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OBJECTIVES Translingual neurostimulation (TLNS) studies indicate improved outcomes in neurodegenerative disease or spinal cord injury patients. This study was designed to assess the safety and efficacy of TLNS plus targeted physical therapy (PT) in people with a chronic balance deficit after mild-to-moderate traumatic brain injury (mmTBI). MATERIALS AND METHODS This international, multicenter, randomized study enrolled 122 participants with a chronic balance deficit who had undergone PT following an mmTBI and had plateaued in recovery. Randomized participants received PT plus either high-frequency pulse (HFP; n = 59) or low-frequency pulse (LFP; n = 63) TLNS. The primary efficacy and safety endpoints were the proportion of sensory organization test (SOT) responders (SOT composite score improvement of ≥15 points) and fall frequency after five weeks of treatment, respectively. RESULTS The proportion of SOT responders was significant in the HFP + PT (71.2%) and LFP + PT (63.5%) groups compared with baseline (p

Background Postpartum hemorrhage is a leading cause of maternal mortality globally. A tamponade agent that can be quickly and easily placed in a range of settings could advance the treatment of atonic hemorrhage. Method We adapted a highly effective trauma dressing for use in postpartum hemorrhage. This mini-sponge tamponade device is comprised of two components: compressed mini-sponges contained within a strong mesh pouch and a tubular applicator. Compressed mini-sponges rapidly absorb blood, expand within seconds, and exert sustained pressure uniformly to bleeding sites. The sponges are deployed within a mesh pouch to facilitate simple vaginal removal. Experience We successfully placed the mini-sponge device in nine patients experiencing postpartum hemorrhage after vaginal birth, with resolution of bleeding within 1 minute. The mean time to place the device was 62 seconds. Uterine fill was documented in all cases by ultrasound scan, and device placement was rated as "easy" to "very easy." Mini-sponges were left in place on average for 1 hour (0.5 hours-14 hours). Bleeding did not recur. There were no adverse events; all patients remained afebrile and did not require subsequent surgical intervention. Conclusion This study supports further evaluation of the mini-sponge device for the management of postpartum hemorrhage. Funding This study was funded by OBSTETRX, Inc.

The growing field of regenerative rehabilitation has great potential to improve clinical outcomes for individuals with disabilities. However, the science to elucidate the specific biological underpinnings of regenerative rehabilitation-based approaches is still in its infancy and critical questions regarding clinical translation and implementation still exist. In a recent roundtable discussion from International Consortium for Regenerative Rehabilitation stakeholders, key challenges to progress in the field were identified. The goal of this article is to summarize those discussions and to initiate a broader discussion among clinicians and scientists across the fields of regenerative medicine and rehabilitation science to ultimately progress regenerative rehabilitation from an emerging field to an established interdisciplinary one. Strategies and case studies from consortium institutions-including interdisciplinary research centers, formalized courses, degree programs, international symposia, and collaborative grants-are presented. We propose that these strategic directions have the potential to engage and train clinical practitioners and basic scientists, transform clinical practice, and, ultimately, optimize patient outcomes.

Following spinal cord injury (SCI), inflammation amplifies damage beyond the initial insult, providing an opportunity for targeted treatments. An ideal protective therapy would reduce both edema within the lesion area and the activation/infiltration of detrimental immune cells. Previous investigations demonstrated the efficacy of intravenous injection of multipotent adult progenitor cells (MAPC®) to modulate immune response following SCI, leading to significant improvements in tissue sparing, locomotor and urological functions. Separate studies have demonstrated that tissue inhibitor of matrix metalloproteinase-3 (TIMP3) reduces blood-brain barrier permeability following traumatic brain injury in a mouse model, leading to improved functional recovery. This study examined whether TIMP3, delivered alone or in concert with MAPC cells, improves functional recovery from a contusion SCI in a rat model. The results suggest that intravenous delivery of MAPC cell therapy 1 day following acute SCI significantly improves tissue sparing and impacts functional recovery. TIMP3 treatment provided no significant benefit, and further, when co-administered with MAPC cells, it abrogated the therapeutic effects of MAPC cell therapy. Importantly, this study demonstrated for the first time that acute treatment of SCI with MAPC cells can significantly reduce the incidence of urinary tract infection (UTI) and the use of antibiotics for UTI treatment.

Background Polidocanol foam (PF), used clinically as a venous sclerosant, has recently been studied as a safe and inexpensive means for permanent contraception. Delivering the sclerosant to the fallopian tubes as a foam rather than a liquid increases the surface areas and thus enhances the desired epithelial disrupting activity of the agent. However, the foam is inherently unstable and degrades with time. Therefore, increasing foam stability and thus duration of the agent exposure time could increase epithelial effect while allowing reduction in agent concentration and potential toxicity. Materials and Methods We studied methods to improve foam properties that might improve safety and efficacy of PF for intrauterine application. Several types of microporous filters adapted to a syringe-based foaming device were used to study the effect of pore structures on the formation of PF. The foam drainage time and bubble size were characterized. The addition of benzalkonium chloride (BZK) to polidocanol was also investigated for its effects on foam characteristics. Results A syringe-based foaming device adapted with an inline filter produced smaller bubble PF with a longer foam drainage time. PF generated with a circular pore filter lasts longer than with a noncircular pore filter. The addition of 0.01% of BZK also improved the stability of PF. Conclusion The stability of PF is affected by the pore characteristics of the filter used for foam generation and enhanced by the presence of a small amount of BZK. The improved foam, if shown to be efficacious in animal models of contraception, could lead to a safe, simple and inexpensive method alternative to surgical contraception.

Background Although uterine tamponade is an effective treatment for postpartum hemorrhage (PPH), current methods have key limitations in their use, particularly in low resource settings. The XStat™ Mini Sponge Dressing (MSD) is approved for the management of non-compressible wounds in the battlefield/trauma setting. The MSD applies highly compressed medical sponges capable of stopping high-flow arterial bleeding within seconds. The objective of our study was to adopt the MSD for use in managing PPH. Methods We performed desktop testing using a uterine model with pressure sensors to compare key design elements of the obstetrical prototype MSD (fundal pressure achieved, reduction in fluid loss, time to deploy, and time to remove) with alternativetechniques (uterine packing, balloon tamponade). To evaluate safety, we delivered the fetus of pregnant ewes by cesarean section and used the prototype to deliver the MSD into one uterine horn, and closed the hysterotomy. We followed the clinical recovery of animals (n = 3) over 24 h, and then removed the reproductive tract for histologic evaluation. To evaluate late effects, we surgically removed the MSDs after 24 h, and followed the clinical recovery of animals (n = 6) for an additional seven days before tissue removal. Results The obstetrical prototype has a long tapered delivery system designed to be deployed during vaginal examination, and administers three times the volume of the approved MSD trauma bandage. The MSD are deployed within a mesh bag to facilitate removal by vaginaltraction. On desktop testing, the MSD resulted in the highest average fundal pressure (113 mmHg), followed by the MSD bag device (85.8 mmHg), gauze packing (15.5 mmHg), and the uterine balloon (8.2 mmHg). The MSD bag test group achieved the largest fluid flow reduction of −74%, followed by gauze packing (−55%), MSD (−35%), and uterine balloon (−19%). Animal testing demonstrated good uterine fill with no evidence of adverse clinical recovery, uterine trauma or infection at 24 h, or up to 7 days following device removal. Conclusion We adapted a highly effective trauma dressing and applicator for use in the treatment of severe PPH. Preliminary desktop and animal testing provide a basis for initial clinical trials in women. Electronic supplementary material The online version of this article (doi:10.1186/s12884-017-1373-x) contains supplementary material, which is available to authorized users.

The development of vascular grafts has focused on finding a biomaterial that is non-thrombogenic, minimizes intimal hyperplasia, matches the mechanical properties of native vessels and allows for regeneration of arterial tissue. In this study, the structural and mechanical properties and the vascular cell compatibility of electrospun recombinant human tropoelastin (rTE) were evaluated as a potential vascular graft support matrix. Disuccinimidyl suberate (DSS) was used to cross-link electrospun rTE fibers to produce a polymeric recombinant tropoelastin (prTE) matrix that is stable in aqueous environments. Tubular 1 cm diameter prTE samples were constructed for uniaxial tensile testing and 4 mm small-diameter prTE tubular scaffolds were produced for burst pressure and cell compatibility evaluations from 15 wt% rTE solutions. Uniaxial tensile tests demonstrated an average ultimate tensile strength (UTS) of 0.36±0.05 MPa and elastic moduli of 0.15±0.04 MPa and 0.91±0.16 MPa, which were comparable to extracted native elastin. Burst pressures of 485 ± 25 mmHg were obtained from 4 mm ID scaffolds with 453 ± 74 μm average wall thickness. prTE supported endothelial cell growth with typical endothelial cell cobblestone morphology after 48 hours in culture. Cross-linked electrospun recombinant human tropoelastin has promising properties for utilization as a vascular graft biomaterial with customizable dimensions, a compliant matrix, and vascular cell compatibility.

An off-the-shelf vascular graft biomaterial for vascular bypass surgeries is an unmet clinical need. The vascular biomaterial must support cell growth, be non-thrombogenic, minimize intimal hyperplasia, match the structural properties of native vessels, and allow for regeneration of arterial tissue. Electrospun recombinant human tropoelastin (rTE) as a medial component of a vascular graft scaffold was investigated in this study by evaluating its structural properties, as well as its ability to support primary smooth muscle cell adhesion and growth. rTE solutions of 9, 15, and 20 wt% concentrations were electropun into sheets with average fiber diameters of 167 ± 32, 522 ± 67, and 735 ± 270 nm, and average pore sizes of 0.4 ± 0.1, 5.8 ± 4.3, and 4.9 ± 2.4 μm, respectively. Electrospun rTE fibers were cross-linked with disuccinimidyl suberate (DSS) to produce an insoluble fibrous polymeric recombinant tropoelastin (prTE) biomaterial. The smooth muscle cells attached via integrin binding. The proliferation of the smooth muscle cells on the electrospun prTE biomaterial was comparable to growth on prTE coated glass, glass alone and tissue culture plastic. Electrospun tropoelastin demonstrated the cell compatibility and design flexibility required of a graft biomaterial for vascular applications.

Drs.Bachtell,Grunkemeier,andJinarewithProvidenceHealthSystem;T.GoodelliswithOregonHealthS and Dr. Gregory is with Oregon Medical Laser Center, Portland, Oregon. Background.Bleedingfromcoagulopathichemodialysispuncturesitescancontributetoanemiaindialysispatients,andcurrent compressive dressings may contribute to graft thrombosis. We studied the safety and efficacy of a new chitosan-based bandage with an active clotting surface and compared its time to hemostasis and compression strap usage in dialysis access puncture wounds with that of conventional gauze dressings. Methods. Fifty patients received both the chitosan-based and conventional gauze dressings in random order on 2 successive visits. Time to hemostasis and compression strap usage were compared between the visits. Time to hemostasis was analyzed using the binary response variable at 2 and 4 minutes. A compression strap wasused if dressing application was unsuccessful at 4 minutes. Covariates included coagulation state as measured by laboratory analysis and anticoagulation therapy. Results.Hemostasiswasachievedby2minutesin30%ofthechitosan-basedand38%oftheconventionaldressings(p ¼0.608) andby4minutesin86%ofthechitosan-basedand72%oftheconventionaldressings(p ¼0.040).Compressionstrapusagewas reducedby50%inthechitosan-basedgroupcomparedtotheconventionalgroup(7vs.14patients;p ¼0.052).Noadverseevents were reported with either dressing. Conclusions. The chitosan-based bandage from HemCon is a safe and effective hemostatic agent to reduce prolonged posthemodialysis puncture site bleeding and may reduce the use of occlusive compression straps.

An esophageal injury with significant tissue loss is very difficult to repair. We conducted an in vivo study to test our elastin based acellular biomaterial patch to repair such defect. The patch was made from porcine aorta, by decellularization and sterilization. Collagen fibers were preserved to retain mechanical strength and enhance cellular in-growth. Ten domestic pigs underwent right thoracotomy. A 2 cm circular defect was made on the distal esophagus, excising half its circumference, and was repaired using the biomaterial patch and sutures. Soon after the procedure, the animals resumed oral feeding. They were followed for clinical status, weight gain, barium studies, and endoscopic studies, and were killed after 6 weeks to 4 months. All ten animals survived long term, with a procedure success rate of 100% (10 of 10). With the exception of one pneumothorax, no complications occurred, and all animals resumed oral feeding and gained weight. Endoscopic studies showed mucosal coverage by 6 weeks, with minimal stricture at the repair site. Excised specimens showed complete mucosal coverage with regeneration of all three layers. Our biomaterial patch can be used safely and reliably for repair of esophageal injury with significant tissue loss when repaired immediately as in our experiment.

Photo acoustic drug delivery is a technique for localized drug delivery by laser-induced hydrodynamic pressure following cavitation bubble expansion and collapse. Photoacoustic drug delivery was investigated on gelatin-based thrombus models with planar and cylindrical geometries by use of one microsecond laser pulses. Solutions of a hydrophobic dye in mineral oil permitted monitoring of delivered colored oil into clear gelatin-based thrombus models. Cavitation bubble development and photoacoustic drug delivery were visualized with flash photography. This study demonstrated that cavitation is the governing mechanism for photoacoustic drug delivery, and the deepest penetration of colored oil in gels followed the bubble collapse. Spatial distribution measurements revealed that colored oil could be driven a few millimeters into the gels in both axial and radial directions, and the penetration was less than 500 µm when the gelatin structure was not fractured.

Background The complex data sets generated by higher-order polychromatic flow cytometry experiments are a challenge to analyze. Here we describe Exhaustive Expansion, a data analysis approach for deriving hundreds to thousands of cell phenotypes from raw data, and for interrogating these phenotypes to identify populations of biological interest given the experimental context. Methods We apply this approach to two studies, illustrating its broad applicability. The first examines the longitudinal changes in circulating human memory T cell populations within individual patients in response to a melanoma peptide (gp100209-2M) cancer vaccine, using 5 monoclonal antibodies (mAbs) to delineate subpopulations of viable, gp100-specific, CD8+ T cells. The second study measures the mobilization of stem cells in porcine bone marrow that may be associated with wound healing, and uses 5 different staining panels consisting of 8 mAbs each. Results In the first study, our analysis suggests that the cell surface markers CD45RA, CD27 and CD28, commonly used in historical lower order (2-4 color) flow cytometry analysis to distinguish memory from naïve and effector T cells, may not be obligate parameters in defining central memory T cells (TCM). In the second study, we identify novel phenotypes such as CD29+CD31+CD56+CXCR4+CD90+Sca1-CD44+, which may characterize progenitor cells that are significantly increased in wounded animals as compared to controls. Conclusions Taken together, these results demonstrate that Exhaustive Expansion supports thorough interrogation of complex higher-order flow cytometry data sets and aids in the identification of potentially clinically relevant findings.

It is shown that delivery of laser energy to intravascular targets through a flowing fluid-core laser angioplasty catheter offers new design possibilities and solutions to current practical problems facing laser angioplasty. Fluid-core catheters using iodinated radiographic contrast material as the core fluid can transmit high-peak-power visible laser pulses at high efficiencies while offering improved imaging of the target and distal vasculature. These catheters are simple to produce, are optically and mechanically stable, and are compatible with conventional angioplasty equipment and techniques. In canine coronary arteries in vivo, the catheters proved to be flexible, atraumatic, and able to deliver ablative high-peak-power laser pulses. >

The use of pulsed laser energy to clear arteries obstructed by thrombus (blood clot) and plaque has emerged as a promising method for the treatment of cardiovascular diseases such as myocardial infarction and stroke. Current techniques for laser thrombolysis are limited because they cannot completely clear the clot in arteries, especially where a large volume clot is presented. Mural clot is a potent stimulus for reocclusion. We suggest that the combination of laser thrombolysis and localized intramural delivery of clot-dissolving drugs during the procedure may be a solution to this limitation. Ninety pulses of 30 - 70 mJ were delivered onto gelatin-based thrombus model with a flushing catheter. A solution of 1 micrometer fluorescent particles as a drug model was injected at a rate of 4 mL/min in coincidence with the laser delivery. The controls were performed by injecting drug after laser thrombolysis. We measured the penetration of the particles in gelatin and the sizes of the lumen and stained areas. The results of this study demonstrated the possibility of enhancing laser thrombolysis by delivering drugs into thrombus. It was found that the particles could be driven several hundred micron in gelatin, and the lumen areas would be increased up to 25% if the areas were dissolved by the drugs.

Background Although the relationship between cardiac wavelength (λ) and path length importantly determines the stability of reentrant arrhythmias, the physiological determinants of λ are poorly understood. To investigate the cellular mechanisms that control λ during reentry, we developed an experimental system for continuously monitoring λ within a reentrant circuit with the use of voltage-sensitive dyes and a new guinea pig model of ventricular tachycardia (VT). Methods and Results Action potentials were recorded simultaneously from 128 ventricular sites in Langendorff-perfused hearts (n=15) in which propagation was confined to a two-dimensional rim of epicardium by an endocardial cryoablating procedure. The reentrant path was precisely controlled by creating an epicardial obstacle (2×10 mm) with an argon laser. To control for fiber orientation and rate-dependent membrane properties, λ during reentry was compared with λ during plane wave propagation transverse and longitudinal to cardiac fibers at a stimulus cycle length (CL) comparable to the VT CL. Reentrant VT (CL=97.0±6.2 ms) was reproducibly induced by programmed stimulation in 93% of preparations. λ varied considerably within the reentrant circuit (range, 10.6 to 22.5 mm), because of heterogeneities of conduction rather than action potential duration. λ was significantly shorter during reentrant propagation (ie, with pivoting) parallel to fibers (10.6±4.2 mm) compared with plane wave propagation (ie, without pivoting) parallel to fibers (32.8±6.5 mm, P Conclusions We provide direct experimental evidence that multiple wavelengths are present even within a relatively simple reentrant circuit. Abrupt changes in loading during wave-front pivoting, rather than membrane ionic properties or fiber structure, were a major determinant of λ and, therefore, may play an important role in the stability of reentry.

CABG thrombosis is a common disorder without adequate therapy. To assess the effects of selective laser thrombolysis (LT) in CABG, aortocoronary bypasses were created and completely thrombosed in nine swine. Maximal thrombus removal was achieved with pulsed dye laser light (577 nm, 1 μs pulse, 3 Hz, 64 mJ/pulse) by fluid catheter for 6.7 ± 1 min. Graft flow and thrombosis were assessed by angio with global and grafted segment myocardial function measured by epicardial echo at constant load. Mean graft size: 8 mm × 6 cm. Prior to therapy, grafts had no flow (TIMIO) and complete thrombosis for 60 min. TIMI flow post LTwas 2.8 ± 0.4 (p l 0.001) with focal residual mural thrombus. 90 min post LT, graft appearance and flow were unchanged. Wall motion (WM) scored from normal (1) to dyskinetic (4). Index = total WM/14 segments. Occlusion 90 min postLT Global EF 0.49 ± 0.09 0.55 ± 0.04 NS Index 1.7 ± 0.1 1.1 ± 0.1 (p l 0.05) Grafted Region Wall Motion 4 1 (p l 0.01) %Wall Thick. - 5 31 (p l 0.01) Conclusions 1) LT is able to rapidly remove large amounts of thrombus in CABG. 2) Thrombus removal by LT does not cause detectable changes in regional cardiac function. 3) High patency rates persist 90 min. post LT.

The design, processing, and sequential testing of a novel cylindrical diffusing optical fiber tip for ultraviolet light delivery is described. This device has been shown to uniformly (+/- 15%) illuminate angioplasty balloons, 20 mm in length, that are used in an experimental photochemotherapeutic treatment of swine intimal hyperplasia. Our experiments show that uniform diffusing tips of < 400 micron diameter can be reliably constructed for this and other interstitial applications. Modeling results indicate that this design is scalable to smaller diameters. The diffusing tips are made by stripping the protective buffer and etching away the cladding over a length of 20 mm from the fiber tip and replacing it with a thin layer of optical epoxy mixed with Al 2 O 3 powder. To improve the uniformity and ease of fabrication, we have evaluated a new device configuration where the tip is etched into a modified conical shape, and the distal end face is polished and then coated with an optically opaque epoxy. This is shown to uniformly scatter ~ 70% of the light launched into the fiber without forward transmission. To our knowledge, we are the first to use this device configuration, and we have achieved a uniform cylindrical pattern of laser energy with the uniformity < ± 15% of the average value.

✓ Laser energy of 480 nm was applied in 1-µsec pulses varying between 2.2 and 10 mJ to in vitro and in vivo models of cerebral vasospasm. First, the pulsed-dye laser was applied intravascularly via a 320-µm fiber to basilar artery segments from six dogs. The segments were mounted in a vessel-perfusion apparatus and constricted to, on average, 70% of resting diameter by superfusion with dog hemolysate. Immediate increase in basilar artery diameter occurred to a mean of 83% of control. In a second model, the basilar artery was exposed transclivally in the rabbit. In three normal animals, superfusion of the artery with rabbit hemolysate resulted in a reduction of mean vessel diameter to 81% of control. Following extravascular application of the laser, vessels returned to an average of 106% of the resting state. In six rabbits, the basilar artery was constricted by two intracisternal injections of autologous blood, 3 days apart. Two to 4 days after the second injection, the basilar artery was exposed. Extravascular laser treatment from a quartz fiber placed perpendicular to the vessel adventitia resulted in an immediate 53% average increase in caliber to an estimated 107% of control. No reconstriction was observed over a period of up to 5 hours. Morphologically, damage to the arterial wall was slight. This preliminary investigation suggests that the 1-µsec pulsed-dye laser may be of benefit in the treatment of cerebral vasospasm.

This PDF file contains the editorial “Special Section Guest Editorial: Cardiovascular Photonics” for JBO Vol. 11 Issue 02

A method and apparatus for dilating blood vessels in vasospasm through the use of high frequency wave, e.g., hydraulic or acoustic waves. The invention is suitable to treat any vasospasm, including any vasospasm intractable to medication, including cerebral vasospasm, which currently is not susceptible to any mechanical or chemical treatments. The apparatus for dilating blood vessels includes a catheter having a fluid-filled lumen, a wave generator arranged within the catheter lumen for generating a wave front that propagates through the fluid in the lumen and is transmitted from the distal end of the catheter to propagate through the fluid in the blood vessel, and an energy source connected to the wave generator to provide energy to produce the wave front.

Regenerative medicine studies using autologous bone marrow mononuclear cells (BM-MNCs) have shown improved clinical outcomes that correlate to in vitro BM-MNC invasive capacity. The current Boyden-chamber assay for testing invasive capacity is labor-intensive, provides only a single time point, and takes 36 hours to collect data and results, which is not practical from a clinical cell delivery perspective. To develop a rapid, sensitive and reproducible invasion assay, we employed Electric Cell-substrate Impedance Sensing (ECIS) technology. Chemokine-directed BM-MNC cell invasion across a Matrigel-coated Transwell filter was measurable within minutes using the ECIS system we developed. This ECIS-Transwell chamber system provides a rapid and sensitive test of stem and progenitor cell invasive capacity for evaluation of stem cell functionality to provide timely clinical data for selection of patients likely to realize clinical benefit in regenerative medicine treatments. This device could also supply robust unambiguous, reproducible and cost effective data as a potency assay for cell product release and regulatory strategies.