Reactive oxygen species (ROS) are natural by-products of oxygen metabolism. As signaling molecules, ROS can regulate various physiological processes in the body. However excessive ROS may be a major cause of inflammatory diseases. In the field of neurological diseases, ROS cause neuronal apoptosis and neurodegeneration, which severely impede neuroregeneration. Currently, ROS-scavenging biomaterials are considered as a promising therapeutic strategy for neurological injuries due to their ability to scavenge excessive ROS at defects and modulate the oxidative stress microenvironment. This review provides an overview of the generation and sources of ROS, briefly describes the dangers of generating excessive ROS in nervous system diseases, and highlights the importance of scavenging excessive ROS for neuroregeneration. We have classified ROS-scavenging biomaterials into three categories based on the different mechanisms of ROS clearance. The applications of ROS-responsive biomaterials for neurological diseases, such as spinal cord injury, brain injury, and peripheral nerve injury, are also discussed. Our review contributes to the development of ROS-scavenging biomaterials in the field of neural regeneration.

Microneedle patches have emerged as a promising approach for diabetic wound healing by enabling the targeted delivery of therapeutic agents such as stem cells and their derived exosomes, as well as localized delivery of bioactive moieties. These patches offer a non-invasive and efficient method for administering therapeutic payloads directly to the site of the wound, bypassing systemic circulation and minimizing potential side effects. The targeted delivery of stem cells holds immense potential for promoting tissue regeneration and accelerating wound healing in diabetic patients. Similarly, the localized delivery of stem cell-derived exosomes, which are known for their regenerative and anti-inflammatory properties, can enhance the healing process. Furthermore, microneedle patches enable the precise and controlled release of bioactive moieties, such as growth factors and cytokines, directly to the wound site, creating a conducive microenvironment for tissue repair and regeneration. The challenges associated with microneedle patches for diabetic wound healing are multifaceted. Biocompatibility issues, variability in skin characteristics among diabetic patients, regulatory hurdles, scalability, cost considerations, long-term stability, and patient acceptance and compliance all present significant barriers to the widespread adoption and optimization of microneedle technology in clinical practice. Overcoming these challenges will require collaborative efforts from various stakeholders to advance the field and address critical gaps in research and development. Ongoing research focuses on enhancing the biocompatibility and mechanical properties of microneedle materials, developing customizable technologies for personalized treatment approaches, integrating advanced functionalities such as sensors for real-time monitoring, and improving patient engagement and adherence through education and support mechanisms. These advancements have the potential to improve diabetic wound management by providing tailored and precise therapies that promote faster healing and reduce complications. This review explores the current landscape of microneedle patches in the context of diabetic wound management, highlighting both the challenges that need to be addressed and future perspectives for this innovative treatment modality.

Silk fibroin (SF), a pivotal biomaterial, holds immense promise for diverse applications within the realm of bone tissue engineering. SF is an ideal scaffold material with exceptional biocompatibility, mechanical robustness, biodegradability, and bioactivity. A plethora of investigations have corroborated SF's efficacy in supporting bone tissue repair and regeneration. This comprehensive review delves into the structural attributes, physicochemical characteristics, and extraction methodologies of SF. Moreover, it elucidates the strides taken in harnessing SF across a spectrum of forms, including films, hydrogels, scaffolds, electrospun fibers, and composites for bone tissue engineering applications. Moreover, the application bottleneck of SF as a bone repair material is highlighted, and its development prospects and potential biomedical applications are also presented in this review. We expect that this review can inspire the broad interest of a wide range of readers working in the fields of materials science, tissue engineering, biomaterials, bioengineering, and biomedicine.

Cationic polymers have been widely developed as carriers for intracellular protein delivery, but face tough challenges such as poor serum tolerance and inevitable material toxicity. Here, we present a type of phase-separating polymer with an anionic surface to address the above issues. A cationic dendrimer is first modified with a hydrophobic moiety to obtain a pH-responsive amphiphilic polymer, which is further conjugated with anionic benzenesulphonate at different grafting degrees. The benzenesulphonate modification facilely changes the hydrophobicity of the polymer and reduces the material cytotoxicity. Interestingly, the polymer can co-assemble with cargo proteins to form nanovesicles for intracellular protein delivery. The benzenesulphonate on the polymer surface bolsters the resistance of polymers to serum proteins, allowing the materials to maintain high delivery efficacy in culture media containing abundant serum proteins. This study provides a facile strategy to design materials with high serum tolerance for intracellular protein delivery.

Bone defects and congenital bone deficiencies are common clinical conditions. However, conventional non-degradable artificial materials often lead to serious complications, such as severe infections and material displacement. The emergence of tissue engineering and the organoid concept presents a promising approach for the repair of bone defects, facilitating physiological reconstruction while minimizing complications. Nevertheless, previous studies have not developed injectable organoids that incorporate fully mineralized and organic microenvironments to achieve rapid osteogenesis and convenient application in bone regeneration. Therefore, it is imperative to devise an effective strategy to address these challenges. This study first prepared injectable GL scaffolds with varying concentrations and identified the optimal GL concentration (0.8%) for osteogenesis through systematic evaluation of the osteogenic efficiency. Subsequently, 30% mixture of inorganic salts of native bone (NBIS) and extracellular matrix from the periosteum (pECM) was integrated into the optimal GL scaffold at a ratio of NBIS : pECM = 7 : 3 to create an injectable scaffold featuring biomimetic mineralized and organic microenvironments. This scaffold was further utilized for analysis of osteogenic mechanisms and injected subcutaneously into rabbits for only four weeks to assess its osteogenic efficacy . The results indicated that the incorporation of NBIS and pECM significantly enhanced the osteogenic efficacy by actively regulating ossification and ECM-receptor interaction signaling pathways, as well as upregulating RUNX2, ALP, COL1, and LAMA. This study introduces a promising injectable strategy for rapid osteogenesis using fully mineralized and organic biomimetic organoids.

Correction for 'Bioactivity of cerium dioxide nanoparticles as a function of size and surface features' by Veronika Sarnatskaya , , 2024, , 2689-2704, https://doi.org/10.1039/D3BM01900D.

Natural resource based polymers, especially those derived from proteins, have attracted significant attention for their potential utilization in advanced wound care applications. Protein based wound care materials provide superior biocompatibility, biodegradability, and other functionalities compared to conventional dressings. The effectiveness of various fabrication techniques, such as electrospinning, phase separation, self-assembly, and ball milling, is examined in the context of developing protein-based materials for wound healing. These methods produce a wide range of forms, including hydrogels, scaffolds, sponges, films, and bioinspired nanomaterials, each designed for specific types of wounds and different stages of healing. This review presents a comprehensive analysis of recent research that investigates the transformation of proteins into materials for wound healing applications. Our focus is on essential proteins, such as keratin, collagen, gelatin, silk, zein, and albumin, and we emphasize their distinct traits and roles in wound care management. Protein-based wound care materials show promising potential in biomedical engineering, offering improved healing capabilities and reduced risks of infection. It is crucial to explore the potential use of these materials in clinical settings while also addressing the challenges that may arise from their commercialization in the future.

Pharmacokinetics and biodistribution profiles of active substances are crucial aspects for their safe and successful administration. Since many immunogenic compounds do not meet all requirements for safe and effective administration, well-defined drug nanocarrier systems are necessary with a stimuli-responsive drug-release profile. For this purpose, a novel pH-responsive aliphatic cyclic carbonate is introduced with benzyl ketal side chains and polymerized onto a poly(ethylene glycol) macroinitiator. The resulting block copolymers could be formulated a solvent-evaporation method into well-defined polymeric micelles. The hydrophobic carbonate block was equipped with an acid degradable ketal side group that served as an acid-responsive functional group. Already subtle pH alternations led to micelle disassembly and the release of the active cargo. Furthermore, basic carbonate backbone degradation assured the pH responsiveness of the nanocarriers in both acidic and basic conditions. To investigate the delivery capacity of polymeric micelles, the model small molecule compound CL075, which serves as an immunotherapeutic TLR7/8 agonist, was encapsulated. Incubation studies with human blood plasma revealed the absence of undesirable protein adsorption on the drug-loaded nanoparticles. Furthermore, applications confirmed cell uptake of the nanodrug formulations by macrophages and the induction of payload-mediated immune stimulation. Altogether, these results underline the huge potential of the developed multi-pH-responsive polymeric nanocarrier for immunodrug delivery.

Chiral recognition holds tremendous significance in both life science and chemistry. The ability to differentiate between enantiomers is crucial because one enantiomer typically holds greater biological relevance while its counterpart is often not only unnecessary but also potentially harmful. In this regard, homochiral metallacycle [ZnClL] is used in this study to understand and differentiate between the and enantiomers of amino acids (alanine, proline, serine, and valine). The electronic, geometric, and thermodynamic stabilities of the amino acid enantiomers inside the metallacycle are determined through various analyses. The greater interaction energy () is obtained for the ser@metallacycle complexes , -33.03 and -30.75 kcal mol, respectively for the and enantiomers. The highest chiral discrimination energy of 3.11 kcal mol is achieved for ala@metallacycle complexes. Regarding the electronic properties, the frontier molecular orbital (FMO) analysis indicates that the energy gap decreases after complexation, which is confirmed through density of states (DOS) analysis. Moreover, natural bond orbital (NBO) analysis determines the amount and direction of charge transfer , from metallacycle towards amino acids. The maximum NBO charge transfer is observed for -pro@metallacycle complex , -0.291 ||. Electron density difference (EDD) analysis further proves the direction of charge transfer. Noncovalent interaction index (NCI) and quantum theory of atoms in molecules (QTAIM) analyses demonstrate that the noncovalent interactions present between the host and guest are the weak van der Waals forces and hydrogen bonding. The results of NCI and QTAIM analyses for all the complexes are in alignment with those of the interaction energy () and chiral discrimination energy () analyses, , significantly greater non-bonding interactions are observed for the complexes with greater , , for ala@metallacycle. Overall, our analyses demonstrate the excellent chiral discrimination ability of metallacycle towards chiral molecules, , for enantiomers of amino acids through host-guest supramolecular chemistry.

Over eight million surgical procedures are conducted annually in the United Stats to address organ failure or tissue losses. In response to this pressing need, recent medical advancements have significantly improved patient outcomes, primarily through innovative reconstructive surgeries utilizing tissue grafting techniques. Despite tremendous efforts, repairing damaged tissues remains a major clinical challenge for bioengineers and clinicians. 3D bioprinting is an additive manufacturing technique that holds significant promise for creating intricately detailed constructs of tissues, thereby bridging the gap between engineered and actual tissue constructs. In contrast to non-biological printing, 3D bioprinting introduces added intricacies, including considerations for material selection, cell types, growth, and differentiation factors. However, technical challenges arise, particularly concerning the delicate nature of living cells in bioink for tissue construction and limited knowledge about the cell fate processes in such a complex biomechanical environment. A bioink must have appropriate viscoelastic and rheological properties to mimic the native tissue microenvironment and attain desired biomechanical properties. Hence, the properties of bioink play a vital role in the success of 3D bioprinted substitutes. This review comprehensively delves into the scientific aspects of tissue-centric or tissue-specific bioinks and sheds light on the current challenges of the translation of bioinks and bioprinting.

The healing of complex diabetic wounds with a hyperglycemic microenvironment and bacterial infection is considered an important clinical issue. In this study, glucose oxidase (GOx) and gold nanoclusters (AuNCs) were encapsulated in quaternary carboxymethyl chitosan (QCMCS)/sodium alginate oxide (OSA) hydrogels and were immersed in tannic acid (TA) solution to achieve antioxidant, antibacterial, pro-angiogenesis, pro-collagen deposition and real-time monitoring functions. studies showed that TA-QCMCS/OSA@GOx@AuNC hydrogels had inhibition rates of 98.99% and 99.99% against and , respectively, and the survival rate of mouse fibroblasts (L929) was over 95%. studies showed that TA-QCMCS/OSA@GOx@AuNC hydrogels were 97.28% effective in healing diabetic wounds. In addition, image signals from TA-QCMCS/OSA@GOx@AuNC hydrogels can be collected in real time to accurately obtain glucose concentration values of diabetic wounds and reflect the healing status of diabetic wounds in a timely manner. The results showed that TA-QCMCS/OSA@GOx@AuNC hydrogels provide a novel idea for real-time monitoring of diabetic wound treatment.

Injuries such as articular cartilage defects are prevalent factors in the development and progression of joint diseases. The discontinuity of the articular surface due to cartilage defects significantly accelerates the onset of arthritis. Cartilage tissue-engineered scaffolds are essential for restoring the continuity of the articular surface. This study presents a dual-network hydrogel, GelMA-FT/Sr, which demonstrates excellent lubrication properties and accelerates the healing of cartilage defects. The hydrogel is composed of a methacrylated gelatin (GelMA) network, an -fluorenylmethoxycarbonyl-L-tryptophan (FT) network, and strontium ions (Sr). The results indicate that the hydrogel exhibits lubricating properties, and the incorporation of Sr extends the degradation time of the hydrogel. Additionally, the hydrogel shows biocompatibility and enhances chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into cartilage. studies further confirm the hydrogel's efficacy in promoting the repair of cartilage defects in a rat model of cartilage injury. In conclusion, the GelMA-FT/Sr hydrogel is a promising scaffold for cartilage tissue engineering, notable for its excellent lubrication properties, ability to recruit stem cells, and effectiveness in facilitating cartilage defect repair.

Various oncolytic viruses (OVs) have been adopted as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-T cells against solid tumors. However, the therapeutic effect of OVs has been limited by pre-existing neutralizing antibodies and poor targeting delivery for systemic administration. Herein, we propose using bioorthogonal OV nanovesicles to boost the antitumor effects of CAR-T cells in solid tumors by reshaping the tumor microenvironment. Using a cell-membrane nanomimetic technique, we embedded artificial chemical ligands on cancer cell surfaces and then encapsulated lysoviral particles to obtain dual-targeted OV nanovesicles with bioorthogonal targeting and homologous recognition. OVs can be directly encapsulated into cancer cell nanovesicles and exhibit a liposome-like nanostructure, efficient loading, and excellent tumor-targeting capability. Encouragingly, OV nanovesicles efficiently induced tumor-cell apoptosis while sparing normal tissues and cells, thereby inhibiting tumor growth. Administration of viral nanovesicles effectively increased the secretion of anti-tumor cytokines such as IL-2, TNF-α and IFN-γ, and significantly promoted the infiltration and activation of CD8CAR-T cells in tumors. Our data suggest that bioorthogonal OV nanovesicles hold great potential to overcome the limitations of CAR-T cells as monotherapies against solid tumors and, thus, drive the clinical application of combination therapy.

Melanoma, characterized by rapid tumour progression and a strong tendency to metastasize, poses significant challenges in clinical treatment. Given the vital role of B-cell lymphoma 2 (Bcl-2) protein overexpression in inhibiting apoptosis in tumour cells, the suppression of Bcl-2 has emerged as a promising anticancer therapy. Here, we have developed a straightforward and effective delivery system that combines small interfering RNA (siRNA) targeting Bcl-2 (siBcl-2) with ionic liquids (ILs) for treating melanoma. The unique properties of ILs including structural tunability, inherent charge, and chemical stability have garnered significant attention in the biomedical fields; however, their application in siRNA delivery remains nascent. Rather than the weak function of free siBcl-2, our delivery system (1-hexyl-3-methylimidazolium-siBcl-2, designated as C6-siBcl-2) demonstrated an outstanding capacity to improve the cellular uptake and lysosomal escape, resulting in robust apoptosis and cytotoxicity in melanoma cells. In addition to exhibiting superior gene silencing activity , such events were also evident in mice bearing melanoma tumours. In particular, this IL-based delivery system showed advantages in suppressing tumour growth, preventing metastasis, and enhancing the survival time of mice with melanoma tumours. Therefore, our study offered a novel and powerful nanoplatform that integrated ILs and RNA interference therapy, presenting new strategies for cancer treatment.

DNA modification of the plasma membrane is an excellent approach for controlling membrane-protein interactions, modulating cell-cell/cell-biomolecule interactions, and extending the biosensing field. The hydrophobic insertion of DNA conjugated with hydrophobic anchoring molecules is utilized for tethering DNA on the cell membrane. In this study, we developed an alternative approach to tether DNA on the plasma membrane based on ssDNA- and cholesterol-binding proteins. We designed a fusion protein (Rep-ALOD4) composed of domain 4 of anthrolysin O (ALOD4), which binds to cholesterol in the plasma membrane, and a replication initiator protein derived from porcine circovirus type 2 (Rep), which forms covalent bonds with single-stranded DNA (ssDNA) with a Rep recognition sequence. Rep-ALOD4 conjugates ssDNA to Rep and binds to the plasma membrane cholesterol, thus tethering ssDNA to the cells. Quartz crystal microbalance measurements showed that membrane cholesterol binding of Rep-ALOD4 to the lipid bilayer containing cholesterol was accelerated above 20% (w/w) cholesterol in the lipid bilayer. Rep-ALOD4 was conjugated to fluorescein-labeled ssDNA (S-FITC-Rep-ALOD4) and used to treat human cervical tumor HeLa cells. The green signal assigned to S-FITC-Rep-ALOD4 was detected along HeLa cells, whereas diminished by cholesterol removal with methyl β-cyclodextrins. Moreover, ssDNA-conjugated Rep-ALOD4 tethered ssDNA-conjugated functional proteins on the HeLa cell plasma membrane complementary base pairing. Collectively, Rep-ALOD4 has the potential as an ssDNA-tethering material plasma membrane cholesterol to extend cell surface engineering.

Silk fibroin is a naturally abundant biomaterial renowned for its excellent biocompatibility and biodegradability, making it a promising candidate for biomedical applications like wound dressings. However, traditional silk fibroin materials often lack sufficient mechanical strength, adhesion, and the ability to modulate inflammation and oxidative stress-factors crucial for effective wound healing. To address these limitations, regenerated silk fibroin/magnesium ion [RSF/Mg(II)] composite films were developed by incorporating Mg(II) ions into RSF solutions. These films were characterized using Raman spectroscopy, mechanical testing, and biocompatibility assessments, and their wound-healing efficacy was evaluated in a mouse skin defect model. The RSF/Mg(II) composite films exhibited superior adhesion, higher transparency, and enhanced mechanical flexibility compared to pristine RSF films. They also demonstrated anti-inflammatory and antioxidative properties, effectively reducing cell apoptosis and reactive oxygen species levels . , the RSF/Mg Mg(II) composite films significantly accelerated wound healing in mice, improving epidermal thickness, collagen deposition, and promoting blood vessel formation. This study highlights the potential of RSF/Mg(II) composite films as advanced wound dressings with improved biocompatibility and biological activity, offering valuable insights for the development of Mg(II) ion-based biomaterials in wound healing and tissue regeneration applications.

Most biological materials used in the body undergo protein adsorption, which alters their biological functions. Previously, we introduced surface-degradable hydrogels as adsorbed protein-removing surfaces. However, only a few surface renewals were possible because of the hydrophilic nature of the hydrogels, which accelerated their degradation. In this research, we introduced thermoresponsive properties of hydrogels for limited degradation for protein removal. Hydrogels were synthesized by the radical polymerization of -isopropylacrylamide (NIPAAm), 2-methylene-1,3-dioxepane, and poly(ethylene glycol) monomethacrylate (PEGMA). The synthesized hydrogels demonstrated thermoresponsive behavior derived from poly(NIPAAm). At 10 °C, the hydrogels swelled and exhibited bulk degradation. After 2 h, the prepared hydrogels were degraded completely. However, at 37 °C, the hydrogels shrunk and showed surface degradation. After 7 h of degradation, the swelling ratio of the hydrogels changed marginally. The proteins adsorbed on the hydrogel surfaces were removed surface degradation. However, the fluorescence intensity of adsorbed proteins increased on the hydrogel surfaces without degradable functions. In addition, the fluorescence intensity of adsorbed proteins increased in the hydrogels without PEG graft chains, suggesting that the prepared thermoresponsive hydrogels with PEG chains could be used as potential biomaterial surface coating materials, exhibiting regenerative low-fouling ability.

Peptides are well known for forming nanoparticles, while DNA duplexes, triplexes and tetraplexes create rigid nanostructures. Accordingly, the covalent conjugation of peptides to DNA/RNA produces hybrid self-assembling features and may lead to interesting nano-assemblies distinct from those of their individual components. Herein, we report the preparation of a collagen mimetic peptide incorporating lysine in its backbone, with alkylamino side chains radially conjugated with G-rich PNA [collagen-(PNA-GGG)]. In the presence of complementary C-rich DNA (dCCCTTTCCC) at neutral pH, the collagen mimetic triplexes were interconnected by PNA-GGG : DNA-CCC duplexes, leading to the formation of larger assemblies of nanostructures. Upon decreasing the pH to 4.5, the dissociation of the triplex-duplex assembly released the protonated C-rich DNA, which immediately folded into an -motif. With an increase in the pH to 7.2 (neutral), the -motif unfolded into linear DNA, which reformed the PNA-GGG : DNA-CCC duplex interconnecting the collagen triplexes. The pH-induced switching of the assembly and disassembly was reversible over a few cycles. The hybrid collagen-(PNAGGG) : DNA-CTC triplex-duplex and the individual components of the assembly including the -motif were characterized by UV and CD melting, fluorescence, TEM and gel electrophoresis. The pH-induced reversible switching was established by the changes in the CD and fluorescence properties. Peptide-DNA conjugates have wide applications in both biology and materials science, ranging from therapeutics and drug delivery to diagnostics and molecular switches. Thus, the prototype ensemble of the triplex peptide-PNA conjugate and its duplex with DNA described herein has potential for elaboration into rationally designed systems by varying the PNA/DNA sequences to trap functional ligands/drugs for release in pH-controlled environments.

Nanotechnology in stem cell medicine is an interdisciplinary field which has gained a lot of interest recently. This domain addresses key challenges associated with stem cell medicine such as cell isolation, targeted delivery, and tracking. Nanotechnology-based approaches, including magnetic cell sorting, fluorescent tagging, and drug or biomolecule conjugation for delivery, have enhanced precision in stem cell isolation and guided cell migration, increasing the therapeutic potential. Recent studies have focused on using nanomaterials and scaffolds to drive stem cell differentiation by activating specific molecular pathways, achieved through embedding biomolecules within the scaffold or through the scaffold's material composition and structure alone. These innovations hold promise in therapeutic applications across various diseases, including cancer stem cell targeting, neurodegenerative disorders, pre-eclampsia, cardiovascular conditions, and organoid development. This review examines recent advancements in the field, explores potential applications like biosensors and nanochips, and highlights the challenges and research gaps.

The field of biomedical engineering continually seeks innovative technologies to address complex healthcare challenges, ranging from tissue regeneration to drug delivery and biosensing. Plant skeletons offer promising opportunities for these applications due to their unique hierarchical structures, desirable porosity, inherent biocompatibility, and adjustable mechanical properties. This review comprehensively discusses chemical principles underlying the utilization of plant-based scaffolds in biomedical engineering. Highlighting their structural integrity, tunable properties, and possibility of chemical modification, the review explores diverse preparation strategies to tailor plant skeleton properties for bone, neural, cardiovascular, skeletal muscle, and tendon tissue engineering. Such applications stem from the cellulosic three-dimensional structure of different parts of plants, which can mimic the complexity of native tissues and extracellular matrices, providing an ideal environment for cell adhesion, proliferation, and differentiation. We also discuss the application of plant skeletons as carriers for drug delivery due to their structural diversity and versatility in encapsulating and releasing therapeutic agents with controlled kinetics. Furthermore, we present the emerging role played by plant-derived materials in biosensor development for diagnostic and monitoring purposes. Challenges and future directions in the field are also discussed, offering insights into the opportunities for future translation of sustainable plant-based technologies to address critical healthcare needs.

Donepezil (DNZ) has been used to treat dementia associated with mild, moderate, or severe Alzheimer's disease (AD). DNZ uptake can alleviate cognitive symptoms in AD patients acetylcholinesterase (AChE) inhibition. However, oral administration of DNZ has limitations, including first-pass metabolism, difficulties with swallowing, and low patient compliance. In this work, we disclose a novel transdermal DNZ delivery system utilizing T2 polymer, synthesized the ring-opening polymerization of 2,2,5,5-tetramethyl-2,5-disila-1-oxacyclopentane with trifluoroacetic acid (TFA). In the studies in an AD animal model, the DNZ-loaded T2 polymer (DNZ@T2) facilitated efficient transdermal DNZ delivery to the bloodstream and improved spatial working memory and long-term memory of the AD mouse model. Both the T2 polymer and DNZ@T2 exhibited low cytotoxicity and non-significant toxicity. This research highlights a promising transdermal delivery strategy for AD treatment, potentially enhancing therapeutic efficacy and patient compliance.