Magnetically responsive micro-clustered calcium phosphate-reinforced cell-laden microbead sodium alginate hydrogel for accelerated osteogenic tissue regeneration.

The rising prevalence of bone injuries has increased the demand for minimally invasive treatments. Microbead hydrogels, renowned for cell encapsulation, provide a versatile substrate for bone tissue regeneration. They deliver bioactive agents, support cell growth, and promote osteogenesis, aiding bone repair and regeneration. In this study, we synthesized superparamagnetic iron oxide nanoparticles (Sp) coated with a calcium phosphate layer (m-Sp), achieving a distinctive flower-like micro-cluster morphology. Subsequently, sodium alginate (SA) microbead hydrogels containing m-Sp (McSa@m-Sp) were fabricated using a dropping gelation strategy. McSa@m-Sp is magnetically targetable, enhance cross-linking, control degradation rates, and provide strong antibacterial activity. Encapsulation studies with MC3T3-E1 cells revealed enhanced viability and proliferation. These studies also indicated significantly elevated alkaline phosphatase (ALP) activity and mineralization in MC3T3-E1 cells, as confirmed by Alizarin Red S (ARS) and Von Kossa staining, along with increased collagen production within the McSa@m-Sp microbead hydrogels. Immunocytochemistry (ICC) and gene expression studies supported the osteoinductive potential of McSa@m-Sp, showing increased expression of osteogenic markers including RUNX-2, collagen-I, osteopontin, and osteocalcin. Thus, McSa@m-Sp microbead hydrogels offer a promising strategy for multifunctional scaffolds in bone tissue engineering.

Harnessing the Coil Electrospinning Method for Fabricating Superflexible and Multiscale-Patterned Fibrous Tubular Scaffolds with Topographical Features.

The fibrous tubular scaffold (FTS) has potential as a vascular graft; however, its clinical application is hindered by insufficient mechanical properties. Inadequate mechanical properties of vascular grafts can lead to some serious side effects such as intimal hyperplasia, luminal expansion, and blood thrombogenicity. In this study, we developed a novel fibrous tubular scaffold comprising multiscale fibers to ensure superior mechanical properties. Our novel approach involves a one-step manufacturing method that can fabricate the superflexible fibrous tubular scaffold (SF-FTS) with topographical features via a modified electrospinning setup. We investigated the effect of humidity and temperature during the fabrication process on the formation of multiscale fibers. It was demonstrated that the incorporation of multiscale fibers and topographical features significantly enhances the mechanical properties of FTS. The mechanical advantages of SF-FTS were confirmed through the kinking resistance test, compressive test, and in vivo experiments. Additionally, we explored the interaction between the multiscale fibers and human umbilical vein endothelial cells (HUVECs) behavior. Our results suggest a novel strategy for fabricating FTS with advanced mechanical properties, and the designed SF-FTS holds promise as a potential candidate for clinical applications.

Conducting biointerface of spider-net-like chitosan-adorned polyurethane/SPIONs@SrO2-fMWCNTs for bone tissue engineering and antibacterial efficacy.

In pursuit of enhancing bone cell proliferation, this study delves into the fabrication of porous scaffolds through the integration of nanomaterials. Specifically, we present the development of highly conductive chitosan (CS) nanonets on fibro-porous polyurethane (PU) bio-membranes. These nanofibers comprise functionalized multiwall carbon nanotubes (fMWCNTs), well-dispersed superparamagnetic iron oxide (SPIONs), and strontium oxide (SrO2) nanoparticles. The resulting porous scaffold exhibits remarkable interfacial biocompatibility, antibacterial properties, and load-bearing capability. Through meticulous in vitro investigations, the CS-PU/SPIONs/SrO2-fMWCNTs nanofibrous scaffolds have demonstrated a propensity to promote bone cell regeneration. Notably, the integration of these nanomaterials has been found to upregulate crucial bone-related markers, including ALP, ARS, COL-I, RUNX2, and SPP-I. The evaluation of these markers, conducted through quantitative real-time polymerase chain reaction (qRT-PCR) and immunocytochemistry, substantiates the improved cell survival and enhanced osteogenic differentiation facilitated by the integrated nanomaterials. This comprehensive analysis underscores the efficacy of CS-PU/SPIONs/SrO2-fMWCNTs bioscaffolds in promoting MC3T3-E1 cell regeneration within, thereby holding promise for advancements in bone tissue engineering and regenerative medicine.

Cu-MSNs and ZnO nanoparticles incorporated poly(ethylene glycol) diacrylate/sodium alginate double network hydrogel for simultaneous enhancement of osteogenic differentiation.

In this study, a double network (DN) hydrogel was synthesized using poly(ethylene glycol) diacrylate (PEGDA) and sodium alginate (SA), incorporating copper-doped mesoporous silica nanospheres (Cu-MSNs) and zinc oxide nanoparticles (ZnO NPs). The blending of PEGDA and SA (PS) facilitates the double network and improves the less porous microstructure of pure PEGDA hydrogel. Furthermore, the incorporation of ZnO NPs and Cu-MSNs into the hydrogel network (PS@ZnO/Cu-MSNs) improved the mechanical properties of the hydrogel (Compressive strength = ⁓153 kPa and Young's modulus = ⁓ 1.66 kPa) when compared to PS hydrogel alone (Compressive strength = ⁓ 103 kPa and Young's modulus = ⁓ 0.95 kPa). In addition, the PS@ZnO/Cu-MSNs composite hydrogel showed antibacterial activities against Staphylococcus aureus and Escherichia coli. Importantly, the PS@ZnO/Cu-MSNs hydrogel demonstrated excellent biocompatibility, enhanced MC3T3-E1 cell adhesion, proliferation, and significant early-stage osteoblastic differentiation, as evidenced by increased alkaline phosphatase (ALP), and improved calcium mineralization, as evidenced by increased alizarin red staining (ARS) activities. These findings point to the possible use of the PS@ZnO/Cu-MSNs composite hydrogel in bone tissue regeneration.

Construction of a PEGDA/chitosan hydrogel incorporating mineralized copper-doped mesoporous silica nanospheres for accelerated bone regeneration.

Hydrogels, integrating diverse biocompatible materials, have emerged as promising candidates for bone repair applications. This study presents a double network hydrogel designed for bone tissue engineering, combining poly(ethylene glycol) diacrylate (PEGDA) and chitosan (CS) crosslinked through UV polymerization and ionic crosslinking. Concurrently, copper-doped mesoporous silica nanospheres (Cu-MSNs) were synthesized using a one-pot method. Cu-MSNs underwent additional modification through in-situ biomineralization, resulting in the formation of an apatite layer. Polydopamine was employed to facilitate the deposition of Calcium (Ca) and Phosphate (P) ions on the surface of Cu-MSNs (Cu-MSNs/PDA@CaP). Composite hydrogels were created by integrating varied concentrations of Cu-MSNs/PDA@CaP (25, 50, 100, 150, 200 µg/mL). Characterization unveiled distinctive interconnected porous structures within the composite hydrogel, showcasing a notable 169.6 % enhancement in compressive stress (elevating from 89.01 to 240.19 kPa) compared to pure PEGDA. In vitro biocompatibility experiments illustrated that the composite hydrogel maintained elevated cell viability (up to 106.6 %) and facilitated rapid cell proliferation over 7 days. The hydrogel demonstrated a substantial 57.58 % rise in ALP expression and a surprising 235.27 % increase in ARS staining. Moreover, it significantly enhanced the expression of crucial osteogenic genes, such as run-related transcription factors 2 (RUNX2), collagen 1a1 (Col1a1), and secreted phosphoprotein 1 (Spp1), establishing it as a promising scaffold for bone regeneration. This study shows how Cu-MSNs/PDA@CaP were successfully integrated into a double network hydrogel, resulting in a composite material with good biological responses. Due to its improved characteristics, this composite hydrogel holds the potential for advancing bone regeneration procedures.

Nanoscale Polishing Technique of Biomedical Grade NiTi Wire by Advanced MAF Process: Relationship between Surface Roughness and Bacterial Adhesion.

Nitinol (NiTi), an alloy of nickel and titanium, wires are an important biomedical material that has been used in catheter tubes, guidewires, stents, and other surgical instruments. As such wires are temporarily or permanently inserted inside the human body, their surfaces need to be smoothed and cleaned in order to prevent wear, friction, and adhesion of bacteria. In this study, NiTi wire samples of micro-scale diameters (i.e., Ø 200 µm and Ø 400 µm) were polished by an advanced magnetic abrasive finishing (MAF) process using a nanoscale polishing method. Furthermore, bacterial adhesion (i.e., Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus)) to the initial and final surfaces of NiTi wires were investigated and compared in order to assess the impact of surface roughness on bacterial adhesion to the surfaces of NiTi wires. The finding revealed that the surfaces of NiTi wires were clean and smooth with a lack of particle impurities and toxic components on the final surface polished using the advanced MAF process. The surface roughness Ra values of the Ø 200 µm and Ø 400 µm NiTi wires were smoothly enhanced to 20 nm and 30 nm from the 140 nm and 280 nm initial surface roughness values. Importantly, polishing the surfaces of a biomedical material such as NiTi wire to nano-level roughness can significantly reduce bacterial adhesion on the surface by more than 83.48% in the case of S. aureus, while in the case of E. coli was more than 70.67%.

L-cysteine aided polyaniline capped SrO2 nanoceramics: Assessment of MC3T3-E1-arbitrated osteogenesis and anti-bactericidal efficacy on the polyurethane 2D nanofibrous substrate.

Fabricating bioartificial bone graft ceramics retaining structural, mechanical, and bone induction properties akin to those of native stem-cell niches is a major challenge in the field of bone tissue engineering and regenerative medicine. Moreover, the developed materials are susceptible to microbial invasion leading to biomaterial-centered infections which might limit their clinical translation. Here, we successfully developed biomimetic porous scaffolds of polyurethane-reinforcedL-cysteine-anchored polyaniline capped strontium oxide nanoparticles to improve the scaffold's biocompatibility, osteo-regeneration, mechanical, and antibacterial properties. The engineered nanocomposite substrate PU/L-Cyst-SrO2 @PANI (0.4 wt%) significantly promotes bone repair and regeneration by modulating osteolysis and osteogenesis. ALP activity, collagen-I, ARS staining, as well as biomineralization of MC3T3-E1 cells, were used to assess the biocompatibility and cytocompatibility of the developed scaffolds in vitro, confirming that the scaffold provided a favorable microenvironment with a prominent effect on cell growth, proliferation, and differentiation. Furthermore, osteogenic protein markers were studied using qRT-PCR with expression levels of runt-related transcription factor 2 (RUNX2), secreted phosphoprotein 1 (Spp-I), and collagen type I (Col-I). The overall results suggest that PU/L-Cyst-SrO2 @PANI (0.4 wt%) scaffolds showed superior interfacial biocompatibility, antibacterial properties, load-bearing ability, and osteoinductivity as compared to pristine PU. Thus, prepared bioactive nanocomposite scaffolds perform as a promising biomaterial substrate for bone tissue regeneration.

In Vivo and In Vitro Biodistribution of Inulin-Tethered Boron-Doped Amine-Functionalized Carbon Dots.

Carbon dots (CDs) are considered a potential substance for use in biomarker applications due to their exceptional light stability. However, there are several unsolved uncertainties about CD toxicity in vitro and in vivo. In this study, a redesigned derivative of the natural polysaccharide inulin is connected with boron-doped amine-functionalized carbon dots (In@BN-CDs) through carbodiimide coupling to improve the biocompatibility of the nanoformulation. The toxicity and biodistribution of ln@BN-CDs in vivo and in vitro were explored in detail. The In@BN-CDs were tested after a single inhalation dosage of 10, 7, 5, 3, and 1 mg/kg. We explored a dose- and time-dependent technique of collecting blood samples and then centrifuged the blood samples and obtained serum samples, which were then analyzed for fluorescence inspection; findings showed that the fluorescence intensity decreased with time. Similarly, In@BN-CDs were effectively used as in vitro toxicity and fluorescent probes for cellular imaging in living cells due to their biocompatibility and cell membrane accessibility. The biocompatibility and efficacy of In@BN-CDs as fluorescent imaging agents have been demonstrated. The data suggest that the usage of In@BN-CDs in vitro and in vivo should be examined.

Electroconductive Polythiophene Nanocomposite Fibrous Scaffolds for Enhanced Osteogenic Differentiation via Electrical Stimulation.

Biophysical cues are key distinguishing characteristics that influence tissue development and regeneration, and significant efforts have been made to alter the cellular behavior by means of cell-substrate interactions and external stimuli. Electrically conductive nanofibers are capable of treating bone defects since they closely mimic the fibrillar architecture of the bone matrix and deliver the endogenous and exogenous electric fields required to direct cell activities. Nevertheless, previous studies on conductive polymer-based scaffolds have been limited to polypyrrole, polyaniline, and poly(3,4-ethylenedioxythiophene) (PEDOT). In the present study, chemically synthesized polythiophene nanoparticles (PTh NPs) are incorporated into polycaprolactone (PCL) nanofibers, and subsequent changes in physicochemical, mechanical, and electrical properties are observed in a concentration-dependent manner. In murine preosteoblasts (MC3T3-E1), we examine how substrate properties modified by adding PTh NPs contribute to changes in the cellular behavior, including viability, proliferation, differentiation, and mineralization. Additionally, we determine that external electrical stimulation (ES) mediated by PTh NPs positively affects such osteogenic responses. Together, our results provide insights into polythiophene's potential as an electroconductive composite scaffold material.

A bimetallic load-bearing bioceramics of TiO2 @ ZrO2 integrated polycaprolactone fibrous tissue construct exhibits anti bactericidal effect and induces osteogenesis in MC3T3-E1 cells.

Bioactive mesoporous binary metal oxide nanoparticles allied with polymeric scaffolds can mimic natural extracellular matrix because of their self-mineralized functional matrix. Herein, we developed fibrous scaffolds of polycaprolactone (PCL) integrating well-dispersed TiO2@ZrO2 nanoparticles (NPs) via electrospinning for a tissue engineering approach. The scaffold with 0.1 wt% of bioceramic (TiO2@ZrO2) shows synergistic effects on physicochemical and bioactivity suited to stem cell attachment/proliferation. The bioceramics-based scaffold shows excellent antibacterial activity that can prevent implant-associated infections. In addition, the TiO2@ZrO2 in scaffold serves as a stem cell microenvironment to accelerate cell-to-cell interactions, including cell growth, morphology/orientation, differentiation, and regeneration. The NPs in PCL exert superior biocompatibility on MC3T3-E1 cells inducing osteogenic differentiation. The ALP activity and ARS staining confirm the upregulation of bone-related proteins and minerals suggesting the scaffolds exhibit osteoinductive abilities and contribute to bone cell regeneration. Based on this result, the bimetallic oxide could become a novel bone ceramic tailor TiO2@ZrO2 composite tissue-construct and keep potential nanomaterials-based scaffold for bone tissue engineering strategy.

Biomimetic Cell-Substrate of Chitosan-Cross-linked Polyaniline Patterning on TiO2 Nanotubes Enables hBM-MSCs to Differentiate the Osteoblast Cell Type.

Titanium-based substrates are widely used in orthopedic treatments and hard tissue engineering. However, many of these titanium (Ti) substrates fail to interact properly between the cell-to-implant interface, which can lead to loosening and dislocation from the implant site. As a result, scaffold implant-associated complications and the need for multiple surgeries lead to an increased clinical burden. To address these challenges, we engineered osteoconductive and osteoinductive biosubstrates of chitosan (CS)-cross-linked polyaniline (PANI) nanonets coated on titanium nanotubes (TiO2NTs) in an attempt to mimic bone tissue's major extracellular matrix. Inspired by the architectural and tunable mechanical properties of such tissue, the TiO2NTs-PANI@CS-based biofilm conferred strong anticorrosion, the ability to nucleate hydroxyapatite nanoparticles, and excellent biocompatibility with human bone marrow-derived mesenchymal stem cells (hBM-MSCs). An in vitro study showed that the substrate-supported cell activities induced greater cell proliferation and differentiation compared to cell-TiO2NTs alone. Notably, the bone-related genes (collagen-I, OPN, OCN, and RUNX 2) were highly expressed within TiO2NTs-PANI@CS over a period of 14 days, indicating greater bone cell differentiation. These findings demonstrate that the in vitro functionality of the cells on the osteoinductive-like platform of TiO2NTs-PANI@CS improves the efficiency for osteoblastic cell regeneration and that the substrate potentially has utility in bone tissue engineering applications.

Engineering 2D approaches fibrous platform incorporating turmeric and polyaniline nanoparticles to predict the expression of ßIII-Tubulin and TREK-1 through qRT-PCR to detect neuronal differentiation of PC12 cells.

The bioengineering electroactive construct of a nerve-guided conduit for repairing and restoring injured nerves is an exciting biomedical endeavor that has implications for the treatment of peripheral nerve injury. In this study, we report the development the polycaprolactone (PCL) nanofibrous substrate consisting of turmeric (TUR) and polyaniline nanoparticles (PANINPs) exhibits topological and biological features that mimics the natural extracellular matrix (ECM) for nerve cells. We evaluated the morphology of 2-dimensional (2D) fibrous substrates, and their ability of stem cell adhesion, growth and proliferation rate were influenced by use of various concentrations of turmeric in PCL-TUR substrates. The results showed that 0.62 wt% of TUR and 0.28 wt% of PANINPs in PCL nanofibers substrate exhibited the optimal cellular microenvironment to accelerate PC12 cellular activities. The in vitro experiments revealed that PCL-TUR@PANI substrates significantly stimulated the proliferation, differentiation, and spontaneous outgrowth and extension of neurites from the cells. The substrate has the capacity to respond directly to neuronal markers with significant upregulation of ßIII-Tubulin and TREK-1 through myelination, and also trigger neurotrophic protein expression, which was confirmed via immunocytochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. This study provides a new technique to design substrate of nerve tissue-specific microenvironment for peripheral nerve cell regeneration and could offer promising biomaterials for in vivo peripheral nerve repair.

Supramolecular Caffeic Acid and Bortezomib Nanomedicine: Prodrug Inducing Reactive Oxygen Species and Inhibiting Cancer Cell Survival.

Phenolics from plant materials have garnered attention in nanomedicine research, due to their various medicinal properties. Caffeic acid, a phenolic compound that is abundant in coffee beans, has been proven to have anticancer effects, due to its reactive oxygen species (ROS)-inducing properties. Here, a supramolecular nanomedicine was designed using caffeic acid molecule and the synthetic anticancer drug bortezomib, via catechol-boronic acid conjugation and Fe(III) ion crosslinking. Bortezomib is a proteasome-inhibiting drug and its boronic acid functional group can bind to caffeic acid's catechol moiety. By having a nanoparticle formulation that can deliver bortezomib via intracellular endocytosis, the catechol-boronic acid conjugation can be dissociated, which liberates the boronic acid functional group to bind to the 26S proteasome of the cell. The ROS-inducing property of caffeic acid also complements the bortezomib payload, as the latter suppresses the survival mechanism of the cell through NF-κB inhibition.

In-situ polymerized polypyrrole nanoparticles immobilized poly(ε-caprolactone) electrospun conductive scaffolds for bone tissue engineering.

Despite intensive attempts to fabricate polypyrrole nanoparticles (PPy-NPs) incorporated nanofibrous scaffolds, a low-cost facile strategy is still demanded. Herein, we developed a novel strategy- in-situ polymerization of PPy-NPs and immobilized them into the PCL polymeric matrix in a single step. For the in-situ polymerization of PPy-NPs, ferric chloride hexahydrate (FeCl3.6H2O) was introduced as an oxidant into the blended solution of PCL and pyrrole monomers. Due to the chemical oxidative polymerization process, the clear solution changed into a black PCL/PPy solution. After electrospinning the solution, PCL/PPy composite nanofibers were fabricated. The immobilization of PPy-NPs into PCL matrix was clearly revealed by Bio-TEM images. The Field emission scanning electron microscopy (FESEM) results exhibited that the PCL/PPy scaffolds showed significantly decreased fiber diameter. The atomic force microscopy (AFM) study showed increased surface roughness in the PCL/PPy scaffolds. The mechanical strength test of PCL/PPy scaffolds showed improved Young's Modulus (YM = 2 to 4-folds) and tensile strength (TS = 3 to 4-folds). As well as the YM and TS were gradually increased with increased concentration of PPy-NPs in composite scaffolds. The conductivity measurement conducted on polymeric solution and electrospun scaffolds showed an increasing trend of conductive property in the PCL/PPy solution and scaffolds too. The surface wettability test exhibited decreased water contact angle measurement from 126° for pure PCL to 93° for the PCL/PPy-200 composite scaffold. The biomineralization test conducted by simulated body fluid (SBF) incubation showed enhanced calcium-phosphate crystal deposition on the PCL/PPy scaffolds. The CCK-8 assay and confocal laser scanning microscopic (CLSM) imaging conducted without and with electrical stimulation (ES) displayed enhanced cell adhesion, growth, and proliferation of MC3T3-E1 cells on the PCL/PPy conductive scaffolds. Furthermore, ALP and ARS staining assays showed significant enhancement of the calcium-phosphate deposition on the PCL/PPy scaffolds after ES treatment. Hence, the current study provides a novel strategy for the fabrication of PCL/PPy conductive scaffolds with enhanced bioactivity, biocompatibility, and osteogenic differentiation under electrical stimulation confirmed its promising application towards bone tissue engineering.

The controlled design of electrospun PCL/silk/quercetin fibrous tubular scaffold using a modified wound coil collector and L-shaped ground design for neural repair.

Asymmetrically porous and aligned fibrous tubular conduit with selective permeability as a biomimetic neural scaffold was manufactured using polycaprolactone (PCL), silk, and quercetin by a modified electrospinning method. The outer surface of the randomly oriented fibrous scaffold had microscale pores that could prevent fibrous tissue invasion (FTI), but could permeate neurotrophic factors, nutrients, and oxygen. The inner surface of the aligned fibrous scaffold can be favorable for neurite outgrowth, because of their superior neural cell attachment, migration, and directional growth. In vitro and in vivo studies have demonstrated the therapeutic effect of Quercetin, a ubiquitous flavonoid widely distributed in plants, on neuropathy, by modulating the expression of NRF-2-dependent antioxidant responsive elements. In this study, the controlled inner and outer surface geometry of the 0.5, 1.0, and 2.0 wt% quercetin-containing electrospun PCL/silk fibrous tubular scaffold fabricated via a modified wound coil collector and L-shaped ground design (WCC-LG) was characterized by FE-SEM, TEM, FFT, FT-IR, and XRD. In addition, two types of neural cell lines, PC12 and S42, were used to evaluate the cell proliferation rate of the different amount of quercetin-loaded PCL/silk tubular scaffolds.

Engineered Celery-Structured Electrospun Fibers Surface and Its Initial Cell Attachment Ability Effect.

The fabrication of various types of scaffolds using electrospinning has been greatly researched for tissue engineering applications in recent times. The rapid initial cell adhesion in electrospun scaffolds helps in the rapid recovery of graft sites. The characteristics of nanofibrous scaffolds can be improved by modifying the topological features and surface of the nanofibers. Previous studies have shown that the scaffold structure is related to a cell attachment ability. In this study, we modified the surface of the fibers to mimic celery structure. It was confirmed that solvent evaporation and polymer concentration influenced the formation of the surface. This structural property can improve the initial adhesion ability of cells. Cellulose acetate solutions were prepared and tested in various concentrations (15 wt%, 20 wt%, and 30 wt%). Scanning electron microscopy (SEM), tensile test and cell experiments were performed to evaluate the physical properties and biocompatibility. The structure of the present nanofiber can be applied as a very effective scaffold and it is expected to have a positive effect in the tissue engineering field.

Analysis of Drug Release Behavior Utilizing the Swelling Characteristics of Cellulosic Nanofibers.

It is known that the behavior of a drug released from a supporting carrier is influenced by the surrounding environment and the carrier. In this study, we investigated the drug behavior of a swellable electrospun nanofibrous membrane. Nanofibrous mats with different swelling ratios were prepared by mixing cellulose acetate (CA) and polyurethane (PU). CA has excellent biocompatibility and is capable of high water uptake, while PU has excellent mechanical properties. Paclitaxel (PTX) was the drug of choice for observing drug release behavior, which was characterized by UV-spectroscopy. FE-SEM was used to confirm the morphology of the nanofibrous mats and to measure the average fiber diameters. We observed a noticeable increase in the total volume of the nanofibrous membrane when it was immersed in water. Also, the drug release behavior increased proportionally with increasing swelling rate of the composite nanofibrous mat. Biocompatibility testing of nanofiber materials was confirmed by CCK-8 assay and cell morphology was observed. Based on these results, we propose nanofibrous mats as promising candidates in wound dressing and other drug carrier applications.