Electrical stimulation via repeated biphasic conducting materials for peripheral nerve regeneration.

Improved materials for peripheral nerve repair are needed for the advancement of new surgical techniques in fields spanning from oncology to trauma. In this study, we developed bioresorbable materials capable of producing repeated electric field gradients spaced 600 µm apart to assess the impact on neuronal cell growth, and migration. Electrically conductive, biphasic composites comprised of poly (glycerol) sebacate acrylate (PGSA) alone, and doped with poly (pyrrole) (PPy), were prepared to create alternating segments with high and low electrically conductivity. Conductivity measurements demonstrated that 0.05% PPy added to PSA achieved an optimal value of 1.25 × 10-4 S/cm, for subsequent electrical stimulation. Tensile testing and degradation of PPy doped and undoped PGSA determined that 35-40% acrylation of PGSA matched nerve mechanical properties. Both fibroblast and neuronal cells thrived when cultured upon the composite. Biphasic PGSA/PPy sheets seeded with neuronal cells stimulated for with 3 V, 20 Hz demonstrated a 5x cell increase with 1 day of stimulation and up to a 10x cell increase with 3 days stimulation compared to non-stimulated composites. Tubular conduits composed of repeated high and low conductivity materials suitable for implantation in the rat sciatic nerve model for nerve repair were evaluated in vivo and were superior to silicone conduits. These results suggest that biphasic conducting conduits capable of maintaining mechanical properties without inducing compression injuries while generating repeated electric fields are a promising tool for acceleration of peripheral nerve repair to previously untreatable patients.

Metastatic Merkel cell carcinoma presenting as an orbital mass.

A 67-year-old female presented with 2 weeks of right eye pain, redness, and diplopia. An orbital mass was found on magnetic resonance imaging (MRI), and biopsy revealed Merkel cell carcinoma (MCC). She had no primary head or neck lesion and no previous history of MCC. Positron emission tomography (PET) scan showed hypermetabolic subcutaneous lesions of the lower extremity andmultiple osseous lesions of the axial and appendicular skeleton. She received palliative external radiation of 20 Gy in 5 fractions to the orbit. After discussing immunotherapy, she opted for comfort care and expired 1 month later. To the best of our knowledge, this is only the third case of MCC with distant metastasis to the orbit and the first case in which the patient had no previous diagnosis of MCC and no known primary tumor.

Composite engineered biomaterial adaptable for repair and regeneration of wounds.

Ongoing investigations in wound repair bring new opportunities and challenges for creating novel composite engineered biomaterials. Efforts have been directed toward using different combinations of biomaterials with the goal of providing an ideal biomimetic substitute for native tissue. A universal formula using collagen, fibroin and a synthetic polymer is proposed. By modifying the ratio of the building blocks, the composite material can be fabricated to match the mechanical property of different types of tissues and be further tuned to carry desirable physical and biological function. The results should provide composite engineered materials comparable to native tissue in order to repair and regenerate a variety of wounds and tissues.

A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination.

BACKGROUND: New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. METHODS: In the phase I portion of this phase I/II study, non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals. Inc., Clemmons, NC) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary endpoint was the recommended phase II dosing regimen. RESULTS: The cohort (n = 14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2-29.7) months, median age of 61 years, and median Gleason score of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (five metastatic, one rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose-limiting toxicities led to the selection of 4,000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, P = 0.17). No patients experienced a maintained decline in serum PSA from baseline. CONCLUSION: These data suggest that 4,000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low-dose (500 mg) and high-dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial.

Syndecan-4 Functionalization Reduces the Thrombogenicity of Engineered Vascular Biomaterials.

Blood-biomaterial compatibility is essential for tissue repair especially for endovascular biomaterials where small-diameter vessel patency and endothelium formation is crucial. To address this issue, a composite biomaterial termed PFC fabricated from poly (glycerol sebacate), silk fibroin, and collagen was used to determine if functionalization with syndecan-4 (SYN4) would reduce thrombogenesis through the action of heparan sulfate. The material termed, PFC_SYN4, has structure and composition similar to native arterial tissue and has been reported to facilitate the binding and differentiation of endothelial colony-forming cells (ECFCs). In this study, the hemocompatibility of PFC_SYN4 was evaluated and compared with non-functionalized PFC, electrospun collagen, ePTFE, and bovine pericardial patch (BPV). Ultrastructurally, platelets were less activated when cultured on PFC and PFC_SYN4 compared to collagen where extensive platelet degranulation was observed. Quantitatively, 31% and 44% fewer platelets adhered to PFC_SYN4 compared to non-functionalized PFC and collagen, respectively. Functionalization of PFC resulted in reduced levels of complement activation compared to PFC, collagen, and BPV. Whole blood clotting times indicated that PFC_SYN4 was less thrombogenic compared with PFC, collagen, and BPV. These results suggest that syndecan-4 functionalization of blood-contacting biomaterials provides a novel solution for generating a reduced thrombogenic surface.

Syndecan-4 and stromal cell-derived factor-1 alpha functionalized endovascular scaffold facilitates adhesion, spreading and differentiation of endothelial colony forming cells and functions under flow and shear stress conditions.

Acellular vascular scaffolds with capture molecules have shown great promise in recruiting circulating endothelial colony forming cells (ECFCs) to promote in vivo endothelialization. A microenvironment conducive to cell spreading and differentiation following initial cell capture are key to the eventual formation of a functional endothelium. In this study, syndecan-4 and stromal cell-derived factor-1 alpha were used to functionalize an elastomeric biomaterial composed of poly(glycerol sebacate), Silk Fibroin and Type I Collagen, termed PFC, to enhance ECFC-material interaction. Functionalized PFC (fPFC) showed significantly greater ECFCs capture capability under physiological flow. Individual cell spreading area on fPFC (1474 ± 63 µm2 ) was significantly greater than on PFC (1187 ± 54 µm2 ) as early as 2 h, indicating enhanced cell-material interaction. Moreover, fPFC significantly upregulated the expression of endothelial cell specific markers such as platelet endothelial cell adhesion molecule (24-fold) and Von Willebrand Factor (11-fold) compared with tissue culture plastic after 7 days, demonstrating differentiation of ECFCs into endothelial cells. fPFC fabricated as small diameter conduits and tested using a pulsatile blood flow bioreactor were stable and maintained function. The findings suggest that the new surface functionalization strategy proposed here results in an endovascular material with enhanced endothelialization.

Orbital Wall Fractures and Ocular Injury: Impact on Management.

Background: Orbital wall fractures are often associated with concomitant ocular injury. In some cases, detection and treatment of such injuries requires ophthalmology evaluation. Study Objective: To identify a change in ocular management as a result of ophthalmology evaluation in patients with orbital wall fractures. Materials and Methods: Retrospective cohort, patients >18 years of age with orbital wall fracture, and prompt evaluation by an ophthalmologist from 2012 to 2020 in a tertiary Level 1 trauma center. Results: Fifty percent of patients had a moderate and/or severe ocular injury. Ophthalmology evaluation led to an ocular management change in 27% of patients. Patients with eyelid laceration, extra-ocular motion (EOM) abnormality, and pupillary defect were more likely to have a change in management. There was no delay of surgical bony fracture management. Conclusion: In patients with midface trauma including orbital wall fractures those with eyelid laceration, EOM abnormality, and pupillary defect were likely to undergo ocular management change as a result of ophthalmology consultation.

Syndecan-4 functionalization of tissue regeneration scaffolds improves interaction with endothelial progenitor cells.

Key to most implanted cell free scaffolds for tissue regeneration is the ability to sequester and retain undifferentiated mesenchymal stem cells at the repair site. In this report, syndecan-4, a heparan sulfate containing proteoglycan, was investigated as a unique molecule for use in scaffold functionalization. An electrospun hybrid scaffold comprised of poly (glycerol) sebacate (PGS), silk fibroin and type I collagen (PFC) was used as a model scaffold to develop a procedure and test the hypothesis that functionalization would result in increased scaffold binding of endothelial progenitor cells (EPCs). For these studies both Syndecan-4 and stromal derived factor-1α (SDF-1α) were used in functionalization PFC. Syndecan-4 functionalized PFC bound 4.8 fold more SDF-1α compared to nonfunctionalized PFC. Binding was specific as determined by heparin displacement studies. After culture for 7 days, significantly, more EPCs were detected on PFC scaffolds having both syndecan-4 and SDF-1α compared to scaffolds of PFC with only syndecan-4, or PFC adsorbed with SDF-1α, or PFC alone. Taken together, this study demonstrates that EPCs can be bound to and significantly expanded on PFC material through syndecan-4 mediated growth factor binding. Syndecan-4 with a multiplicity of binding sites has the potential to functionalize and expand stem cells on a variety of scaffold materials for use in tissue regeneration.

Interaction of material stiffness and negative pressure to enhance differentiation of bone marrow-derived stem cells and osteoblast proliferation.

Negative pressure wound therapy (NPWT) results in improved wound repair and the combined use of NPWT with elastomeric materials may further stimulate and accelerate tissue repair. No firmly established treatment modalities using both NPWT and biomaterials exist for orthopedic application. The goal of this study was to investigate the response of osteoblasts and bone marrow-derived mesenchymal stem cells to negative pressure and to determine whether a newly developed elastic osteomimetic bone repair material (BRM), a blend of type I collagen, chondroitin 6-sulfate, and poly (octanediol citrate) could enhance the osteoblastic phenotype. The results indicate that proliferation and alkaline phosphatase activity of hFOB1.19 osteoblasts were significantly increased with exposure to 12 hr of negative pressure (-125 mmHg). Follow-on studies with rat and human mesenchymal stem cells confirmed that negative pressure enhanced osteoblastic maturation. In addition, a significant interaction of negative pressure and electrospun BRM resulted in increased mRNA expression of alkaline phosphatase, osteopontin, collagen1α2, and HIF1α, whereas little or no effect on these genes was observed on electrospun collagen or tissue culture plastic. Together, these results suggest that the use of this novel biomaterial, BRM, with NPWT may ultimately translate into a safe and cost-effective clinical application to accelerate bone repair.

A paradigm shift in eye banking: how new models are challenging the status quo.

This article presents a fact-based, direct approach in order to evaluate the strengths and short comings of both local eye banks and larger companies that have penetrated the market of eye donation. By taking a non-biased approach to the topic, the goal of this article is to create a platform, which furthers the discussion. We focus on SightLife and CorneaGen as well as local eye banks and how their models differ in terms of tissue procurement, distribution, and surgeon partnership.

Astigmatic correction with implantation of a light adjustable vs monofocal lens: a single site analysis of a randomized controlled trial.

AIM: To evaluate the light adjustable lens (LAL) vs a standard monofocal lens in achieving target astigmatic refraction and improving postoperative uncorrected distance visual acuity (UDVA). METHODS: This randomized controlled clinical trial included 40 patients with pre-existing astigmatism and visually significant cataract. Twenty-eight patients received the LAL and 12 control patients received a monofocal intraocular lens (IOL) after cataract extraction at a single institution. The patients with the LAL underwent adjustment by ultraviolet (UV) light postoperatively plus subsequent lock-in procedures and all patients returned to clinic for follow up of study parameters at 6, 9, and 12mo. Manifest refraction, distance visual acuity, and adverse events were recorded at each visit. RESULTS: The mean cylinder before adjustment in eyes with the LAL was -0.89±0.58 D (-2.00 to 0.00 D) and -0.34±0.34 D (-1.25 to 0.00 D) after lock-in (P=1.68x10-8). The mean cylinder in patients with the monofocal lens was -1.00±0.32 D (-1.50 to -0.50 D) at 17-21d postoperatively, which was statistically different from the LAL cylinder post lock-in (P=1.43x10-6). UDVA in the LAL group was 20/20 or better in 79% of patients post lock-in with good stability over 12mo compared with 33% of the control patients with UDVA of 20/20 or better. CONCLUSION: These results demonstrate that the LAL is more effective in achieving target refractions and improving postoperative UDVA in patients with pre-existing corneal astigmatism than a standard monofocal lens.

Muscadine grape skin extract inhibits prostate cancer cells by inducing cell-cycle arrest, and decreasing migration through heat shock protein 40.

Previously we demonstrated that muscadine grape skin extract (MSKE), a natural product, significantly inhibited androgen-responsive prostate cancer cell growth by inducing apoptosis through the targeting of survival pathways. However, the therapeutic effect of MSKE on more aggressive androgen-independent prostate cancer remains unknown. This study examined the effects of MSKE treatment in metastatic prostate cancer using complementary PC-3 cells and xenograft model. MSKE significantly inhibited PC-3 human prostate cancer cell tumor growth in vitro and in vivo. The growth-inhibitory effect of MSKE appeared to be through the induction of cell-cycle arrest. This induction was accompanied by a reduction in the protein expression of Hsp40 and cell-cycle regulation proteins, cyclin D1 and NF-kBp65. In addition, MSKE induced p21 expression independent of wild-type p53 induced protein expression. Moreover, we demonstrate that MSKE significantly inhibited cell migration in PC-3 prostate cancer cells. Overall, these results demonstrate that MSKE inhibits prostate tumor growth and migration, and induces cell-cycle arrest by targeting Hsp40 and proteins involved in cell-cycle regulation and proliferation. This suggests that MSKE may also be explored either as a neo-adjuvant or therapeutic for castration resistant prostate cancer.

Fabrication of biodegradable foams for deep tissue negative pressure treatments.

Devices for negative pressure wound therapy (NPWT) rely on compressible foams operating at the tissue-device interface. Clinically used foams are nonabsorbable and if used on deep wounds or left in place for an extended period of time, excessive cell ingrowth and formation of granulation tissue into the foam may require a surgical procedure to remove the foam. Foams with fast degradation and with low immunogenicity and fibrotic response are required. Foams composed of combinations of poly(lactide-co-glycolide) (PLGA), poly(lactide-co-caprolactone) (PLCL), and polycaprolactone (PCL) were created by combined salt leaching and solvent displacement protocols. In vitro and in vivo degradation studies and mechanical properties of foams were evaluated and compared to clinically used poly(vinyl alcohol) (PVA) foam and PCL foams. Foams composed of PLGA (50:50 lactide:glycolide) of low molecular weight blended with PCL maintained mechanical properties and degraded significantly after 21 days of subcutaneous implantation in rats. The most ideal formulations for use in NPWT were identified as copolymeric PLGA (Mn 3000 Da) at a lactide:glycolide ratio of 50:50 combined with PCL at either a 75:25 or 50:50 ratio, and copolymeric PLGA (Mn 7500 Da) at a lactide:glycolide ratio of 50:50 combined with PCL at a 50:50 ratio. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1998-2007, 2018.

Transgender Corneal Donors: A Dilemma Worthy of Attention.

Currently, there are no specific guidelines in place to direct eye banks on how to deal with donated tissue from transgender individuals. This commentary will examine the history of corneal transplantation and the importance of the corneal tissue donor. In doing so, the donor selection criteria established by the Food and Drug Administration will be presented. Additionally, the history of blood donor deferral policies created for men who have sex with men and how those policies have changed over time will be explored. We provide an evidence-based framework for potential guidelines regarding the transgender population and eye tissue donation.

Muscadine Grape Skin Extract (MPX) in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial.

Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy.Experimental Design: This was a 12-month, multicenter, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics.Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7-83.1), low dose 1.5 months (n = 52; range, 10.3-87.2), high dose 0.9 months (n = 40; range, 27.3-88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25).Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306-15. ©2017 AACR.

Artery regional properties and atherosclerosis susceptibility.

White carneau (WC) pigeons develop spontaneous atherosclerosis in contrast to atherosclerosis-resistant show racer (SR) pigeons. In this study, cellular and extracellular components and smooth muscle cell (SMC) proliferation rates of specific aortic sites were assessed in both breeds of pigeons prior to lesion development. The atherosclerosis-susceptible site of the WC aorta was characterized by larger lumen diameter without accompanying increase in wall thickness, as well as by SMC hypocellularity, increased proteoglycan content and higher elastin content. For both breeds, cells derived from the lesion site had lower proliferation rates compared to proximal aortic control sites. WC cells had greater proliferation rates than SR cells (109% greater at the atherosclerosis-prone site and 133% greater at the control site). Fibroblast growth factor (FGF) increased the proliferation of WC lesion site cells compared to SR cells (79% vs. 35%); whereas, transforming growth factor beta (TGFbeta) reduced growth in SR but not in WC cells. Differences in hemodynamic properties, in cell-matrix, elastin, proteoglycan and proliferation rates of cells and responses to FGF and TGFbeta in cells of the atherosclerosis-prone area have been identified as potential contributors to the enhanced atherosclerosis potential of this site in WC pigeons.

Chondroitin sulfate anticoagulant activity is linked to water transfer: relevance to proteoglycan structure in atherosclerosis.

OBJECTIVE: Changes in chondroitin sulfate (CS) proteoglycan (PG) during atherosclerosis are associated with chronic inflammatory changes and increased incidence of thrombosis. To explore how glycosaminoglycan changes could influence the thrombogenicity of atherosclerotic lesions, water-transfer reactions were examined during activation of antithrombin by CS. METHODS AND RESULTS: Advanced type IV atherosclerotic lesions prone to thrombosis contained CSPG (versican) with undersulfated CS relative to CS of the adjacent healthy aorta. Approximately 11% of the CS disaccharide in versican from healthy arteries was oversulfated, but this proportion decreased markedly to 3% in atherosclerotic lesions. Oversulfated CS functionally bound antithrombin with a dissociation constant of 3.3+/-1.9 micromol/L. Measured by osmotic stress (OS) techniques with an approximately 26-A probe, the reaction was linked to transfer of approximately 2500 mol water per mole of coagulation factor Xa inhibited. Under OS, the anticoagulant efficiency of CS was 1.3 (micromol/L)(-1) x s(-1), approximately 5- and 15-fold higher than heparan sulfate efficiency measured under OS and standard conditions, respectively. CONCLUSIONS: Decreased sulfation of high molecular weight CSPG in the advancing atherosclerotic lesions may predispose the lesions to thrombosis by disrupting osmotic regulation, limiting avidity for antithrombin and decreasing activation efficiency.

Molecular interactions leading to lipoprotein retention and the initiation of atherosclerosis.

Atherosclerosis is distinguished by the accumulation of lipoprotein lipid within the arterial wall. An ionic interaction of positively charged regions of apolipoprotein (apo) B with matrix proteins, including proteoglycans, collagen, and fibronectin, is thought to initiate this process. Proteoglycans are complex glycoproteins containing highly negatively charged carbohydrate chains. These proteins are abundant in atherosclerosis lesions, and they associate with apoB-containing lipoproteins. Several specific regions of apoB may mediate this process. Other lipoprotein-associated proteins, including apoE and lipases, might also participate in this process. In addition, retention may occur via lipoprotein association with other matrix molecules or as a consequence of intra-arterial lipoprotein aggregation.

Novel nanofiber-based material for endovascular scaffolds.

Conventional collagen-based heart valves eventually fail because of insufficient replacement of graft material by host tissue. In this study, type I collagen was blended with silk fibroin and the synthetic elastic polymer poly (glycerol-sebacate) (PGS) in varying proportions to create multifunctional electrospun nanofibrous materials tailored for use as endovascular scaffolds such as heart valve replacement. Depending on the blended material the elastic moduli ranged from 2.3 to 5.0 Mpa; tensile stresses ranged from 0.8 to 1.5 Mpa; and strains ranged from 30% to 70%. Electrospun materials with a weight ratio of 4.5:4.5:1 (collagen, fibroin, and PGS) (termed PFC mats) were the most similar to native heart valves. In vitro degradation of PFC mats was 0.01% per week. Endothelial cells adhered to, proliferated, and formed cell-cell junctions on PFC mats. Compared with collagen hydrogels and electrospun collagen mats respectively 220-290% less platelet adhesion was observed for PFC mats. The study demonstrates that PFC material has superior mechanical properties, low degradation, and reduced thrombogenic potential and suggests that further investigation of this biomaterial for cardiovascular applications is warranted.

Development and characterization of elastic nanocomposites for craniofacial contraction osteogenesis.

Development of resorbable elastic composites as an alternative means to apply contractive forces for manipulating craniofacial bones is described herein. Composites made from the biodegradable elastomer, poly (1,8-octanediol co-citric acid) (POC), and hydroxyapatite (nHA) with a 200 nm diameter (0-20% loadings) were created to develop a material capable of applying continuous contractive forces. The composites were evaluated for variation in their mechanical properties, rate of degradation, and interaction of the hydroxyapatite nanoparticles with the polymer chains. First, an ex vivo porcine model of cleft palate was used to determine the rate of cleft closure with applied force. The closure rate was found to be 0.505 mm N(-1) . From this approximation, the ideal maximum load was calculated to be 19.82 N, and the elastic modulus calculated to be 1.98 MPa. The addition of nHA strengthens POC, but also reduces the degradation time by 45%, for 3% nHA loading, compared to POC without nHA. X-ray diffraction data indicates that the addition of nHA to amorphous POC results in the formation of a semicrystalline phase of the POC adjacent to the nHA crystals. Based on the data, we conclude that amongst the 0-20% nHA loadings, a 3% loading of nHA in POC may be an ideal material (1.21 MPa elastic modulus and 13.17 N maximum load) to induce contraction forces capable of facilitating osteogenesis and craniofacial bone repair.