A pregnant woman with long-standing, retained intraabdominal glass shards who gave birth to a live infant with no complications: a case report.

BACKGROUND: Most cases of traumatic injury during pregnancy involve blunt trauma, with penetrating trauma being uncommonly rare. In glass shard injuries, fragments often penetrate deeply, and multiple injuries may occur simultaneously; attention must be paid to the possibility of organ injury from the residual fragments. However, no case of this occurring during pregnancy has been reported yet. CASE PRESENTATION: We present the case of a 34-year-old pregnant Cameroonian woman who retained intraabdominal glass shards following a penetrating injury at 13 weeks gestation and not diagnosed until 22 weeks gestation. Notably, this patient continued the pregnancy without complications and gave birth via cesarean section at 36 weeks gestation. CONCLUSION: In pregnant women sustaining a penetrating glass trauma during pregnancy, careful attention should be paid to the fragments; in that case, computed tomography is a useful modality for accurately visualizing any remaining fragments in the body. Essentially, the foreign bodies in glass shard injuries during pregnancy should be removed immediately, but conservative management for term delivery is an important choice for patients at risk for preterm delivery.

Preparation of Degradable and Transformable Core-Corona-Type Particles that Control Cellular Uptake by Thermal Shape Change.

Particle-cell interactions, such as cellular uptake, vary depending on the particle size, shape, and surface properties. By dynamic control of the physical properties of particles, microparticle-cell interactions can intentionally be altered. Particle degradability is also necessary for their application in the body. In this study, we aimed to prepare degradable core-corona-type particles that are deformed near the body temperature and investigated particle shape-dependent cellular uptake. Degradable and transformable particles consisting of poly(2-methylene-1,3-dioxepane)-co-poly(ethylene glycol) with three-armed poly(ε-caprolactone) (PCL) were prepared. The particle melting point was controlled by the chain length of the three-armed PCL. Particle degradation occurred under both acidic and alkaline conditions via ester group hydrolysis in the polymer backbones. The rod-shaped microparticles prepared by uniaxial stretching at a temperature above the melting point of the core showed less uptake into macrophages than did the spherical microparticles. Therefore, the degradable transformable particles enable macrophage interaction control via stimuli-regulated particle shapes and are expected to be applied as drug delivery carriers that can be decomposed and excreted from the body.

Phosphoric Acid Triester Micelles: Characterization and Self-Assembly.

In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl ether of poly(ethylene glycol)350, and alkyldichloro phosphates. Interestingly, these triesters combine two biodegradable bonds, -P(O)-O-C and -C(O)-O-C-, and include hydrophilic (MePEG350-lactate) and hydrophobic (R-aliphatic chain of alcohols) moieties. The properties of these esters resemble those of phospholipids. After being placed in an aqueous solution, they self-assembled. We also determined the effects of ester composition on micelle formation, stability, and size using dynamic light scattering. Solubilization tests using Sudan III or doxorubicin hydrochloride (Dox·HCl) revealed that they could be incorporated into the hydrophobic cores of dodecyl di(MePEG350-lactate) phosphate and hexadecyl di(MePEG350-lactate) phosphate. Notably, dodecyl di(MePEG350-lactate) phosphate was stable for five days, whereas hexadecyl di(MePEG350-lactate) phosphate was stable for seven days in phosphate-buffered saline. Moreover, Dox·HCl release rates from the micelles were approximately 30-40, 70-80, and 90-100% after 1, 5, and 28 d, respectively.

Transient Recovery of Complete Atrioventricular Block Due to Maternal Anti-SS-A Antibody Through Antenatal Steroid Administration After 27 Weeks of Gestation.

Maternal anti-SS-A antibodies may cause complete atrioventricular block or myocardial damage in a fetus. Effective treatment for this has not been established. Although antenatal steroids may be a treatment option for anti-SS-A antibody-related myocarditis or atrioventricular block, a complete atrioventricular block is usually considered irreversible once established. Previous reports have indicated that, in cases where antenatal steroids were effective for atrioventricular block, they were administered earlier in the pregnancy. Here we present a case where maternal steroid administration initiated from 27 weeks, which is beyond the recommended optimal treatment period, was effective in altering a complete atrioventricular block to a grade I atrioventricular block.

Physicochemical Properties of Egg-Box-Mediated Hydrogels with Transiently Decreased pH Employing Carbonated Water.

Anionic polysaccharides, including low-methoxy (LM) pectin, are extensively used in biomaterial applications owing to their safety, biocompatibility, and feasibility in constructing supramolecular assemblies by forming egg-box structures with divalent cations. Mixing an LM pectin solution with CaCO3 spontaneously forms a hydrogel. The gelation behavior can be controlled by adding an acidic compound to change the solubility of CaCO3. CO2 is used as the acidic agent and can be easily removed after gelation, thereby reducing the acidity of the final hydrogel. However, CO2 addition has been controlled under varied thermodynamical conditions; therefore, specific CO2 effects on gelation are not necessarily visualized. To evaluate the CO2 impact on the final hydrogel, which would be extended to control hydrogel properties further, we utilized carbonated water to supply CO2 into the gelation mixture without changing its thermodynamic conditions. The addition of the carbonated water accelerated gelation and significantly increased the mechanical strength, promoting cross-linking. However, the CO2 volatilized into the atmosphere, and the final hydrogel became more alkaline than that without the carbonated water, probably because a considerable amount of the carboxy group was consumed for cross-linking. Moreover, when aerogels were prepared from the hydrogels with carbonated water, they exhibited highly ordered networks of elongated porosity in scanning electron microscopy, proposing an intrinsic structural change by CO2 in the carbonated water. We also controlled the pH and strength of the final hydrogels by changing the CO2 amounts in the carbonated water added, thereby validating the significant effect of CO2 on hydrogel properties and the feasibility of using carbonated water.

A Simple Colorimetric Assay of Bleomycin-Mediated DNA Cleavage Utilizing Double-Stranded DNA-Modified Gold Nanoparticles.

A colorimetric assay of DNA cleavage by bleomycin (BLM) derivatives was developed utilizing high colloidal stability on double-stranded (ds) DNA-modified gold nanoparticles (dsDNA-AuNPs) possessing a cleavage site. The assay was performed using dsDNA-AuNPs treated with inactive BLM or activated BLM (Fe(II)⋅BLM). A 10-min exposure in dsDNA-AuNPs with inactive BLM treatment resulted in a rapid color change from red to purple because of salt-induced non-crosslinking aggregation of dsDNA-AuNPs. In contrast, the addition of active Fe(II)⋅BLM retained the red color, probably because of the formation of protruding structures at the outermost phase of dsDNA-AuNPs caused by BLM-mediated DNA cleavage. Furthermore, the results of our model experiments indicate that oxidative base release and DNA-cleavage pathways could be visually distinguished with color change. The present methodology was also applicable to model screening assays using several drugs with different mechanisms related to antitumor activity. These results strongly suggest that this assay with a rapid color change could lead to simple and efficient screening of potent antitumor agents.

Changes in In-Hospital Survival and Long-Term Neurodevelopmental Outcomes of Extremely Preterm Infants: A Retrospective Study of a Japanese Tertiary Center.

OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.

Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography.

BACKGROUND: Early recognition of hypofibrinogenemia and prompt initiation of transfusion therapy in patients with massive obstetrical hemorrhage can improve prognosis. There are reports on the usefulness of point-of-care testing, which provides quicker test results compared with fibrinogen measurements using the conventional Clauss method. OBJECTIVE: This study aimed to compare and investigate the diagnostic accuracy of dry hematology and thromboelastography in point-of-care testing for the diagnosis of hypofibrinogenemia. STUDY DESIGN: A single-center, retrospective study of 126 massive obstetrical hemorrhage cases with point-of-care testing before treatment was initiated. The correlation of fibrinogen values with the Clauss method and the diagnostic accuracy for hypofibrinogenemia were compared between dry hematology and thromboelastography. RESULTS: Fibrinogen value in dry hematology showed a strong positive correlation with values measured by the Clauss method, and the diagnostic accuracy for hypofibrinogenemia was high, but there were many residuals above 100 mg/dL, and the distribution of these residuals was not uniform. Although thromboelastography cannot be used to directly measure fibrinogen values, maximum amplitude citrated functional fibrinogen, amplitude-10 citrated rapid thromboelastography, and amplitude-10 citrated functional fibrinogen showed a strong positive correlation with fibrinogen values using the Clauss method, and no significant difference in correlation or diagnostic accuracy was observed relative to dry hematology. CONCLUSION: Dry hematology and thromboelastography were equally accurate in diagnosing hypofibrinogenemia, with results correlating well with fibrinogen values measured by the Clauss method.

Thermoresponsive Polyphosphoester via Polycondensation Reactions: Synthesis, Characterization, and Self-Assembly.

Using a novel strategy, amphiphilic polyphosphoesters based on poly(oxyethylene H-phosphonate)s (POEHP) with different poly(ethylene glycol) segment lengths and aliphatic alcohols with various alkyl chain lengths were synthesized using polycondensation reactions. They were characterized by 1H NMR, 13C {H} NMR 31P NMR, IR, and size exclusion chromatography (SEC). The effects of the polymer structure on micelle formation and stability, micelle size, and critical micelle temperature were studied via dynamic light scattering (DLS). The hydrophilic/hydrophobic balance of these polymers can be controlled by changing the chain lengths of hydrophilic PEG and hydrophobic alcohols. A solubilizing test, using Sudan III, revealed that hydrophobic substances can be incorporated inside the hydrophobic core of polymer associates. Loading capacity depends on the length of alkyl side chains. The results obtained indicate that these structurally flexible polymers have the potential as drug carriers.

Design of a Sensitive Extracellular Vesicle Detection Method Utilizing a Surface-Functionalized Power-Free Microchip.

Extracellular vesicles (EVs), which are small membrane vesicles secreted from cells into bodily fluids, are promising candidates as biomarkers for various diseases. We propose a simple, highly sensitive method for detecting EVs using a microchip. The limit of detection (LOD) for EVs was improved 29-fold by changing the microchannel structure of the microchip and by optimizing the EV detection protocols. The height of the microchannel was changed from 25 to 8 µm only at the detection region, and the time for EV capture was extended from 5 to 10 min. The LOD was 6.3 × 1010 particles/mL, which is lower than the concentration of EVs in the blood. The detection time was 19 min, and the volume of EV solution used was 2.0 µL. These results indicate that an efficient supply of EVs to the detection region is effective in improving the sensitivity of EV detection. The proposed EV detection method is expected to contribute to the establishment of EV-based cancer point-of-care testing.

The safety and effectiveness of elective laparoscopic surgery for benign ovarian cysts during pregnancy-Comparison with emergency surgery.

AIM: Relatively small benign ovarian cysts are conservatively managed in early pregnancy. However, emergency surgery is required should acute abdomen occur. Our study aimed to examine and compare the outcomes of benign ovarian cysts treated with elective laparoscopic surgery or emergency surgery during pregnancy. METHODS: From 2004 to 2017, we treated 135 pregnant patients (110 elective and 25 emergencies) with benign ovarian cysts at our tertiary perinatal center and compared their surgical and perinatal outcomes. RESULTS: There was no significant difference in cyst diameter (7.6 ± 2.5 vs. 6.8 ± 2.1 cm), but cysts <6 cm were significantly more common in emergency (36%) than in elective (15%) cases. Mature teratomas were significantly more common in elective cases (89% vs. 52%) but corpus luteum cysts were more common in emergency cases (0% vs. 32%). The rates of laparoscopic surgery (98.2% vs. 52.0%) and ovarian conservation (99.1% vs. 80.0%) were significantly higher, and post-surgical hospitalization (4.6 ± 1.3 vs. 9.8 ± 10.5 days) was significantly shorter in elective than in emergency cases. There was no significant difference in the gestational age for delivery (38.9 ± 1.9 vs. 38.4 ± 2.7 weeks), preterm birth rate (12% vs. 20%), or birth weight (2939 ± 469 vs. 3019 ± 510 g). CONCLUSIONS: We cannot state that an emergency surgery during pregnancy is rarely required for small benign ovarian cysts. However, the surgical outcomes were significantly better for elective than for emergency surgery, with no difference in perinatal outcomes. If a benign ovarian cyst is found early in pregnancy, elective laparoscopic surgery may be considered with adequate informed consent.

Nailfold capillary patterns correlate with age, gender, lifestyle habits, and fingertip temperature.

Nailfold capillaroscopy is a simple and noninvasive imaging tool to visualize the pattern of capillaries. Microvascular abnormalities have been previously observed in autoimmune disease such as systemic sclerosis and diabetes. Thus, early detection of microvascular dysfunction or changes has promising way for the one of the disease preventions. In this study, for routine health checkups, we evaluated the relationship between the structure of nailfold capillaries and lifestyle habits in healthy participants. First, we analyzed the correlation of structural parameters of nailfold capillaries with values of responses to questions on their lifestyle habits in 224 participants. The results suggested that an unhealthy lifestyle, including poor sleeping habits, smoking, intense exercise, and drinking alcohol, causes a change in the pattern of nailfold capillaries. We then investigated whether the pattern of nailfold capillaries changed after a conscious improvement in lifestyle habits. One to two weeks after the self-improvement of lifestyle habits, the hairpin loops sharpened or straightened. In conclusion, this study is the first report indicating a correlation between the structure of nailfold capillaries and lifestyle habits in a non-clinical population. The simple, inexpensive, and noninvasive method using nailfold microscopy can be employed for routine health checkups everywhere even at a bedside.

Shape-memory balloon offering simultaneous thermo/chemotherapies to improve anti-osteosarcoma efficacy.

This paper proposes a shape-memory balloon (SMB) to improve bone cement injection efficiency and postoperative thermo/chemotherapy for bone tumors. The SMB consists of biodegradable poly(ε-caprolactone) (PCL), an anticancer drug (doxorubicin, DOX), and heat-generating magnetic nanoparticles (MNPs). The balloon shape is fabricated in a mold by crosslinking PCL macromonomers with DOX and MNPs. The mechanical properties and shape-transition temperature (approximately 40 °C) of the SMB are modulated by adjusting the molecular weight of PCL and the crosslinking density. This allows safe inflation at the affected site with a 400% expansion rate by simple blow molding. The expanded shape is temporarily memorized at 37 °C, and the computed tomography image shows that the bone cement is successfully injected without extra pressure or leakage. The SMB releases DOX for over 4 weeks, allowing a prolonged effect at the local site. The local dosing is constant as the medication is continuously released, demonstrating an ON-OFF switchable heating/cooling response to alternating magnetic field irradiation. In vitro cytotoxic studies have demonstrated that heat generation/drug release and only drug release from the balloon kill approximately 99% and 60% of human osteosarcoma cells, respectively. The proposed SMB is promising in postoperative local thermo/chemotherapy for bone tumors.

Terminal cationization of poly(N-isopropylacrylamide) brush surfaces facilitates efficient thermoresponsive control of cell adhesion and detachment.

A variety of poly(N-isopropylacrylamide) (PIPAAm)-grafted surfaces have been reported for temperature-controlled cell adhesion/detachment. However, the surfaces reported to date need further improvement to achieve good outcomes for both cell adhesion and detachment, which are inherently contradictory behaviors. This study investigated the effects of terminal cationization and length of grafted PIPAAm chains on temperature-dependent cell behavior. PIPAAm brushes with three chain lengths were constructed on glass coverslips via surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization. Terminal substitution of the grafted PIPAAm chains with either monocationic trimethylammonium or nonionic isopropyl moieties was performed through the reduction of terminal RAFT-related groups and subsequent thiol-ene reaction with the corresponding acrylamide derivatives. Although the thermoresponsive properties of the PIPAAm brush surfaces were scarcely affected by the terminal functional moiety, the zeta potentials of the cationized PIPAAm surfaces were higher than those of the nonionized ones, both below and above the phase transition temperature of PIPAAm (30°C). When bovine endothelial cells were cultured on each surface at 37°C, the number of adherent cells decreased with longer PIPAAm. Notably, cell adhesion on the cationized PIPAAm surfaces was higher than that on the nonionized surfaces. This terminal effect on cell adhesion gradually weakened with increasing PIPAAm length. In particular, long-chain PIPAAm brushes virtually showed cell repellency even at 37°C, regardless of the termini. Interestingly, moderately long-chain PIPAAm brushes promoted cell detachment at 20°C, with negligible terminal electrostatic interruption. Consequently, both cell adhesion and detachment were successfully improved by choosing an appropriate PIPAAm length with terminal cationization.

Conjugation of antibody with temperature-responsive polymer via in situ click reaction to enable biomarker enrichment for increased diagnostic sensitivity.

Early diagnosis of infectious diseases is one of the current prevalent challenges, especially in low and limited resource settings where simple, fast, portable, cheap, and sensitive diagnostic approaches are needed. Lateral flow immunoassay (LFIA) is a common, rapid screening assay. However, the low assay sensitivity limits the utility of LFIA for specimens with low pathogenic loads (early infection stages). Antibodies conjugated with stimulus-responsive polymers have been previously utilized to improve assay sensitivity for detection of biomarkers at low concentrations. However, the loss of antibody affinity after polymer conjugation remains a significant challenge. In this study, we developed poly(N-isopropylacrylamide-co-N-(2-hydroxyisopropyl)acrylamide-co-strained alkyne-isopropylacrylamide), a novel polymer for biomarker enrichment, by polymer conjugation after antibody-antigen recognition. We employed and promoted the click chemistry in situ, to facilitate highly specific conjugation between novel temperature-responsive polymers and antibody-antigen complexes. This method could suppress the decrease in the binding constant associated with polymer conjugation (>20-fold). The conjugation was successfully demonstrated in body fluids such as urine and saliva. We achieved >5-fold antigen enrichment via thermal precipitation by conjugating polymers to the antibodies after antigen recognition. Concentrated biomarkers resulted in improved LFIA detection. This approach can potentially be utilized to improve diagnostic tests for infectious diseases in low and limited resource settings.

Facile preparation of multi-stimuli-responsive degradable hydrogels for protein loading and release.

Functional materials that can recognize the tumor microenvironment, characterized by acidic or reducing conditions, are needed for the designing of drug delivery carriers for cancer treatment. Hydrogels are potential protein drug carriers because they contain a large amount of water and stimuli-responsive functions can easily be introduced in them. However, it is difficult to introduce multi-stimuli-responsive functions and degradability at the same time. Here, we synthesized thermo- and pH-responsive hydrogels via a coupling reaction between poly(ethylene glycol) diglycidyl ether (PEGDE) and cystamine (CA). The prepared hydrogels showed lower critical solution temperature-type thermoresponsive behavior and pH-responsive swelling changes due to the protonation of secondary and/or tertiary amino groups arising from the crosslinking agent CA. Under reducing conditions, the hydrogels were degraded via the thiol exchange reaction in the presence of dithiothreitol or glutathione. The loading and release properties of FITC-labeled model proteins from the hydrogels were investigated. The loaded amount of the protein increased with decreasing molecular weight or hydrodynamic radius, which is based on the size of the network structure of the hydrogels. Notably, loaded proteins in the hydrogels were released only under reducing conditions, which mimic the tumor microenvironment. Thus, the prepared multi-responsive degradable hydrogels are expected to be used as functional drug delivery carriers for cancer treatment.

Preparation of Spherical Nucleic Acid Nanoparticles Containing a Self-immolative Poly(carbamate) Core.

We prepared a novel spherical nucleic acid, containing a core structure of self-immolative poly(carbamate) (PC), with aminobenzyl alcohol as a repeating unit, by conjugating an end-activated PC derivative with an amine-terminated oligoDNA on a solid support for PC-oligoDNA. Dynamic light-scattering measurements revealed a hydrodynamic diameter of 107 nm with a narrow size distribution. A fluorescent monomer with aminobenzyl alcohol is available for PC-oligoDNA synthesis to enhance the fluorescence emission by a domino-like disassembly of PC in response to various external stimuli.

Multiplex MicroRNA Detection on a Surface-Functionalized Power-Free Microfluidic Chip.

Circulating microRNAs (miRNAs) have emerged as promising cancer biomarkers because their concentration profiles in body fluids are associated with the type and clinical stage of cancer. For multiplex miRNA detection, a novel surface-functionalized power-free microfluidic chip (SF-PF microchip) has been developed. The inner surface of the SF-PF microchip microchannels was functionalized via electron beam-induced graft polymerization and immobilization of capture probe DNAs. Simultaneous and specific duplex miRNA detection was achieved on the line-type SF-PF microchip with detection limits of 19.1 and 47.6 nmol L-1 for hsa-miR-16 and hsa-miR-500a-3p, respectively. Moreover, simultaneous and specific triplex miRNA detection was achieved on the stripe-type SF-PF microchip. The sample volume required for this microchip was 0.5 µL, and the time required for detection was 17 min. These results indicate that up to six types of miRNAs could be detected without compromising the advantages of the previous SF-PF microchips for cancer point-of-care testing.

Micropatterned Smart Culture Surfaces via Multi-Step Physical Coating of Functional Block Copolymers for Harvesting Cell Sheets with Controlled Sizes and Shapes.

Cell micropatterning on micropatterned thermoresponsive polymer-based culture surfaces facilitates the creation of on-demand and functional cell sheets. However, the fabrication of micropatterned surfaces generally includes complicated procedures with multi-step chemical reactions. To overcome this issue, this study proposes a facile preparation of micropatterned thermoresponsive surfaces via a two-step physical coating of two different diblock copolymers. Both copolymers contain poly(butyl methacrylate) blocks as hydrophobic anchors for water-stable polymer deposition. At first, thermoresponsive polymer layers are constructed on cell culture dishes via spin-coating block copolymers containing poly(N-isopropylacrylamide) blocks that exhibit a transition temperature of ≈30 °C in aqueous media. To create polymer micropatterns on the thermoresponsive surfaces, microcontact printing of block copolymers containing hydrophilic poly(N-acryloylmorpholine) (PNAM) blocks is performed using polydimethylsiloxane stamps. Stamped PNAM-based block polymers are adsorbed to the outermost thermoresponsive surfaces, and increase the surface hydrophilicity with decreasing protein adsorption. Cells adhere and proliferate on the thermoresponsive domains at 37 °C, whereas the stamped hydrophilic domains remain cell-repellent for 7 days. At 20 °C, cell sheets with controlled sizes and shapes are harvested from the surfaces with the desired micropatterns. This technique is useful for the preparation of micropatterned polymer surfaces for various biomedical applications.

Protein Removal from Hydrogels through Repetitive Surface Degradation.

Suppression of protein adsorption is a necessary property for materials used in the living body. In this study, thermoresponsive and degradable hydrogels were prepared by the radical polymerization of 2-methylene-1,3-dioxepane, 2-hydroxyethyl acrylate (HEA), and poly(ethylene glycol) monomethacrylate (PEGMA). The prepared hydrogels re-exposed PEG-grafted chains to the interface through surface degradation, which was confirmed by the maintenance of the chemical composition of the hydrogel surfaces after hydrolysis. Notably, adsorbed proteins can be removed from the hydrogel surfaces through hydrogel surface degradation at least thrice.