“Smart” Materials Based on Cellulose: A Review of the Preparations,Properties, and Applications

Cellulose is the most abundant biomass material in nature, and possesses some promising properties, such as mechanical robustness, hydrophilicity, biocompatibility, and biodegradability. Thus, cellulose has been widely applied in many fields. “Smart” materials based on cellulose have great advantages—especially their intelligent behaviors in reaction to environmental stimuli—and they can be applied to many circumstances, especially as biomaterials. This review aims to present the developments of “smart” materials based on cellulose in the last decade, including the preparations, properties, and applications of these materials. The preparations of “smart” materials based on cellulose by chemical modifications and physical incorporating/blending were reviewed. The responsiveness to pH, temperature, light, electricity, magnetic fields, and mechanical forces, etc. of these “smart” materials in their different forms such as copolymers, nanoparticles, gels, and membranes were also reviewed, and the applications as drug delivery systems, hydrogels, electronic active papers, sensors, shape memory materials and smart membranes, etc. were also described in this review.     

Blended Natural Support Materials—Collagen Based Hydrogels Used in Biomedicine

Due to their unique properties—the are biocompatible, easily accessible, and inexpensive with programmable properties—biopolymers are used in pharmaceutical and biomedical research, as well as in cosmetics and food. Collagen is one of the most-used biomaterials in biomedicine, being the most abundant protein in animals with a triple helices structure, biocompatible, biomimetic, biodegradable, and hemostatic. Its disadvantages are its poor mechanical and thermal properties and enzymatic degradation. In order to solve this problem and to use its benefits, collagen can be used blended with other biomaterials such as alginate, chitosan, and cellulose. The purpose of this review article is to offer a brief paper with updated information on blended collagen-based formulations and their potential application in biomedicine.     

Peptide-Based Hydrogels: New Materials for Biosensing and Biomedical Applications

Peptide-based hydrogels have attracted increasing attention for biological applications and diagnostic research due to their impressive features including biocompatibility and biodegradability, injectability, mechanical stability, high water absorption capacity, and tissue-like elasticity. The aim of this review will be to present an updated report on the advancement of peptide-based hydrogels research activity in recent years in the field of anticancer drug delivery, antimicrobial and wound healing materials, 3D bioprinting and tissue engineering, and vaccines. Additionally, the biosensing applications of this key group of hydrogels will be discussed mainly focusing the attention on cancer detection.     

Textile Materials Modified with Stimuli-Responsive Drug Carrier for Skin Topical and Transdermal Delivery

Textile materials, as a suitable matrix for different active substances facilitating their gradual release, can have an important role in skin topical or transdermal therapy. Characterized by compositional and structural variety, those materials readily meet the requirements for applications in specific therapies. Aromatherapy, antimicrobial substances and painkillers, hormone therapy, psoriasis treatment, atopic dermatitis, melanoma, etc., are some of the areas where textiles can be used as carriers. There are versatile optional methods for loading the biologically active substances onto textile materials. The oldest ones are by exhaustion, spraying, and a pad-dry-cure method. Another widespread method is the microencapsulation. The modification of textile materials with stimuli-responsive polymers is a perspective route to obtaining new textiles of improved multifunctional properties and intelligent response. In recent years, research has focused on new structures such as dendrimers, polymer micelles, liposomes, polymer nanoparticles, and hydrogels. Numerous functional groups and the ability to encapsulate different substances define dendrimer molecules as promising carriers for drug delivery. Hydrogels are also high molecular hydrophilic structures that can be used to modify textile material. They absorb a large amount of water or biological fluids and can support the delivery of medicines. These characteristics correspond to one of the current trends in the development of materials used in transdermal therapy, namely production of intelligent materials, i.e., such that allow controlled concentration and time delivery of the active substance and simultaneous visualization of the process, which can only be achieved with appropriate and purposeful modification of the textile material.     

Hydrogels Based on Poly(Ether-Ester)s as Highly Controlled 5-Fluorouracil Delivery Systems—Synthesis and Characterization

A novel and promising hydrogel drug delivery system (DDS) capable of releasing 5‑fluorouracil (5-FU) in a prolonged and controlled manner was obtained using ε‑caprolactone‑poly(ethylene glycol) (CL-PEG) or rac‑lactide-poly(ethylene glycol) (rac‑LA-PEG) copolymers. Copolymers were synthesized via the ring-opening polymerization (ROP) process of cyclic monomers, ε‑caprolactone (CL) or rac-lactide (rac-LA), in the presence of zirconium(IV) octoate (Zr(Oct)₄) and poly(ethylene glycol) 200 (PEG 200) as catalyst and initiator, respectively. Obtained triblock copolymers were characterized by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the structure and tacticity of the macromolecules were determined. The relationship between the copolymer structure and the reaction conditions was evaluated. The optimal conditions were specified as 140 °C and 24 h. In the next step, CL-PEG and rac-LA-PEG copolymers were chemically crosslinked using hexamethylene diisocyanate (HDI). Selected hydrogels were subjected to in vitro antitumor drug release studies, and the release data were analyzed using zero-order, first-order, and Korsmeyer-Peppas mathematical models. Controlled and prolonged (up to 432 h) 5-FU release profiles were observed for all examined hydrogels with first-order or zero-order kinetics. The drug release mechanism was generally denoted as non-Fickian transport.     

Phosphates-Containing Interpenetrating Polymer Networks (IPNs) Acting as Slow Release Fertilizer Hydrogels (SRFHs) Suitable for Agricultural Applications

Novel, phosphorus-containing slow release fertilizer hydrogels (SRFHs) composed of interpenetrating polymer networks (IPNs) with very good swelling and mechanical properties have been obtained and characterized. It was found that introducing organophosphorus polymer based on a commercially available monomer, 2-methacryloyloxyethyl phosphate (MEP), as the IPN’s first component network results in much better swelling properties than for a terpolymer with acrylic acid (AAc), 2-methacryloyloxyethyl phosphate (MEP) and bis[2-(methacryloyloxy)ethyl] phosphate (BMEP) when the same weight ratios of monomers are employed. The procedure described in this paper enables the introduction of much larger amounts of phosphorus into polymer structures without significant loss of water regain ability, which is crucial in the application of such materials in the agricultural field.     

Diflunisal Targeted Delivery Systems: A Review

Diflunisal is a well-known drug for the treatment of rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, and colon cancer. This molecule belongs to the group of nonsteroidal anti-inflammatory drugs (NSAID) and thus possesses serious side effects such as cardiovascular diseases risk development, renal injury, and hepatic reactions. The last clinical data demonstrated that diflunisal is one of the recognized drugs for the treatment of cardiac amyloidosis and possesses a survival benefit similar to that of clinically approved tafamidis. Diflunisal stabilizes the transthyretin (TTR) tetramer and prevents the misfolding of monomers and dimers from forming amyloid deposits in the heart. To avoid serious side effects of diflunisal, the various delivery systems have been developed. In the present review, attention is given to the recent development of diflunisal-loaded delivery systems, its technology, release profiles, and effectiveness.     

Enzymatically Crosslinked In Situ Synthesized Silk/Gelatin/Calcium Phosphate Hydrogels for Drug Delivery

Our research focuses on combining the valuable properties of silk fibroin (SF) and calcium phosphate (CaP). SF is a natural protein with an easily modifiable structure; CaP is a mineral found in the human body. Most of the new age biocomposites lack interaction between organic/inorganic phase, thus SF/CaP composite could not only mimic the natural bone, but could also be used to make drug delivery systems as well, which can ensure both healing and regeneration. CaP was synthesized in situ in SF at different pH values, and then crosslinked with gelatin (G), horseradish peroxide (HRP), and hydrogen peroxide (H₂O₂). In addition, dexamethasone phosphate (DEX) was incorporated in the hydrogel and drug delivery kinetics was studied. Hydrogel made at pH 10.0 was found to have the highest gel fraction 110.24%, swelling degree 956.32%, and sustained drug delivery for 72 h. The highest cell viability was observed for the hydrogel, which contained brushite (pH 6)—512.43%.     

Strategies for Cancer Treatment Based on Photonic Nanomedicine

Traditional cancer treatments, such as surgery, radiotherapy, and chemotherapy, are still the most effective clinical practice options. However, these treatments may display moderate to severe side effects caused by their low temporal or spatial resolution. In this sense, photonic nanomedicine therapies have been arising as an alternative to traditional cancer treatments since they display more control of temporal and spatial resolution, thereby yielding fewer side effects. In this work, we reviewed the challenge of current cancer treatments, using the PubMed and Web of Science database, focusing on the advances of three prominent therapies approached by photonic nanomedicine: (i) photothermal therapy; (ii) photodynamic therapy; (iii) photoresponsive drug delivery systems. These photonic nanomedicines act on the cancer cells through different mechanisms, such as hyperthermic effect and delivery of chemotherapeutics and species that cause oxidative stress. Furthermore, we covered the recent advances in materials science applied in photonic nanomedicine, highlighting the main classes of materials used in each therapy, their applications in the context of cancer treatment, as well as their advantages, limitations, and future perspectives. Finally, although some photonic nanomedicines are undergoing clinical trials, their effectiveness in cancer treatment have already been highlighted by pre-clinical studies.     

CuZn Complex Used in Electrical Biosensors for Drug Delivery Systems

This paper is to discuss the potential of using CuZn in an electrical biosensor drug carrier for drug delivery systems. CuZn is the main semiconductor ingredient that has great promise as an electrochemical detector to trigger releases of active pharmaceutical ingredients (API). This CuZn biosensor is produced with a green metal of frameworks, which is an anion node in conductive polymers linked by bioactive ligands using metal–polymerisation technology. The studies of Cu, Zn, and their oxides are highlighted by their electrochemical performance as electrical biosensors to electrically trigger API. The three main problems, which are glucose oxidisation, binding affinity, and toxicity, are highlighted, and their solutions are given. Moreover, their biocompatibilities, therapeutic efficacies, and drug delivery efficiencies are discussed with details given. Our three previous investigations of CuZn found results similar to those of other authors’ in terms of multiphases, polymerisation, and structure. This affirms that our research is on the right track, especially that related to green synthesis using plant extract, CuZn as a nanochip electric biosensor, and bioactive ligands to bind API, which are limited to the innermost circle of the non-enzymatic glucose sensor category.     

Physicochemical Characteristics of Chitosan-Based Hydrogels Containing Albumin Particles and Aloe vera Juice as Transdermal Systems Functionalized in the Viewpoint of Potential Biomedical Applications

In recent years, many investigations on the development of innovative dressing materials with potential applications, e.g., for cytostatics delivery, have been performed. One of the most promising carriers is albumin, which tends to accumulate near cancer cells. Here, chitosan-based hydrogels containing albumin spheres and Aloe vera juice, designed for the treatment of skin cancers or burn wounds resulting from radiotherapy, were developed. The presence of albumin in hydrogel matrices was confirmed via Fourier transform infrared (FT-IR) and Raman spectroscopy. Albumin spheres were clearly visible in microscopic images. It was proved that the introduction of albumin into hydrogels resulted in their increased resistance to the tensile load, i.e., approximately 30% more force was needed to break such materials. Modified hydrogels showed approximately 10% more swelling ability. All hydrogels were characterized by hydrophilicity (contact angles were <90°) which may support the regeneration of epithelial cells and non-cytotoxicity towards murine fibroblasts L929 and released Aloe vera juice more effectively in an acidic environment than in a neutral one wherein spheres introduced into the hydrogel matrix extended the release time. Thus, the developed materials, due to their chemical composition and physicochemical properties, constitute promising materials with great application potential for biomedical purposes.     

Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis

Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity <*geq>70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 μm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 μm. Spirometry was performed at baseline and following 14 days of treatment. Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents. Pediatr. Pulmonol. 1998; 25:83–87. © 1998 Wiley-Liss, Inc.     

Evaluation of Lapatinib Powder-Entrapped Biodegradable Polymeric Microstructures Fabricated by X-Ray Lithography for a Targeted and Sustained Drug Delivery System

An oral medication of a molecular targeted drug, lapatinib, is taken regularly to maintain the drug concentration within the desired therapeutic levels. To alleviate the need for such cumbersome administration schedules in several drugs, advanced drug delivery systems (DDSs), which can provide time-controlled and sustained drug release, have recently received significant attention. A biodegradable synthetic polymer, such as polycaprolactone (PCL), is usually used as a carrier material for DDSs. In this paper, lapatinib powder-entrapped, PCL microstructures were fabricated with a precise X-ray lithography-based method. In vitro experiments on HER2 positive-human gastric cancer derived NCI-N87 cells were performed to appraise the drug release characteristics of the fabricated DDSs. The in vitro results indicate that after the X-ray lithography process, the lapatinib powder is still working well and show time- and dose- dependent drug release efficiencies. The cell growth inhibition characteristics of one hundred 40-μm sized microstructures were similar to those of a 1 μM lapatinib solution for over 144 h. In conclusion, the developed lapatinib-entrapped PCL microstructures can be used in molecular targeted delivery and sustained release as effective cancer-targeted DDSs.     

Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

The spindle checkpoint is essential to ensure proper chromosome segregation and thereby maintain genomic stability. Mitotic arrest deficiency 2 (Mad2), a critical component of the spindle checkpoint, is overexpressed in many cancer cells. Thus, we hypothesized that Mad2 overexpression could specifically make cancer cells susceptible to death by inducing a synthetic dosage lethality defect. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a synthetic genetic array analysis in yeast, which revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of candidate genes, knockdown of PPP2R1A, a gene encoding a constant regulatory subunit of protein phosphatase 2, significantly inhibited the growth of Mad2-overexpressing tumor cells. PPP2R1A inhibition induced Mad2 phosphorylation and suppressed Mad2 protein levels. Depletion of PPP2R1A inhibited colony formation of Mad2-overexpressing HeLa cells but not of unphosphorylated Mad2 mutant-overexpressing cells, suggesting that the lethality induced by PP2A depletion in Mad2-overexpressing cells is dependent on Mad2 phosphorylation. Also, the PP2A inhibitor cantharidin induced Mad2 phosphorylation and inhibited the growth of Mad2-overexpressing cancer cells. Aurora B knockdown inhibited Mad2 phosphorylation in mitosis, resulting in the blocking of PPP2R1A inhibition–induced cell death. Taken together, our results strongly suggest that PP2A is a good therapeutic target in Mad2-overexpressing tumors.The spindle checkpoint is a surveillance mechanism that ensures faithful chromosome segregation during mitosis by monitoring the attachment of chromosomes to the spindle microtubules. Several key components of the spindle checkpoint have been identified, such as Mad1, Mad2, Bub1, BubR1, Bub3, Mps1, and Aurora B kinase. The mitotic arrest deficiency 2 (MAD2) gene was the first gene of the spindle checkpoint pathway to be characterized (1, 2). Mad2 is a key component of the spindle checkpoint, playing an important role in preventing the loss or gain of chromosomes during cell division (3). Sotillo et al. reported that mice genetically engineered to overexpress Mad2 developed chromosome instability (CIN) and aneuploidy (4). High levels of Mad2 also resulted in the formation of aggressive tumors in multiple organs (5). Recent studies show that overexpression of Mad2 is caused by loss of the tumor suppressor Rb or p53 (6, 7). Mad2 is overexpressed in many cancers (Table S1), such as malignant lymphoma, liver cancer, lung cancer, soft tissue sarcoma, hepatocellular carcinoma, gastric cancer, colorectal carcinoma, and human osteosarcoma (8).Protein phosphatase 2A (PP2A), an important and ubiquitously expressed serine/threonine phosphatase, dephosphorylates many key cellular molecules such as Akt, p53, and c-Myc. It plays an important role in cellular processes such as cell proliferation, signal transduction, and apoptosis (9). PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple cyclin-dependent kinase substrates (10). PP2A consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit. PPP2R1A encodes an α isoform of the constant regulatory subunit A, and it serves as a scaffolding molecule (11) to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit (12).On the basis of the hypothesis that a candidate gene’s inhibition can induces lethality specifically in Mad2-overexpressing tumors, we investigated the role of PPP2R1A in Mad2-overexpressing tumor cells. Inhibition of PP2A killed Mad2-overexpressing cells by increasing Mad2 phosphorylation while suppressing Mad2 protein levels. We propose that the inhibition of PP2A to target Mad2-overexpressing tumors can be a unique strategy for developing potential anticancer therapies.     

Micro- and Nanoscale Hydrogel Systems for Drug Delivery and Tissue Engineering

The pursuit for targeted drug delivery systems has led to the development of highly improved biomaterials with enhanced biocompatibility and biodegradability properties. Micro- and nanoscale components of hydrogels prepared from both natural and artificial components have been gaining significant importance due to their potential uses in cell based therapies, tissue engineering, liquid micro-lenses, cancer therapy, and drug delivery. In this review some of the recent methodologies used in the preparation of a number of synthetic hydrogels such as poly(N-isopropylacrylamide) (pNIPAm), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), polyvinyl alcohol methylacrylate co-polymers (PVA-MA) and polylactic acid (PLA), as well as some of the natural hydrogels and their applications have been discussed in detail.     

Bioactive Glasses as Carriers of Cancer-Targeted Drugs: Challenges and Opportunities in Bone Cancer Treatment

The treatment of bone cancer involves tumor resection followed by bone reconstruction of the defect caused by the tumor using biomaterials. Additionally, post-surgery protocols cover chemotherapy, radiotherapy, or drug administration, which are employed as adjuvant treatments to prevent tumor recurrence. In this work, we reviewed new strategies for bone cancer treatment based on bioactive glasses as carriers of cancer-targeted and other drugs that are intended for bone regeneration in conjunction with adjuvant treatments. Drugs used in combination with bioactive glasses can be classified into cancer-target, osteoclast-target, and new therapies (such as gene delivery and bioinorganic). Microparticulated, nanoparticulated, or mesoporous bioactive glasses have been used as drug-delivery systems. Additionally, surface modification through functionalization or the production of composites based on polymers and hydrogels has been employed to improve drug-release kinetics. Overall, although different drugs and drug delivery systems have been developed, there is still room for new studies involving kinase inhibitors or antibody-conjugated drugs, as these drugs have been poorly explored in combination with bioactive glasses.     

In vitro and in vivo studies with human carrier erythrocytes loaded with polyethylene glycol-conjugated and native adenosine deaminase

Polyethylene glycol-conjugated adenosine deaminase (pegademase) is used for enzyme replacement therapy for patients with severe combined immunodeficiency caused by adenosine deaminase deficiency. The entrapment of pegademase within human energy-replete carrier erythrocytes using a hypo-osmotic dialysis procedure was investigated with the objective of prolonging the in vivo circulatory half-life of the enzyme and maintaining therapeutic blood levels. Native unmodified adenosine deaminase (ADA) was similarly studied. The efficiency of pegademase entrapment was low (9%) whereas the entrapment of native unmodified ADA was substantial (50%), suggesting that the polyethylene glycol side-chains were impeding intracellular entrapment. The biochemical characteristics and the osmotic fragility of these carrier erythrocytes were not adversely affected by the entrapment of either pegademase or native ADA. In vivo survival studies of pegademase-loaded 51Cr-labelled carrier erythrocytes in an ADA-deficient adult patient showed a mean cell half-life of 16 d. Carrier erythrocyte-entrapped pegademase and native ADA had in vivo half-lives of 20 and 12.5 d, respectively, demonstrating that entrapment prolongs the half-life over that of plasma pegademase, which has a circulating half-life of 3-6 d. These results provide the basis for a more extensive clinical evaluation of carrier erythrocyte-entrapped native adenosine deaminase therapy.     

Targeting extracellular vesicles‐mediated hepatic inflammation as a therapeutic strategy in liver diseases

Extracellular Vesicles (EVs) are nano‐ to micro‐sized membranous vesicles that can be produced by normal and diseased cells. As carriers of biologically active molecules including proteins, lipids and nucleic acids, EVs mediate cell‐to‐cell communication and execute diverse functions by delivering their cargoes to specific cell types. Hepatic inflammation caused by virus infection, autoimmunity and malignancy is a common driver of progressive liver fibrosis and permanent liver damage. Emerging evidence has shown that EVs‐mediated inflammation as critical player in the progression of liver diseases since they shuttle within the liver as well as between other tissues with inflammatory signals. Therefore, targeting inflammatory EVs could represent a potential therapeutic strategy in liver diseases. Moreover, EVs are emerging as a promising tool for intracellular delivery of therapeutic nucleic acid. In this review, we will discuss not only recent advances on the role of EVs in mediating hepatic inflammation and present strategies for targeted therapy on the context of liver diseases but also the challenging questions that need to be answered in the field.     

A 9-yr evaluation of carrier erythrocyte encapsulated adenosine deaminase (ADA) therapy in a patient with adult-type ADA deficiency

Adenosine deaminase (ADA) deficiency is an inherited disorder which leads to elevated cellular levels of deoxyadenosine triphosphate (dATP) and systemic accumulation of its precursor, 2-deoxyadenosine. These metabolites impair lymphocyte function, and inactivate S-adenosylhomocysteine hydrolase (SAHH) respectively, leading to severe immunodeficiency. Enzyme replacement therapy with polyethylene glycol-conjugated ADA is available, but its efficacy is reduced by anti-ADA neutralising antibody formation. We report here carrier erythrocyte encapsulated native ADA therapy in an adult-type ADA deficient patient. Encapsulated enzyme is protected from antigenic responses and therapeutic activities are sustained. ADA-loaded autologous carrier erythrocytes were prepared using a hypo-osmotic dialysis procedure. Over a 9-yr period 225 treatment cycles were administered at 2-3 weekly intervals. Therapeutic efficacy was determined by monitoring immunological and metabolic parameters. After 9 yr of therapy, erythrocyte dATP concentration ranged between 24 and 44 micromol/L (diagnosis, 234) and SAHH activity between 1.69 and 2.29 nmol/h/mg haemoglobin (diagnosis, 0.34). Erythrocyte ADA activities were above the reference range of 40-100 nmol/h/mg haemoglobin (0 at diagnosis). Initial increases in absolute lymphocyte counts were not sustained; however, despite subnormal circulating CD20(+) cell numbers, serum immunoglobulin levels were normal. The patient tolerated the treatment well. The frequency of respiratory problems was reduced and the decline in the forced expiratory volume in 1 s and vital capacity reduced compared with the 4 yr preceding carrier erythrocyte therapy. Carrier erythrocyte-ADA therapy in an adult patient with ADA deficiency was shown to be metabolically and clinically effective.