Extracellular matrix stiffness mediates insulin secretion in pancreatic islets via mechanosensitive Piezo1 channel regulated Ca2+ dynamics.

The pancreatic islet is surrounded by ECM that provides both biochemical and mechanical cues to the islet ß-cell to regulate cell survival and insulin secretion. Changes in ECM composition and mechanical properties drive ß-cell dysfunction in many pancreatic diseases. While several studies have characterized changes in islet insulin secretion with changes in substrate stiffness, little is known about the mechanotransduction signaling driving altered islet function in response to mechanical cues. We hypothesized that increasing matrix stiffness will lead to insulin secretion dysfunction by opening the mechanosensitive ion channel Piezo1 and disrupting intracellular Ca2+ dynamics in mouse and human islets. To test our hypothesis, mouse and human cadaveric islets were encapsulated in a biomimetic reverse thermal gel (RTG) scaffold with tailorable stiffness that allows formation of islet focal adhesions with the scaffold and activation of Piezo1 in 3D. Our results indicate that increased scaffold stiffness causes insulin secretion dysfunction mediated by increases in Ca2+ influx and altered Ca2+ dynamics via opening of the mechanosensitive Piezo1 channel. Additionally, inhibition of Piezo1 rescued glucose-stimulated insulin secretion (GSIS) in islets in stiff scaffolds. Overall, our results emphasize the role mechanical properties of the islet microenvironment plays in regulating function. It also supports further investigation into the modulation of Piezo1 channel activity to restore islet function in diseases like type 2 diabetes (T2D) and pancreatic cancer where fibrosis of the peri-islet ECM leads to increased tissue stiffness and islet dysfunction.

Radiological evaluation of atlantoaxial fusion using C2 translaminar screws and C2 pedicle screws: Does the screw halo sign imply fusion failure?

The purpose of this study was to identify the criteria for atlantoaxial (AA) fusion by comparing follow-up lateral radiographs and computed tomography (CT) images. We retrospectively analyzed data from 161 consecutive patients undergoing AA fusion. Patients with a minimum of 1 year of CT follow-up after AA fusion surgery using C2 pedicle screws or translaminar screws (C2TLS) were included. Patients were followed up radiographically at 3, 6, and 12 months after surgery, and dynamic lateral radiographs were also evaluated. A total of 49 patients were analyzed, with a mean CT image follow-up of 41.6 ±â€…37.6 months. Thirty eight patients had C2 pedicle screw placement, and 11 patients underwent planned C2TLS. AA fusion with bridging bone mass formation was achieved in 45/49 (91.8%) patients. Screw halos were observed in 14/49 (28.6%) patients. Among them, final fusion failure occurred in 2 (14.3%) patients. The last follow-up CT showed no difference in the fusion failure rate according to the presence or absence of a screw halo (no halo, 5.7%; halo, 14.3%; P = .33). The differences in C1-2 segmental angles (SA) in flexion-extension dynamic lateral radiographs were 1.99 ±â€…1.62° in the fusion group and 4.37 ±â€…2.13° in the non-fusion group (P = .01). The likelihood of fusion failure increased when the SA gap was greater than 2.62° (P = .05). C2TLS placement had a significantly higher incidence of screw halos. However, the halo sign was not significantly related to final bone fusion. Bone fusion could be predicted when the SA gap of C1-2 was less than 2.62° on the dynamic radiograph.

Making a Painless Drain: Proof of Concept.

Chest tubes account for a large proportion of postoperative pain after cardiothoracic operations. The objective of this study was to develop a novel, cost-effective, easy-to-use, lidocaine-eluting coating to reduce pain associated with postoperative chest tubes. A lidocaine-eluting hydrogel was developed by dispersing lidocaine-loaded nanoparticles in an aqueous solution containing gelatin (5%). Glutaraldehyde (1%) was added to crosslink the gelatin into a hydrogel. The hydrogel was dehydrated, resulting in a thin, stable polymer. Sterile lidocaine hydrogel-coated silicone discs and control discs were prepared and surgically implanted in the subcutaneous space of C57B6 mice. Using von Frey filaments, mice underwent preoperative baseline pain testing, followed by pain testing on post-procedure day 1 and 3. On post-procedure day 1, mice implanted with control discs demonstrated no change in pain tolerance compared to baseline, while mice implanted with 20 mg and 80 mg lidocaine-loaded discs demonstrated a 2.4-fold (P = 0.36) and 4.7-fold (P = 0.01) increase in pain tolerance, respectively. On post-procedure day 3, mice implanted with control discs demonstrated a 0.7-fold decrease in pain tolerance compared to baseline, while mice implanted with 20 mg and 80 mg lidocaine-loaded discs demonstrated a 1.8-fold (P = 0.88) and 8.4-fold (P = 0.02) increase in pain tolerance, respectively. Our results demonstrate successful development of a lidocaine-eluting chest tube with hydrogel coating, leading to improved pain tolerance in vivo. The concept of a drug-eluting drain coating has significant importance due to its potential universal application in a variety of drain types and insertion locations.

Indirect Decompression Using Oblique Lumbar Interbody Fusion Revision Surgery Following Previous Posterior Decompression: Comparison of Clinical and Radiologic Outcomes Between Direct and Indirect Decompression Revision Surgery.

OBJECTIVE: This study compared the radiological and clinical outcomes with transforaminal lumbar interbody fusion (TLIF) to evaluate the effect of indirect decompression through oblique lumbar interbody fusion (OLIF) as revision surgery. METHODS: We enrolled patients who underwent single-level fusion with revision surgery at the same level as the previous decompression level. We retrospectively reviewed 25 patients who underwent OLIF from 2017 to 2018 and 25 who received TLIF from 2014 to 2018. Radiologic and clinical outcomes were evaluated by cross-sectional area (CSA) of the spinal canal, thickness and area of ligamentum flavum (LF), subsidence, disc height, fusion rate, Oswestry Disability Index (ODI), and visual analogue scale (VAS). RESULTS: Compared with OLIF, the thickness and area of the LF after surgery were significantly less in TLIF, and the resulting CSA extension was also significantly higher. However, both groups showed improvement in ODI and VAS after surgery, and there was no difference between the groups. Complications related to the posterior approach in TLIF were 4 cases, and in OLIF, there were 2 cases that underwent additional posterior decompression surgery and 6 cases of transient paresthesia. CONCLUSION: Since complications associated with the posterior approach can be avoided, OLIF is a safer and useful minimally invasive surgery. Therefore, appropriate indications are applied, OLIF is a good alternative to TLIF when revision surgery is considered.

Sulfonated Thermoresponsive Injectable Gel for Sequential Release of Therapeutic Proteins to Protect Cardiac Function after Myocardial Infarction.

Myocardial infarction causes cardiomyocyte death and persistent inflammatory responses, which generate adverse pathological remodeling. Delivering therapeutic proteins from injectable materials in a controlled-release manner may present an effective biomedical approach for treating this disease. A thermoresponsive injectable gel composed of chitosan, conjugated with poly(N-isopropylacrylamide) and sulfonate groups, was developed for spatiotemporal protein delivery to protect cardiac function after myocardial infarction. The thermoresponsive gel delivered vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and platelet-derived growth factor (PDGF) in a sequential and sustained manner in vitro. An acute myocardial infarction mouse model was used to evaluate polymer biocompatibility and to determine therapeutic effects from the delivery system on cardiac function. Immunohistochemistry showed biocompatibility of the hydrogel, while the controlled delivery of the proteins reduced macrophage infiltration and increased vascularization. Echocardiography showed an improvement in ejection fraction and fractional shortening after injecting the thermal gel and proteins. A factorial design of experimental study was implemented to optimize the delivery system for the best combination and doses of proteins for further increasing stable vascularization and reducing inflammation using a subcutaneous injection mouse model. The results showed that VEGF, IL-10, and FGF-2 demonstrated significant contributions toward promoting long-term vascularization, while PDGF's effect was minimal.

In vivo monitoring platform of transplanted human stem cells using magnetic resonance imaging.

As stem cells show great promise in regenerative therapy, stem cell-mediated therapeutic efficacy must be demonstrated through the migration and transplantation of stem cells into target disease areas at the pre-clinical level. In this study, we developed manganese-based magnetic nanoparticles with hollow structures (MnOHo) and modified them with the anti-human integrin ß1 antibody (MnOHo-Ab) to enable the minimal-invasive monitoring of transplanted human stem cells at the pre-clinical level. Compared to common magnetic resonance imaging (MRI)-based stem cell monitoring systems that use pre-labeled stem cells with magnetic particles before stem cell injection, the MnOHo-Ab is a new technology that does not require stem cell modification to monitor the therapeutic capability of stem cells. Additionally, MnOHo-Ab provides improved T1 MRI owing to the hollow structure of the MnOHo. Particularly, the anti-integrin ß1 antibody (Ab) introduced in the MnOHo targets integrin ß1 expressed in the entire stem cell lineage, enabling targeted monitoring regardless of the differentiation stage of the stem cells. Furthermore, we verified that intravenously injected MnOHo-Ab specifically targeted human induced pluripotent stem cells (hiPSCs) that were transferred to mice testes and differentiated into various lineages. The new stem cell monitoring method using MnOHo-Ab demonstrates whether the injected human stem cells have migrated and transplanted themselves in the target area during long-term stem cell regenerative therapy.

One-Stage Anatomical Revision Anterior Cruciate Ligament Reconstruction: Results According to Tunnel Overlaps.

PURPOSE: To present clinical results according to tunnel overlap in 1-stage anatomical revision anterior cruciate ligament reconstruction (ACLR). METHODS: All patients who underwent revision ACLR performed by a single surgeon (J.H.A.) from 2012 to 2017 and were followed up for >24 months were retrospectively evaluated. The exclusion criteria were concomitant ligament injury, including medial collateral ligament injury, modified Outerbridge grade ≥3 cartilage lesion, and severe meniscus defects. Tunnel overlap was measured on 3-dimensionally reconstructed computed tomography images. Patients in the nonoverlapped femoral tunnel group (group NO, n = 52) were treated with new tunnel drilling that completely avoided previous tunnels, and those in the overlapped femoral tunnel group (group O, n = 41) were treated with a new tunnel that overlapped with previous tunnels. Clinical outcomes were evaluated using the subjective International Knee Documentation Committee (IKDC) and Lysholm scores. Knee joint stability was measured using the Lachman and pivot shift tests. Patients with femoral tunnel widening of ≥14 mm underwent 2-stage ACLR. RESULTS: The mean follow-up duration of 93 patients was 46.9 months (range, 24-97 months). All preoperative subjective and objective IKDC (P<0.001) and Telos stress test scores (P = .016) were significantly improved at the last follow-up. Forty-one patients had overlapping femoral tunnels, whereas 87 had overlapping tibial tunnels. At the last follow-up, subjective IKDC and Lysholm scores (73.6 ± 15.3 vs 74.9 ± 12.1, P = .799 and 80.0 ± 19.2 vs 81.44 ± 13.5, P = .505, respectively) and objective pivot shift (IKDC grade) in the Lachman test (P = .183 and P = .450, respectively) did not differ significantly between groups NO and O, respectively. CONCLUSIONS: One-stage anatomical revision ACLR significantly improved the clinical results. Most tibial tunnels (94%) and approximately one-half (44%) of the femoral tunnels overlapped. The overlapped femoral tunnel group did not show inferior outcomes or stability. LEVEL OF EVIDENCE: Level III, cohort study.

Co-delivery of antigens and immunostimulants via a polymersome for improvement of antigen-specific immune response.

Cellular uptake of antigens (Ags) by antigen-presenting cells (APCs) is vital for effective functioning of the immune system. Intramuscular or subcutaneous administration of vaccine Ags alone is not sufficient to elicit optimal immune responses. Thus, adjuvants are required to induce strong immunogenicity. Here, we developed nanoparticulate adjuvants that assemble into a bilayer spherical polymersome (PSome) to promote the cellular uptake of Ags by APCs. PSomes were synthesized by using a biodegradable and biocompatible block copolymer methoxy-poly(ethylene glycol)-b-poly(d,l-lactide) to encapsulate both hydrophilic and lipophilic biomacromolecules, such as ovalbumin (OVA) as a model Ag and monophosphoryl lipid A (MPLA) as an immunostimulant. After co-encapsulation of OVA and MPLA, the PSome synthetic vehicle exhibited the sustained release of OVA in cell environments and allowed efficient delivery of cargos into APCs. The administration of PSomes loaded with OVA and MPLA induced the production of interleukin-6 and tumor necrosis factor-alpha cytokines by macrophage activation in vitro and elicited effective Ag-specific antibody responses in vivo. These findings indicate that the nano-sized PSome may serve as a potent adjuvant for vaccine delivery systems to modulate enhanced immune responses.

Three-Dimensional Morphometric Analysis of Penetrative Depth and Size of Nonarthritic and Degenerative Arthritic Glenoids: Implications for Glenoid Replacement in Shoulder Arthroplasty.

BACKGROUND: Shoulder arthroplasty is technically demanding and relies heavily on the precision of surgical techniques. Proper glenoid component sizing plays a crucial role in successful shoulder arthroplasty. We measured the size and penetrative depth of the glenoid for peg or screw fixation in nonarthritic and degenerative arthritic shoulders by using three-dimensional computed tomography to determine the reference dimensions of the glenoid in nonarthritic and degenerative arthritic shoulders. METHODS: From January 2010 to January 2011, data on two groups of patients were collected and reviewed. Group 1 comprised 38 patients who underwent surgical treatment due to fracture of the proximal humerus and who had no evidence of a pathological glenoid. Group 2 comprised 14 patients who underwent surgical treatment due to osteoarthritis of the glenohumeral joint. The height (maximal superoinferior diameter) of the glenoid was measured, and the width (anteroposterior [AP] diameter) of the glenoid was measured at five different levels (H1-H5). Axial images were taken at H1-H5 levels, the AP glenoid diameter of each was divided into eight areas, and division points were labeled as W1-W7. The penetrative depths between the near cortex and far cortex of the glenoid (thickness) at each point (W1-W7) were measured. RESULTS: The overall mean glenoid height was 37.67 ± 4.09 mm in nonarthritic glenoids and 39.42 ± 3.54 mm in degenerative arthritic glenoids. The nonarthritic glenoid was significantly thicker than the degenerative arthritic glenoid at the H1W3, H1W4, H1W5, H2W7, H3W1, H3W6, H3W7, H4W5, H4W6, H4W7, H5W4, H5W5, H5W6, and H5W7 points. The posteroinferior quadrant had the smallest penetrative depth in both nonarthritic and degenerative arthritic glenoids. Also, the degenerative arthritic glenoids were significantly thinner than the nonarthritic glenoids along the posterior and inferior parts of the glenoid. CONCLUSIONS: The posterior and inferior parts of the degenerative arthritic glenoid appears thinner than the nonarthritic glenoid. Thus, caution has to be taken when drilling the screw hole or inserting screws into the posteroinferior parts, where the glenoid is thinner than 15 mm on average, to avoid penetration of the far cortex.

Injectable Polymeric Delivery System for Spatiotemporal and Sequential Release of Therapeutic Proteins To Promote Therapeutic Angiogenesis and Reduce Inflammation.

Myocardial infarction (MI) causes cardiac cell death, induces persistent inflammatory responses, and generates harmful pathological remodeling, which leads to heart failure. Biomedical approaches to restore blood supply to ischemic myocardium, via controlled delivery of angiogenic and immunoregulatory proteins, may present an efficient treatment option for coronary artery disease (CAD). Vascular endothelial growth factor (VEGF) is necessary to initiate neovessel formation, while platelet-derived growth factor (PDGF) is needed later to recruit pericytes, which stabilizes new vessels. Anti-inflammatory cytokines like interleukin-10 (IL-10) can help optimize cardiac repair and limit the damaging effects of inflammation following MI. To meet these angiogenic and anti-inflammatory needs, an injectable polymeric delivery system composed of encapsulating micelle nanoparticles embedded in a sulfonated reverse thermal gel was developed. The sulfonate groups on the thermal gel electrostatically bind to VEGF and IL-10, and their specific binding affinities control their release rates, while PDGF-loaded micelles are embedded in the gel to provide the sequential release of the growth factors. An in vitro release study was performed, which demonstrated the sequential release capabilities of the delivery system. The ability of the delivery system to induce new blood vessel formation was analyzed in vivo using a subcutaneous injection mouse model. Histological assessment was used to quantify blood vessel formation and an inflammatory response, which showed that the polymeric delivery system significantly increased functional and mature vessel formation while reducing inflammation. Overall, the results demonstrate the effective delivery of therapeutic proteins to promote angiogenesis and limit inflammatory responses.

An Injectable Reverse Thermal Gel for Minimally Invasive Coverage of Mouse Myelomeningocele.

BACKGROUND: Myelomeningocele (MMC) results in lifelong neurologic and functional deficits. Currently, prenatal repair of MMC closes the defect, resulting in a 50% reduction in postnatal ventriculoperitoneal shunting. However, this invasive fetal surgery is associated with significant morbidities to mother and baby. We have pioneered a novel reverse thermal gel (RTG) to cover MMC defects in a minimally invasive manner. Here, we test in-vitro RTG long-term stability in amniotic fluid and in vivo application in the Grainy head-like 3 (Grhl3) mouse MMC model. MATERIALS AND METHODS: RTG stability in amniotic fluid (in-vitro) was monitored for 6 mo and measured using gel permeation chromatography and solution-gel transition temperature (lower critical solution temperature). E16.5 Grhl3 mouse fetuses were injected with the RTG or saline and harvested on E19.5. Tissue was assessed for RTG coverage of the gross defect and inflammatory response by immunohistochemistry for macrophages. RESULTS: Polymer backbone molecular weight and lower critical solution temperature remain stable in amniotic fluid after 6 mo. Needle injection over the MMC of Grhl3 fetuses successfully forms a stable gel that covers the entire defect. On harvest, some animals demonstrate >50% RTG coverage. RTG injection is not associated with inflammation. CONCLUSIONS: Our results demonstrate that the RTG is a promising candidate for a minimally invasive approach to patch MMC. We are now poised to test our RTG patch in the large preclinical ovine model used to evaluate prenatal repair of MMC.

A sulfonated reversible thermal gel for the spatiotemporal control of VEGF delivery to promote therapeutic angiogenesis.

Despite medical and surgical advancements for the treatment of cardiovascular disease, mortality and morbidity remain high. Therapeutic angiogenesis has been one approach to address the major clinical need for a more effective treatment to restoring blood flow in ischemic organs and tissues, but current progress in angiogenic drug delivery is inadequate at providing sufficient bioavailability without causing safety concerns. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for the delivery of angiogenic factors. The thermal gel allowed for the spatiotemporal control of vascular endothelial growth factor release with a decreased initial burst release and reduced release rate in vitro. A subcutaneous injection mouse model was used to evaluate efficacious vascularization and assess the inflammatory response due to a foreign body. Thermal gel injections showed substantial vascularization properties by inducing vessel formation, recruitment and differentiation of vascular endothelial cells, and vessel stabilization by perivascular cells, while infiltrating macrophages due to the thermal gel injections decreased over time. These results demonstrated effective localization and delivery of angiogenic factors for therapeutic angiogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3053-3064, 2018.

Reverse Thermal Gel for In Utero Coverage of Spina Bifida Defects: An Innovative Bioengineering Alternative to Open Fetal Repair.

Current state-of-the-art management of open spina bifida defects entails an open fetal surgery approach associated with significant morbidities. In an attempt to reduce these risks and provide for an earlier minimally invasive repair, it is aimed to develop and characterize an innovative alternative using a unique reverse thermal gel. This study focuses on characterization of the physical and biological properties of the polymer and its in vivo applicability. Based on the knowledge and benchmarking, the "ideal" biomaterial should have the following characteristics: stability in amniotic fluid, limited permeability, biocompatibility, biologically functional, nontoxic, ability to support cellular functions, and in vivo applicability. The results demonstrate that the polymer possesses a unique ultrastructure, is stable in amniotic fluid, possesses limited yet predictable permeability, biocompatible with cells exposed in neural tube defects, is nontoxic, and can support cellular migration. These characteristics make it a potential novel alternative to open fetal repairs.

Biomimetic Polymers for Cardiac Tissue Engineering.

Heart failure is a morbid disorder characterized by progressive cardiomyocyte (CM) dysfunction and death. Interest in cell-based therapies is growing, but sustainability of injected CMs remains a challenge. To mitigate this, we developed an injectable biomimetic Reverse Thermal Gel (RTG) specifically engineered to support long-term CM survival. This RTG biopolymer provided a solution-based delivery vehicle of CMs, which transitioned to a gel-based matrix shortly after reaching body temperature. In this study we tested the suitability of this biopolymer to sustain CM viability. The RTG was biomolecule-functionalized with poly-l-lysine or laminin. Neonatal rat ventricular myocytes (NRVM) and adult rat ventricular myocytes (ARVM) were cultured in plain-RTG and biomolecule-functionalized-RTG both under 3-dimensional (3D) conditions. Traditional 2D biomolecule-coated dishes were used as controls. We found that the RTG-lysine stimulated NRVM to spread and form heart-like functional syncytia. Regarding cell contraction, in both RTG and RTG-lysine, beating cells were recorded after 21 days. Additionally, more than 50% (p value < 0.05; n = 5) viable ARVMs, characterized by a well-defined cardiac phenotype represented by sarcomeric cross-striations, were found in the RTG-laminin after 8 days. These results exhibit the tremendous potential of a minimally invasive CM transplantation through our designed RTG-cell therapy platform.

Substantial Differentiation of Human Neural Stem Cells Into Motor Neurons on a Biomimetic Polyurea.

To find the first restorative treatment for spinal cord injury (SCI), researchers have focused on stem cell therapies. However, one obstacle is the lack of an implantable cell scaffold that can support efficient motor neuron (MN) differentiation and proliferation. We aimed to overcome this through the use of an RGD functionalized novel biomimetic polyurea, optimized to encourage efficient differentiation of MNs. Images taken after 14-days showed increased differentiation (∼40%) of hNSCs into MNs as well as increased cell count on the biomimetic polymer compared to PDL-Laminin coating, indicating that the RGD-polyurea provides a favorable microenvironment for hNSC survival, having promising implications for future SCI therapies.

Biomimetic poly(serinol hexamethylene urea) for promotion of neurite outgrowth and guidance.

Nerve function recovery is a major technical challenge in the rehabilitation of patients suffering from severe neuropathies. Facilitating functional recovery requires the creation of a growth-permissive environment that directs the extension and myelination of surviving neurons. To this end, an electrospun nanofiber scaffold composed of arginine-glycine-aspartate-modified poly(serinol hexamethylene urea)-blend-poly-ε-caprolactone (PSHU-RGD/PCL) has been employed. Initially, we investigated the cytotoxicity of PSHU in PC12 cell culture. This was followed by functional examinations of PSHU-RGD for cell viability, proliferation, differentiation, and neurite outgrowth, and finally we examined electrospun scaffolds for guided neurite sprouting. MTT proliferation assays indicated no cytotoxic effects of polymer as compared to laminin-coated surfaces. Functional testing revealed PSHU-RGD surfaces to be comparable to the positive control, laminin-coated surface, in neurite outgrowth studies with average neurite lengths of 84.6 µm (laminin), 218.2 µm (PSHU-RGD), 570.2 µm (laminin + NGF), and 958.2 µm (PSHU-RGD + NGF) after two weeks on homogeneously modified surfaces, and 554.8 µm (nonwoven mats) and 1512.3 µm (uniaxially aligned mats) for PSHU-RGD/PCL + NGF scaffolds after one week. We created PSHU functionalized with the tripeptide, RGD, which provided chemical and physical cues to PC12 cell proliferation and differentiation. We expect that PSHU-RGD will be capable of directing and promoting neurite outgrowth in many neuropathy models.

The effect of a polyurethane-based reverse thermal gel on bone marrow stromal cell transplant survival and spinal cord repair.

Cell therapy for nervous tissue repair is limited by low transplant survival. We investigated the effects of a polyurethane-based reverse thermal gel, poly(ethylene glycol)-poly(serinol hexamethylene urethane) (ESHU) on bone marrow stromal cell (BMSC) transplant survival and repair using a rat model of spinal cord contusion. Transplantation of BMSCs in ESHU at three days post-contusion resulted in a 3.5-fold increase in BMSC survival at one week post-injury and a 66% increase in spared nervous tissue volume at four weeks post-injury. These improvements were accompanied by enhanced hindlimb motor and sensorimotor recovery. In vitro, we found that ESHU protected BMSCs from hydrogen peroxide-mediated death, resulting in a four-fold increase in BMSC survival with two-fold fewer BMSCs expressing the apoptosis marker, caspase 3 and the DNA oxidation marker, 8-oxo-deoxyguanosine. We argue that ESHU protected BMSCs transplanted is a spinal cord contusion from death thereby augmenting their effects on neuroprotection leading to improved behavioral restoration. The data show that the repair effects of intraneural BMSC transplants depend on the degree of their survival and may have a widespread impact on cell-based regenerative medicine.

Mesoporous silica nanoparticles as a breast-cancer targeting ultrasound contrast agent.

Ultrasound (US) is used widely in the context of breast cancer. While it is advantageous for a number of reasons, it has low specificity and requires the use of a contrast agent. Its use as a standalone diagnostic and real-time imaging modality could be achieved by development of a tumor-targeted ultrasound contrast agent (UCA); functionalizing the UCA with a tumor-targeting agent would also allow the targeted administration of anti-cancer drugs at the tumor site. In this article, clinical US techniques are used to show that mesoporous silica nanoparticles (MSNs), functionalized with the monoclonal antibody Herceptin(®), can be used as an effective UCA by increasing US image contrast. Furthermore, in vitro assays show the successful localization and binding of the MSN-Herceptin conjugate to HER2+ cancer cells, resulting in tumor-specific cytotoxicity. These results demonstrate the potential of MSNs as a stable, biocompatible, and effective therapeutic and diagnostic ("theranostic") agent for US-based breast cancer imaging, diagnosis, and treatment.

Biocompatible reverse thermal gel sustains the release of intravitreal bevacizumab in vivo.

PURPOSE: We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery. METHODS: The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. RESULTS: The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections. CONCLUSIONS: To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.

Hybrid inorganic-organic framework as efficient heterogeneous catalyst for the synthesis of allyl glycidyl carbonate from CO2 and allyl glycidyl ether.

A mixed-linker nanoporous coordination polymer Zn2(HIP)2(bipy)(H2O)2 x H2O (ZnHipBipy) constructed from polyfunctional linker 5-hydroxy isophthalic acid (HIP) and exo-bidentate ligand 4,4'-bipyridyl (bipy) was employed as heterogeneous catalyst for allyl glycidyl carbonate (AGC) synthesis from CO2 and allyl glycidyl ether (AGE) under solventless conditions. Besides being the organic linker, 5-hydroxy isophthalic acid enriches the functionality of the material through accessible hydroxyl group capable of contributing extensive hydrogen bonding interactions. The cycloaddition of CO2 and epoxide was catalyzed through a synergistic pathway offered by inherent hydroxyl group together with the catalytically active metal centre. Method of synthesis and texture of the catalyst were key factors in determining the conversion and selectivity. The effects of reaction parameters like catalyst amount, temperature, CO2 pressure and reaction time on the yield of AGC were also studied.