once injected into the myocardium. The purpose is to materially support the infarcted myocardium while at the same time repositioning the papillary muscles that become apically tethered in MR. METHODS AND RESULTS: Nine sheep underwent ligation of circumflex branches to produce acute ischemic MR. PVA polymer was then injected by echo guidance into the myocardium underlying the infarcted papillary muscle. Hemodynamic data, left ventricular ejection fraction, elastance, tau (relaxation constant), left ventricular stiffness coefficient, and 2-dimensional and 3-dimensional echocardiograms were obtained post-MR and post-PVA injection. One animal died after coronary ligation and 2 did not develop MR. In the remaining 6, moderate MR developed. With PVA injection, the MR decreased significantly from moderate to trace-mild (vena contracta: 5+/-0.4 mm versus 2+/-0.7 mm, post-MR versus post-PVA injection; P<0.0001). This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (27+/-4 to 24+/-4 mm, post-MR versus post-PVA, P<0.001). Importantly, PVA injection was not associated with significant decreases in left ventricular ejection fraction (43+/-6% versus 37+/-4%, post-MR versus post-PVA, P=nonsignificant), elastance (3.5+/-1.4 versus 2.9+/-1.3; post-MR versus post-PVA injection, P=nonsignificant). Measures of left ventricular diastolic function, tau (100+/-51 ms to 84+/-37 ms, post-MR versus post-PVA; P=nonsignificant), and left ventricular stiffness coefficient (0.18+/-0.12 versus 0.14+/-0.08, post-MR versus post-PVA; P=nonsignificant) did not increase post-PVA. CONCLUSIONS: PVA polymer injection resulted in acute reverse remodeling of the ventricle with papillary muscle repositioning to decrease MR. This was not associated with an adverse effect on left ventricular systolic and diastolic function. This new approach to alter pathological anatomy after infarction may offer an alternative strategy for relieving ischemic MR by correcting the position of the affected papillary muscle, thus relieving apical tethering.

The effect of polyethylene glycol on the stability of pores in polyvinyl alcohol hydrogels during annealing.

Poly(vinyl alcohol) (PVA) hydrogels are candidate biomaterials for cartilage resurfacing or interpositional arthroplasty devices requiring high-creep resistance and high water content to maintain lubricity. Annealing of PVA improves creep resistance but also reduces the water content. We hypothesized that maintaining poly(ethylene glycol) (PEG) within PVA during annealing would prevent the collapse of the pores and thus would result in high equilibrium water content (EWC). Our hypothesis tested positive. The PVA hydrogels containing PEG maintained their opacity through annealing and exhibited large pores under confocal imaging while hydrogels not containing PEG turned translucent and no pores were visible after annealing. The EWC of gels annealed with PEG (83 +/- 1.0%) was higher than that of the gels processed without PEG (55 +/- 4.8). The crystallinity of the former was 8.0 +/- 1.7% and the latter was 27.5 +/- 8.7%. The hydrogels processed in the presence of PEG exhibited a significantly higher total creep strain (69 +/- 3.4%) when compared to the PEG-free hydrogels (17 +/- 3.7) under an initial contact stress of 0.45 MPa. EWC appeared to be strongly related to the creep resistance of annealed PVA theta-gels.

Application of polymer-mesh device to remodel left ventricular-mitral valve apparatus in ischemic mitral regurgitation.

OBJECTIVES: Ischemic mitral regurgitation (IMR) results from ischemic left ventricular (LV) distortion and remodeling, which displaces the papillary muscles and tethers the mitral valve leaflets apically. The aim of this experimental study was to examine efficacy of an adjustable novel polymer filled mesh (poly-mesh) device to reverse LV remodeling and reduce IMR. METHODS: Acute (N = 8) and chronic (8 weeks; N = 5) sheep models of IMR were studied. IMR was produced by ligation of circumflex branches to create myocardial infarction. An adjustable poly-mesh device was attached to infarcted myocardium in acute and chronic IMR models and compared with untreated sham sheep. Two- and 3-dimensional echocardiography and hemodynamic measurements were performed at baseline, post IMR, and post poly-mesh (humanely killed). RESULTS: In acute models, moderate IMR developed in all sheep and decreased to trace/mild (vena contracta: 0.50 ± 0.09 cm to 0.26 ± 0.12 cm; P < .01) after poly-mesh. In chronic models, IMR decreased in all sheep after poly-mesh, and this reduction persisted over 8 weeks (vena contracta: 0.42 ± 0.09 cm to 0.08 ± 0.12 cm; P < .01) with significant increase in the slope of end-systolic pressure-volume relationship (1.1 ± 0.5 mm Hg/mL to 2.9 ± 0.7 mm Hg/mL; P < .05). There was a significant reduction in LV volumes from chronic IMR to euthanasia stage with poly-mesh compared with sham group (%end-diastolic volume change -20 ± 11 vs 15% ± 16%, P < .01; %end-systolic volume change -14% ± 19% vs 22% ± 22%, P < .05; poly-mesh vs sham group) consistent with reverse remodeling. CONCLUSIONS: An adjustable polymer filled mesh device reduces IMR and prevents continued LV remodeling during chronic follow-up.

Corneal Cross-Linking With Verteporfin and Nonthermal Laser Therapy.

PURPOSE: To test whether verteporfin with a nonthermal laser increases corneal mechanical stiffness and resistance to enzymatic degradation ex vivo. METHODS: Thirty human corneas (n = 5 per group) were treated with verteporfin alone (V), irradiated with nonthermal laser therapy (689 nm) alone (NTL), or received combined treatment of verteporfin with nonthermal laser therapy for 1 sequence (V+NTL1) or 6 sequences (V+NTL6) of 1 minute of NTL exposure. Positive controls were pretreated with 0.1% riboflavin/20% dextran every 3 to 5 minutes for 30 minutes and irradiated with ultraviolet light type A (λ = 370 nm, irradiance = 3 mW/cm) for 30 minutes using the Dresden protocol (R+UVA). Untreated corneas were used as negative controls. The corneal biomechanical properties were measured with enzymatic digestion, compression, creep, and tensile strength testing. RESULTS: V+NTL6- and R+UVA-treated corneas acquired higher rigidity and more pronounced curvature than untreated corneas. The stress-strain tests showed that V+NTL6 and R+UVA corneas became significantly stiffer than controls (P < 0.005). The V+NTL6 group seemed to be slightly stiffer than the R+UVA group, although the differences were not statistically significant. V+NTL6 corneas were found to have a significantly lower absolute creep rate (-1.87 vs. -3.46, P < 0.05) and significantly higher maximum stress values (7.67 vs. 3.02 P < 0.05) compared with untreated corneas. CONCLUSIONS: Verteporfin-NTL (V+NTL6) increases corneal mechanical stiffness and resistance to enzymatic collagenase degradation. Although a clinical study is needed, our results suggest that V+NTL6 induces corneal cross-linking and corneal biomechanical changes that are similar to those induced by standard corneal collagen cross-linking.

Rheological and molecular weight comparisons of approved hyaluronic acid products - preliminary standards for establishing class III medical device equivalence.

Hyaluronic acid of various molecular weights has been in use for the treatment of osteoarthritis knee pain for decades. Worldwide, these products are regulated as either as drugs or devices and in some countries as both. In the US, this class of products is regulated as Class III medical devices, which places specific regulatory requirements on developers of these materials under a Pre-Market Approval process, typically requiring data from prospective randomized controlled clinical studies. In 1984 pharmaceutical manufacturers became able to file an Abbreviated New Drug Application for approval of a generic drug, thus establishing standards for demonstrating equivalence to an existing chemical entity. Recently, the first biosimilar, or 'generic biologic', was approved. Biosimilars are biological products that are approved by the FDA because they are 'highly similar' to a reference product, and have been shown to have no clinically meaningful differences from the reference product. For devices, Class II medical devices have a pathway for declaring equivalence to an existing product by filing a 510 k application for FDA clearance. However, until recently no equivalent regulatory pathway was available to Class III devices. In this paper, we consider the critical mechanical performance parameters for intra-articular hyaluronic products to demonstrate indistinguishable characteristics. Analogous to the aforementioned pathways that allow for a demonstration of equivalence, we examine these parameters for an existing, marketed device and compare molecular weight and rheological properties of multiple batches of a similar product. We propose that this establishes a scientific rationale for establishing Class III medical device equivalence.

Quantifying the lubricity of mechanically tough polyvinyl alcohol hydrogels for cartilage repair.

Polyvinyl alcohol hydrogels are biocompatible and can be used as synthetic articular cartilage. Their mechanical characteristics can be tailored by various techniques such as annealing or blending with other hydrophilic polymers. In this study, we quantified the coefficient of friction of various candidate polyvinyl alcohol hydrogels against cobalt-chrome alloy or swine cartilage using a new rheometer-based method. We investigated the coefficient of friction of polyvinyl alcohol-only hydrogels and blends with polyethylene glycol, polyacrylic acid, and polyacrylamide against swine cartilage and polished cobalt-chrome surfaces. The addition of the functional groups to polyvinyl alcohol, such as acrylamide (semi-interpenetrating network) and acrylic acid (blend), significantly reduced the coefficient of friction. The coefficient of friction of the polyvinyl alcohol-only hydrogel was measured as 0.4 ± 0.03 against cobalt-chrome alloy, and 0.09 ± 0.004 against cartilage, while those measurements for the polyvinyl alcohol-polyacrylic acid blends and polyvinyl alcohol-polyacrylamide semi-interpenetrating network were 0.07 ± 0.01 and 0.1 ± 0.003 against cobalt-chrome alloy, and 0.03 ± 0.001 and 0.02 ± 0.001 against cartilage, respectively. There was no significant or minimal difference in the coefficient of friction between samples from different regions of the knee, or animals, or when the cartilage samples were frozen for 1 day or 2 days before testing. However, changing lubricant from deionized water to ionic media, for example, saline or simulated body fluid, increased the coefficient of friction significantly.

Oxidative-induction time as a measure of vitamin E concentration in ultra-high molecular weight polyethylene.

A novel, sensitive method for quantifying an equivalent antioxidant concentration, specifically vitamin E (VE), in postprocessed ultra-high molecular weight polyethylene (UHMWPE) for orthopedic implants is presented. This method correlates oxidative-induction time (OIT) determined from differential scanning calorimetry with starting VE weight percent in solvent blended samples using a nonlinear power law fit. The generated calibration curve reliably determined the equivalent VE concentration down to blended concentrations lower than 0.007 wt %, with a measurement uncertainty of 0.0009 wt %. This measurement uncertainty implies a detection limit that is significantly lower than currently achievable with the established method using Fourier transform infrared spectroscopy to calculate a VE index. However, exact processes that are influencing the OIT in irradiated materials are unclear at this time. UHMWPE blended with VE in powder, consolidated and irradiated form were investigated. In addition, intralaboratory results give support that this technique may lend itself to standardization in quality control and verification.

Efficacy of polymer injection for ischemic mitral regurgitation: persistent reduction of mitral regurgitation and attenuation of left ventricular remodeling.

OBJECTIVES: The aim of this study was to examine the chronic effects of polyvinyl-alcohol (PVA) injection on mitral regurgitation (MR) reduction, mitral valve geometry, and left ventricular (LV) remodeling in a chronic ischemic MR sheep model. BACKGROUND: Previous studies have demonstrated acute efficacy of PVA hydrogel polymer injection into infarcted myocardium underlying the papillary muscle to relieve MR by papillary muscle repositioning. However, the chronic efficacy of PVA injection in the chronic infarction setting remains unclear. METHODS: Sixteen sheep developed chronic MR 8 weeks after induced inferoposterior myocardial infarction. Ten consecutive sheep underwent PVA injection (PVA group) and 6 sheep served as control subjects with saline injection. Epicardial 2-/3-dimensional echocardiography was performed at the baseline, chronic MR (pre-injection), and sacrifice (8 weeks after injection) stages. RESULTS: Both groups were comparable at the baseline and chronic MR stages. At sacrifice, MR decreased from moderate to trace or mild (vena contracta: 0.17 ± 0.08 cm vs. 0.56 ± 0.10 cm, p < 0.001) in the PVA group but progressed to moderate to severe in the control group. End-systolic and -diastolic volumes remained stable in the PVA group but increased significantly in the control group (both p < 0.05). At sacrifice, compared with the control group, the PVA group had significantly less left ventricular remodeling (end-systolic volume: 41.1 ± 10.4 ml vs. 55.9 ± 12.4 ml, p < 0.05), lower MR severity (vena contracta: 0.17 ± 0.08 cm vs. 0.60 ± 0.14 cm, p < 0.01), and favorable changes in mitral valve geometry. CONCLUSIONS: Polymer injection in a chronic ischemic MR model results in persistent reduction of MR and attenuation of continued left ventricular remodeling over 8 weeks of follow-up.

Polymer injection therapy to reverse remodel the papillary muscles: efficacy in reducing mitral regurgitation in a chronic ischemic model.

BACKGROUND: Ischemic mitral regurgitation (MR) results from displacement of the papillary muscles caused by ischemic ventricular distortion. Progressive left ventricular (LV) remodeling has challenged therapy. Our hypothesis is that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) hydrogel polymer into the myocardium in chronic MR despite advanced LV remodeling. METHODS AND RESULTS: Ten sheep underwent ligation of the circumflex branches to produce chronic ischemic MR over 8 weeks. PVA was injected into the myocardium underlying the infarcted papillary muscle. Two-dimensional and 3D echocardiograms and hemodynamic data were obtained before infarct (baseline), before PVA (chronic MR), and after PVA. PVA injection significantly decreased MR from moderate to severe to trace (MR vena contracta, 5.8±1.2 to1.8±1.3 mm; chronic MR to post-PVA stage; P=0.0003). This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (30.3±5.7 to 25.9±4.6 mm, P=0.02), tenting volume (1.8±0.7 to 1.4±0.5 mL, P=0.01), and leaflet closure area (8.8±1.3 cm(2)to 7.6±1.3 cm(2), P=0.004) from chronic MR to post-PVA stages. PVA was not associated with significant decreases in LV ejection fraction (41±3% versus 40±3%, P=NS), end-systolic elastance, τ (82±36 ms to 72±26, P=NS), or LV stiffness coefficient (0.05±0.04 to 0.03±0.01). CONCLUSIONS: PVA hydrogel injections improve coaptation and reduce remodeling in chronic MR without impairing LV systolic and diastolic function. This new approach offers a potential alternative for relieving tethering and ischemic MR by correcting papillary muscle position.