Gavin J. C. Braithwaite

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/cm²) 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. 3.02P< 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.

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.

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. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 106–115, 2015.

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.

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 P 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.