Low-Initial-Modulus Biodegradable Polyurethane Elastomers for Soft Tissue Regeneration

The mechanical match between synthetic scaffold and host tissue remains challenging in tissue regeneration. The elastic soft tissues exhibit low initial moduli with a J-shaped tensile curve. Suitable synthetic polymer scaffolds require low initial modulus and elasticity. To achieve these requirements, random copolymers poly­(δ-valerolactone-<i>co</i>-ε-caprolactone) (PVCL) and hydrophilic poly­(ethylene glycol) (PEG) were combined into a triblock copolymer, PVCL–PEG–PVCL, which was used as a soft segment to synthesize a family of biodegradable elastomeric polyurethanes (PU) with low initial moduli. The triblock copolymers were varied in chemical components, molecular weights, and hydrophilicities. The mechanical properties of polyurethanes in dry and wet states can be tuned by altering the molecular weights and hydrophilicities of the soft segments. Increasing the length of either PVCL or PEG in the soft segments reduced initial moduli of the polyurethane films and scaffolds in dry and wet states. The polymer films are found to have good cell compatibility and to support fibroblast growth in vitro. Selected polyurethanes were processed into porous scaffolds by a thermally induced phase-separation technique. The scaffold from PU–PEG_1K–PVCL_6K had an initial modulus of 0.60 ± 0.14 MPa, which is comparable with the initial modulus of human myocardium (0.02–0.50 MPa). In vivo mouse subcutaneous implantation of the porous scaffolds showed minimal chronic inflammatory response and intensive cell infiltration, which indicated good tissue compatibility of the scaffolds. Biodegradable polyurethane elastomers with low initial modulus and good biocompatibility and processability would be an attractive alternative scaffold material for soft tissue regeneration, especially for heart muscle

Triggerable Degradation of Polyurethanes for Tissue Engineering Applications

Tissue engineered and bioactive scaffolds with different degradation rates are required for the regeneration of diverse tissues/organs. To optimize tissue regeneration in different tissues, it is desirable that the degradation rate of scaffolds can be manipulated to comply with various stages of tissue regeneration. Unfortunately, the degradation of most degradable polymers relies solely on passive controlled degradation mechanisms. To overcome this challenge, we report a new family of reduction-sensitive biodegradable elastomeric polyurethanes containing various amounts of disulfide bonds (PU-SS), in which degradation can be initiated and accelerated with the supplement of a biological product: antioxidant-glutathione (GSH). The polyurethanes can be processed into films and electrospun fibrous scaffolds. Synthesized materials exhibited robust mechanical properties and high elasticity. Accelerated degradation of the materials was observed in the presence of GSH, and the rate of such degradation depends on the amount of disulfide present in the polymer backbone. The polymers and their degradation products exhibited no apparent cell toxicity while the electrospun scaffolds supported fibroblast growth <i>in vitro</i>. The <i>in vivo</i> subcutaneous implantation model showed that the polymers prompt minimal inflammatory responses, and as anticipated, the polymer with the higher disulfide bond amount had faster degradation <i>in vivo</i>. This new family of polyurethanes offers tremendous potential for directed scaffold degradation to promote maximal tissue regeneration

Optimizing Anisotropic Polyurethane Scaffolds to Mechanically Match with Native Myocardium

The biodegradable cardiac patch is desirable to possess mechanical properties mimicking native myocardium for heart infarction treatment. We fabricated a series of anisotropic and biodegradable polyurethane porous scaffolds via thermally induced phase separation (TIPS) and tailored their mechanical properties by using various polyurethanes with different soft segments and varying polymer concentrations. The uniaxial mechanical properties, suture retention strength, ball-burst strength, and biaxial mechanical properties of the anisotropic porous scaffolds were optimized to mechanically match native myocardium. The optimal anisotropic scaffold had a ball burst strength (20.7 ± 1.5 N) comparable to that of native porcine myocardium (20.4 ± 6.0 N) and showed anisotropic behavior close to biaxial stretching behavior of the native porcine myocardium. Furthermore, the optimized porous scaffold was combined with a porcine myocardium-derived hydrogel to form a biohybrid scaffold. The biohybrid scaffold showed morphologies similar to the decellularized porcine myocardial matrix. This combination did not affect the mechanical properties of the synthetic scaffold alone. After in vivo rat subcutaneous implantation, the biohybrid scaffolds showed minimal immune response and exhibited higher cell penetration than the polyurethane scaffold alone. This biohybrid scaffold with biomimetic mechanics and good tissue compatibility would have great potential to be applied as a biodegradable acellular cardiac patch for myocardial infarction treatment

Table_1_Patients Aged ≥55 Years With Stage T1-2N1M1 Differentiated Thyroid Cancer Should Be Downstaged in the Eighth Edition AJCC/TNM Cancer Staging System.DOCX

Objectives: Since the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis (AJCC/TNM) cancer staging system introduced some significant changes, we investigated whether patients with stage T1-2N1M1 differentiated thyroid cancer (DTC) should be placed in stage IVB, with the goal of providing suggestions for improved survival prediction.Materials and Methods: We divided 30,234 DTC patients aged ≥55 years enrolled from the Surveillance, Epidemiology, and End Results (SEER) database into different stage groups based on the new stage system but in a more thorough manner. Univariate and multivariate Cox regression analyses were conducted to explore the clinicopathological factors associated with cancer-specific survival. Survival of different stage groups was assessed by mortality rates per 1,000 person-years, Cox proportional hazards regression analyses, and Kaplan-Meier analyses with log-rank tests and the propensity score matching method.Results: Univariate and multivariate analyses demonstrated that age at diagnosis, T stage, lymph node metastasis, distant metastasis, histological types, extrathyroidal extension, and radiation therapy were associated with cancer-specific survival. Patients with stage T1-2N1M1 had a lower cancer-specific mortality rate per 1,000 person-years (28.081, 95% confidence interval [CI]: 12.616–62.505) and all-cause mortality rate per 1,000 person-years (70.203, 95% CI: 42.323–116.448) than those with low-level stages such as stage T4aN1M0, stage IVA, and stage T1-2N0M1. Cox proportional hazards regression analyses suggested that patients with stage T4bN1M0 belonging to stage IVA (hazard ratio: 2.529, 95% CI: 1.018–6.278, p = 0.046) had a significantly higher risk of cancer-specific mortality than those with stage T1-2N1M1. Kaplan-Meier analyses with log-rank tests suggested that the cancer-specific survival curve of patients with stage T1-2N1M1 had a more modest decline than that of stage T4bN1M0 (p = 0.0125), and the cancer-specific survival curve and all-cause survival curve of patients with stage T1-2N1M1 were not different from those of stage T3N1M0, stage T4aN0M0, stage T4aN1M0, stage T4bN0M0, and stage T1-2N0M1 (all, p > 0.05). The analysis yielded similar results after propensity score matching for other clinicopathological characteristics.Conclusion: Patients aged ≥55 years with stage T1-2N1M1 DTC according to the eighth edition AJCC/TNM cancer staging system should be downstaged and those with stage T4bN1M0 upstaged accordingly.</p

Homochiral Layered Coordination Polymers from Chiral <i>N</i>‑Carbamylglutamate and Achiral Flexible Bis(pyridine) Ligands: Syntheses, Crystal Structures, and Properties

Four new homochiral two-dimensional (2D) coordination polymers, namely, [Zn₂L­(NCG)₂­(H₂O)₂·4H₂O]_<i>n</i> (<b>1</b>), [Zn­(bpe)­(NCG)·3H₂O]_<i>n</i> (<b>2</b>), [Zn­(bpe)­(NCG)­(NaNO₃)_0.5H₂O]_<i>n</i> (<b>3</b>), and [Zn­(bpp)­(NCG)·3.5H₂O]<i>_n</i> (<b>4</b>) (NCG = <i>N</i>-carbamyl­glutamate, L = 1,2-bis­(4′-pyridyl­methyl­amino)­ethane, bpe = 1,2-bis­(4-pyridyl)­ethane, bpp = 1,3-bis­(4-pyridyl)­propane), have been prepared under mild conditions. The structures of CPs <b>1</b>–<b>4</b> were determined by single-crystal X-ray diffraction analysis. Complexes <b>1</b> and <b>2</b> display novel homochiral wavelike networks, with adjacent layers stacked in an AA type arrangement. Complex <b>3</b> shows an interesting 2D double-layered framework, which is further connected to form a 3D supermolecular structure through hydrogen bonding and aromatic π–π stacking interactions. The 2D structure of complex <b>4</b> contains two uncommon helical chains of bpp and NCG, with two flexures in each single strand. Different layers are stacked in an offset ABAB fashion. The mixed-ligand strategy, cooperation of a chiral and an achiral ligand, is applied to prepare the homochiral neutral layered CPs. Complexes <b>1</b>–<b>4</b> display second harmonic generation efficiencies, which are approximately 0.7, 0.9, 0.4, and 0.6 times as much as that of urea powder. In addition, the photoluminescence of all complexes has also been investigated in the solid state

Homochiral Layered Coordination Polymers from Chiral <i>N</i>‑Carbamylglutamate and Achiral Flexible Bis(pyridine) Ligands: Syntheses, Crystal Structures, and Properties

Four new homochiral two-dimensional (2D) coordination polymers, namely, [Zn₂L­(NCG)₂­(H₂O)₂·4H₂O]_<i>n</i> (<b>1</b>), [Zn­(bpe)­(NCG)·3H₂O]_<i>n</i> (<b>2</b>), [Zn­(bpe)­(NCG)­(NaNO₃)_0.5H₂O]_<i>n</i> (<b>3</b>), and [Zn­(bpp)­(NCG)·3.5H₂O]<i>_n</i> (<b>4</b>) (NCG = <i>N</i>-carbamyl­glutamate, L = 1,2-bis­(4′-pyridyl­methyl­amino)­ethane, bpe = 1,2-bis­(4-pyridyl)­ethane, bpp = 1,3-bis­(4-pyridyl)­propane), have been prepared under mild conditions. The structures of CPs <b>1</b>–<b>4</b> were determined by single-crystal X-ray diffraction analysis. Complexes <b>1</b> and <b>2</b> display novel homochiral wavelike networks, with adjacent layers stacked in an AA type arrangement. Complex <b>3</b> shows an interesting 2D double-layered framework, which is further connected to form a 3D supermolecular structure through hydrogen bonding and aromatic π–π stacking interactions. The 2D structure of complex <b>4</b> contains two uncommon helical chains of bpp and NCG, with two flexures in each single strand. Different layers are stacked in an offset ABAB fashion. The mixed-ligand strategy, cooperation of a chiral and an achiral ligand, is applied to prepare the homochiral neutral layered CPs. Complexes <b>1</b>–<b>4</b> display second harmonic generation efficiencies, which are approximately 0.7, 0.9, 0.4, and 0.6 times as much as that of urea powder. In addition, the photoluminescence of all complexes has also been investigated in the solid state

Table_1_Assessment of the Novel, Practical, and Prognosis-Relevant TNM Staging System for Stage I-III Cutaneous Melanoma.docx

BackgroundThe clinical TNM staging system does not differ between the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging manual. A more practical TNM staging system for patients with stage I-III cutaneous melanoma are needed.MethodsData were accessed from the Surveillance, Epidemiology, and End Results (SEER) open database. We divided the patients into 32 groups based on the T and N categories. The Kaplan-Meier survival curves and treatment guidelines were used to proposed a new TNM staging system. Cox proportional hazards model and 1000-person-years were used to verify accuracy.ResultsThis retrospective study included 68 861 patients from 2010 to 2015. The new proposed staging system was as follows: stage IA, T1aN0M0; stage IB, T1b/T2aN0M0; stage IIA, T3-4aN0M0 and T2bN0M0; stage IIB, T1-4aN1-2M0 and T3-4bN0M0; and stage III, T1-4aN3M0 and T1-4bN1-3M0. Hazard ratios for the new stages IB, IIA, IIB, and III, with stage IA as reference, were 4.311 (95% confidence interval [CI]: 3.217-5.778), 8.993 (95% CI: 6.637-12.186), 13.179 (95% CI: 9.435-18.407), and 20.693 (95% CI: 13.655-31.356), respectively (all p-values ConclusionWe developed a more practical and prognosis-relevant staging system than that of the 8th edition AJCC manual for patients with stage I-III cutaneous melanoma. Treatments using this new model would improve the quality of life and survival rates of patients with melanoma.</p

Table_9_Integrative transcriptomic profiling of mRNA, miRNA, circRNA, and lncRNA in alveolar macrophages isolated from PRRSV-infected porcine.xlsx

IntroductionThe porcine reproductive and respiratory syndrome virus (PRRSV) continues to pose a significant threat to the global swine industry, attributed largely to its immunosuppressive properties and the chronic nature of its infection. The absence of effective vaccines and therapeutics amplifies the urgency to deepen our comprehension of PRRSV’s intricate pathogenic mechanisms. Previous transcriptomic studies, although informative, are partially constrained by their predominant reliance on in vitro models or lack of long-term infections. Moreover, the role of circular RNAs (circRNAs) during PRRSV invasion is yet to be elucidated.MethodsIn this study, we employed an in vivo approach, exposing piglets to a PRRSV challenge over varied durations of 3, 7, or 21 days. Subsequently, porcine alveolar macrophages were isolated for a comprehensive transcriptomic investigation, examining the expression patterns of mRNAs, miRNAs, circRNAs, and long non-coding RNAs (lncRNAs).ResultsDifferentially expressed RNAs from all four categories were identified, underscoring the dynamic interplay among these RNA species during PRRSV infection. Functional enrichment analyses indicate that these differentially expressed RNAs, as well as their target genes, play a pivotal role in immune related pathways. For the first time, we integrated circRNAs into the lncRNA-miRNA-mRNA relationship, constructing a competitive endogenous RNA (ceRNA) network. Our findings highlight the immune-related genes, CTLA4 and SAMHD1, as well as their associated miRNAs, lncRNAs, and circRNAs, suggesting potential therapeutic targets for PRRS. Importantly, we corroborated the expression patterns of selected RNAs through RT-qPCR, ensuring consistency with our transcriptomic sequencing data.DiscussionThis study sheds lights on the intricate RNA interplay during PRRSV infection and provides a solid foundation for future therapeutic strategizing.</p

Image_2_Integrative transcriptomic profiling of mRNA, miRNA, circRNA, and lncRNA in alveolar macrophages isolated from PRRSV-infected porcine.tif

IntroductionThe porcine reproductive and respiratory syndrome virus (PRRSV) continues to pose a significant threat to the global swine industry, attributed largely to its immunosuppressive properties and the chronic nature of its infection. The absence of effective vaccines and therapeutics amplifies the urgency to deepen our comprehension of PRRSV’s intricate pathogenic mechanisms. Previous transcriptomic studies, although informative, are partially constrained by their predominant reliance on in vitro models or lack of long-term infections. Moreover, the role of circular RNAs (circRNAs) during PRRSV invasion is yet to be elucidated.MethodsIn this study, we employed an in vivo approach, exposing piglets to a PRRSV challenge over varied durations of 3, 7, or 21 days. Subsequently, porcine alveolar macrophages were isolated for a comprehensive transcriptomic investigation, examining the expression patterns of mRNAs, miRNAs, circRNAs, and long non-coding RNAs (lncRNAs).ResultsDifferentially expressed RNAs from all four categories were identified, underscoring the dynamic interplay among these RNA species during PRRSV infection. Functional enrichment analyses indicate that these differentially expressed RNAs, as well as their target genes, play a pivotal role in immune related pathways. For the first time, we integrated circRNAs into the lncRNA-miRNA-mRNA relationship, constructing a competitive endogenous RNA (ceRNA) network. Our findings highlight the immune-related genes, CTLA4 and SAMHD1, as well as their associated miRNAs, lncRNAs, and circRNAs, suggesting potential therapeutic targets for PRRS. Importantly, we corroborated the expression patterns of selected RNAs through RT-qPCR, ensuring consistency with our transcriptomic sequencing data.DiscussionThis study sheds lights on the intricate RNA interplay during PRRSV infection and provides a solid foundation for future therapeutic strategizing.</p

Table_6_Integrative transcriptomic profiling of mRNA, miRNA, circRNA, and lncRNA in alveolar macrophages isolated from PRRSV-infected porcine.xlsx

IntroductionThe porcine reproductive and respiratory syndrome virus (PRRSV) continues to pose a significant threat to the global swine industry, attributed largely to its immunosuppressive properties and the chronic nature of its infection. The absence of effective vaccines and therapeutics amplifies the urgency to deepen our comprehension of PRRSV’s intricate pathogenic mechanisms. Previous transcriptomic studies, although informative, are partially constrained by their predominant reliance on in vitro models or lack of long-term infections. Moreover, the role of circular RNAs (circRNAs) during PRRSV invasion is yet to be elucidated.MethodsIn this study, we employed an in vivo approach, exposing piglets to a PRRSV challenge over varied durations of 3, 7, or 21 days. Subsequently, porcine alveolar macrophages were isolated for a comprehensive transcriptomic investigation, examining the expression patterns of mRNAs, miRNAs, circRNAs, and long non-coding RNAs (lncRNAs).ResultsDifferentially expressed RNAs from all four categories were identified, underscoring the dynamic interplay among these RNA species during PRRSV infection. Functional enrichment analyses indicate that these differentially expressed RNAs, as well as their target genes, play a pivotal role in immune related pathways. For the first time, we integrated circRNAs into the lncRNA-miRNA-mRNA relationship, constructing a competitive endogenous RNA (ceRNA) network. Our findings highlight the immune-related genes, CTLA4 and SAMHD1, as well as their associated miRNAs, lncRNAs, and circRNAs, suggesting potential therapeutic targets for PRRS. Importantly, we corroborated the expression patterns of selected RNAs through RT-qPCR, ensuring consistency with our transcriptomic sequencing data.DiscussionThis study sheds lights on the intricate RNA interplay during PRRSV infection and provides a solid foundation for future therapeutic strategizing.</p