Multifunctional Liposomes Targeting Amyloid-ß Oligomers for Early Diagnosis and Therapy of Alzheimer's Disease.

Early detection and treatment are crucial for Alzheimer's disease (AD) management. Current diagnostic and therapeutic methods focus on late-stage amyloid fibrils and plaques, overlooking toxic soluble amyloid ß oligomers (AßOs) accumulating early in AD. A multifunctional liposome-based platform is designed for early diagnosis and therapy of AD, leveraging a novel self-assembled cyclic d,l-α-peptide (CP-2) that selectively targets AßOs. Biocompatible CP-2 conjugated liposomes (CP-2-LPs) effectively disrupt Aß aggregation and mitigate Aß-mediated toxicity in human neuroblastoma cells. In transgenic Caenorhabditis elegans AD models, CP-2-LPs significantly outperformed free CP-2 by improving cognitive and behavioral functions, extending lifespan, and reducing toxic AßO levels. Intravenous injection of fluorescently labeled CP-2-LPs reveals effective blood-brain barrier penetration, with significantly higher brain fluorescence in transgenic mice than WT, enabling precise diagnosis. These findings underscore CP-2-LPs as a valuable tool for early detection and targeted therapy in AD.

Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies.

Aging, tau pathology, and chronic inflammation in the brain play crucial roles in synaptic loss, neurodegeneration, and cognitive decline in tauopathies, including Alzheimer's disease. Senescent cells accumulate in the aging brain, accelerate the aging process, and promote tauopathy progression through their abnormal inflammatory secretome known as the senescence-associated secretory phenotype (SASP). Tau oligomers (TauO)-the most neurotoxic tau species-are known to induce senescence and the SASP, which subsequently promote neuropathology, inflammation, oxidative stress, synaptic dysfunction, neuronal death, and cognitive dysfunction. TauO, brain inflammation, and senescence are associated with heterogeneity in tauopathy progression and cognitive decline. However, the underlying mechanisms driving the disease heterogeneity remain largely unknown, impeding the development of therapies for tauopathies. Based on clinical and preclinical evidence, this review highlights the critical role of TauO and senescence in neurodegeneration. We discuss key knowledge gaps and potential strategies for targeting senescence and TauO to treat tauopathies. HIGHLIGHTS: Senescence, oligomeric Tau (TauO), and brain inflammation accelerate the aging process and promote the progression of tauopathies, including Alzheimer's disease. We discuss their role in contributing to heterogeneity in tauopathy and cognitive decline. We highlight strategies to target senescence and TauO to treat tauopathies while addressing key knowledge gaps.

Noninvasive Treatment of Alzheimer's Disease with Scintillating Nanotubes.

Effective and accessible treatments for Alzheimer's disease (AD) are urgently needed. Soluble Aß oligomers are identified as neurotoxic species in AD and targeted in antibody-based drug development to mitigate cognitive decline. However, controversy exists concerning their efficacy and safety. In this study, an alternative strategy is proposed to inhibit the formation of Aß oligomers by selectively oxidizing specific amino acids in the Aß sequence, thereby preventing its aggregation. Targeted oxidation is achieved using biocompatible and blood-brain barrier-permeable multicomponent nanoscintillators that generate singlet oxygen upon X-ray interaction. Surface-modified scintillators interact selectively with Aß and, upon X-ray irradiation, inhibit the formation of neurotoxic aggregates both in vitro and in vivo. Feeding transgenic Caenorhabditis elegans expressing human Aß with the nanoscintillators and subsequent irradiation with soft X-ray reduces Aß oligomer levels, extends lifespan, and restores memory and behavioral deficits. These findings support the potential of X-ray-based therapy for AD and warrant further development.

Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.

Transient soluble oligomers of amyloid-ß (Aß) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aß oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (1) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aß aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aß. Moreover, certain azapeptides disassembled preformed Aß fibrils and protected cells from Aß-mediated toxicity. Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aß oligomer levels.

Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aß oligomers.

Transient soluble oligomers of amyloid-ß (Aß) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross ß-sheet nanotubes, react with early Aß species (1-3 mers), and inhibit Aß aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly6]-1 inhibited Aß aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-1 and Aß42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aß oligomers may spread to other brain parts with disease progression. Compared with standard 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aß plaques, 64Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aß oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly6]-1 reduced Aß oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans, and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.

Controlled DNA Delivery Using Poly(lactide) Nanoparticles and Understanding the Binding Interactions.

Cationic polymer-based gene delivery vectors suffer from several limitations such as low DNA-loading capacity, poor transfection, toxicity, environmental degradations, etc. Again, very limited works are available addressing the binding interactions in detail at the atomic level explaining the loading capacity, protection ability against harsh environments, and controlled release behavior of the DNA-encapsulated vehicles. Here, a poly(l-lactide) (PLA) nanoparticle-based controlled DNA release system is proposed. The developed vehicle possesses a high DNA-loading capacity and can release the loaded DNA in a controlled manner. Spectroscopic, physicochemical, and molecular simulation techniques (AM1 and atomistic molecular dynamics) have been employed to understand the binding interactions between PLA and DNA molecules enabling high DNA loading, protection against external harsh environments, and controlled DNA release behavior. Methyl thiazolyl tetrazolium (MTT) assay experiments confirm the biocompatible nature of the vehicle. Cellular uptake efficiency and endo-lysosomal escape capabilities have been investigated against HeLA cells. This study, therefore, demonstrates the development of a promising nonviral DNA delivery vector and includes a detailed investigation of the atomic-level interaction behavior between PLA and DNA molecules.

Layered Double Hydroxide Nanoparticles for Efficient Gene Delivery for Cancer Treatment.

The use of cationic polymer based gene delivery vectors has several limitations such as low transfection efficiency, high toxicity, and inactivation by serum. The present work provides an inorganic based nanocarrier for efficient gene delivery and a method for preparing the same through a facile coprecipitation technique. The vehicle showed high loading capacity of DNA and can release the loaded DNA in a controlled pH-responsive manner. The developed gene delivery vehicle offers remarkable protection against DNase I and also provides protection against thermal damage. This vehicle also demonstrated efficient cellular uptake performance. Transfection and expression of plasmid gene encoding GFP proteins is achieved successfully by this LDH based vehicle. More interestingly, the developed Li-Al LDH efficiently induces GFP-p53 mediated apoptosis in HeLa cells exclusively sparing the normal tissue cells like NIH-3T3. The study demonstrates the potential of the developed inorganic based nanocarrier as a promising nonviral gene vector for tumor treatment.

Highly selective fluorescence 'turn off' sensing of picric acid and efficient cell labelling by water-soluble luminescent anthracene-bridged poly(N-vinyl pyrrolidone).

A novel, water-soluble, luminescent anthracene-bridged AA-type bi-arm poly(N-vinylpyrrolidone) (ATC-PNVP) was synthesized using a click reaction between alkyne-terminated PNVP and 9,10-bis(azidomethyl)anthracene. The resultant anthracene-bridged PNVP (ATC-PNVP) was characterized using 1H NMR, FTIR, UV-Vis, and fluorescence spectroscopic methods and GPC analysis. ATC-PNVP showed effective fluorescence properties in an aqueous medium. It showed highly selective "turn off" sensing behaviour towards picric acid, a common nitro-aromatic explosive, with a wide linear range of detection of 0.01-0.3 mM and LOD value of 0.006 mM in water. ATC-PNVP-based paper sensors also showed very effective detection of picric acid in the concentration range 0.001-1.0 mM. Its binding with bovine serum albumin (BSA) was studied using steady-state, synchronous and 3D fluorescence spectroscopy and this study showed effective quenching of the intrinsic fluorescence of BSA and occurrence of a FRET-type interaction. Furthermore, this luminescent ATC-PNVP was efficiently used as a fluorescence microscopy labelling agent in NIH-3T3 and HeLa cells, and showed greater uptake and hence better fluorescent labelling in the cytosols of the tested cells than free 9,10-bis(azidomethyl) anthracene. The cell viability study also showed a very good biocompatible and non-toxic nature of ATC-PNVP at lower working concentrations towards each of the types of cells tested.

Fluorescent-functionalized graphene oxide for selective labeling of tumor cells.

Fluorescence probe has attracted significant attention for biomedical imaging in recent years due to their high resolution at the cellular level. Organic-based fluorescent probes with high quantum yield are widely applied in bioimaging, but most of them suffer from a serious obstacle called aggregation-caused quenching in cellular systems. New fluorophore has been designed through functionalization of graphene oxide which emphatically exhibits aggregation-induced emission along with pH-responsive nanoprobe. Significantly higher emission of this material in slightly acidic media helps to detect tumor cell by creating a sharp contrast with the image of normal cells. The reason for pH-induced enhanced emission phenomenon is revealed through aggregation of sulfonated species in acidic media. Furthermore, the biocompatible nature of the newly developed material is found to be suitable for its application in biomedical imaging for cancer detection with better accuracy at lower cost. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1917-1924, 2019.

Controlling Drug Delivery Using Nanosheet-Embedded Electrospun Fibers for Efficient Tumor Treatment.

The objective of this study is to fabricate biodegradable polymers into scaffolds to embed drugs for tumor treatment without any toxic side effects. Scaffold preparation is optimized by changing the conditions, e.g., poly(lactic acid) concentration (10% w/v), applied potential (15 kV), flow rate (1 mL/h), distance between needle and collector (20 cm), and nanosheet concentration (4 wt % nanoclay), during electrospinning. A drug-embedded nanofiber scaffold is used to regulate the drug delivery in a sustainable manner utilizing the enhanced barrier effect from dispersed nanosheet and good interaction between the components. The effect of thermal treatment improves the stability and slower release of drug through alteration in microstructure. Cell culture studies using a nanofiber scaffold indicate its biocompatibility and applicability as a biomaterial for tumor treatment. Sustained drug release from the scaffold enhances the in vitro cancer cytotoxicity up to 85% in 3 days. In vivo studies clearly suggest suppression of tumor volume using scaffold as a patch over the tumor site as compared to control, pure drug, and drug-embedded film in the mice model. Evaluation of biochemical parameters indicates no toxic side effects for the liver and kidney using a hybrid scaffold as a delivery vehicle as opposed to severe liver injury in control and pure drug-treated mice group. Histopathology of the organs confirms the side effects for the pure drug-treated mice group against normal tissue morphology observed in scaffold-treated animals. Thus, sustained release of drug from this novel delivery vehicle has every potential to be used for tumor treatment more efficiently without any considerable side effects.

Nanoparticle-Induced Controlled Drug Delivery Using Chitosan-Based Hydrogel and Scaffold: Application to Bone Regeneration.

The novel chitosan nanohybrid hydrogel and scaffold have been developed with high mechanical strength and tailor the drug release ability for their applications in the biomedical arena. Nanohybrid hydrogels are prepared in dilute acetic acid medium using two different types of two-dimensional-layered nanoparticles. Scaffolds are prepared through lyophilization of hydrogels. Highly porous, open, and 3D interconnected morphologies are observed in the nanohybrid scaffolds, as opposed to the thick wall, smaller pore dimension in pure chitosan. The interaction between the nanoparticles and chitosan chains are elucidated using different spectroscopic techniques, which in turn are responsible for the uniform distribution of the nanoparticle in the chitosan matrix. Nanohybrids are found to be highly mechanically stable in both states (hydrogel and scaffold), as compared to pure chitosan because of the good reinforcing ability of 2D nanoparticles. Sustained drug release has been achieved in nanohybrid in vitro, as compared to the pure chitosan hydrogel/scaffold, mainly due to greater interactions between the components and the better barrier effect of 2D nanoparticles. Cytotoxicity of the nanohybrids is verified using NIH 3T3 mouse embryonic fibroblast cells for their possible use as controlled drug delivery vehicles. Nanohybrids are found to be nontoxic in nature and more biocompatible as compared to pure chitosan, as observed through cell viability and cell imaging studies. Interestingly, cell growth occurs within the pores of the nanohybrid scaffold, vis-à-vis the surface proliferation noticed in the pure chitosan scaffold. Better biocompatibility, hydrophilic nature, and sustained delivery with location specific cell growth make this nanohybrid hydrogel unique for biomedical uses. The bone regeneration rate is found to be significantly higher for the nanohybrid scaffold as compared to blank/pure chitosan without any side effect, suggesting nanohybrid systems are superior biomaterials.

Sustained release of herbal drugs using biodegradable scaffold for faster wound healing and better patient compliance.

Electrospun scaffold has been developed using biodegradable polymer and age old herbal drug for efficient wound healing patch with much better patient compliance. Positively charged smaller particle size (40 nm) of the drug has been prepared for greater penetration through epidermal barrier to enhance the wound healing activity of drug. Controlled drug release has been understood in terms of interactions between the components through spectroscopic techniques and calorimetric studies. In-vivo study using albino rats shows better wound healing efficiency of scaffold in terms of higher wound area contraction, minimum inflammation, faster epithelialization and vascularization. Cellular studies also endorse the scaffold as better biomaterial. Clinical studies also demonstrate fast healing of different type of wounds in presence of all three wound dressing materials with histological evidences. The complete biodegradation of the patch confirms its green nature of the developed patch.

Controlled drug delivery vehicles for cancer treatment and their performance.

Although conventional chemotherapy has been successful to some extent, the main drawbacks of chemotherapy are its poor bioavailability, high-dose requirements, adverse side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting. The main aim in the development of drug delivery vehicles is to successfully address these delivery-related problems and carry drugs to the desired sites of therapeutic action while reducing adverse side effects. In this review, we will discuss the different types of materials used as delivery vehicles for chemotherapeutic agents and their structural characteristics that improve the therapeutic efficacy of their drugs and will describe recent scientific advances in the area of chemotherapy, emphasizing challenges in cancer treatments.

Engineered Cellular Uptake and Controlled Drug Delivery Using Two Dimensional Nanoparticle and Polymer for Cancer Treatment.

Two major problems in chemotherapy, poor bioavailability of hydrophobic anticancer drug and its adverse side effects causing nausea, are taken into account by developing a sustained drug release vehicle along with enhanced bioavailability using two-dimensional layered double hydroxides (LDHs) with appropriate surface charge and its subsequent embedment in polymer matrix. A model hydrophobic anticancer drug, raloxifene hydrochloride (RH), is intercalated into a series of zinc iron LDHs with varying anion charge densities using an ion exchange technique. To achieve significant sustained delivery, drug-intercalated LDH is embedded in poly(ε-caprolactone) (PCL) matrix to develop intravenous administration and to improve the therapeutic index of the drug. The cause of sustained release is visualized from the strong interaction between LDH and drug, as measured through spectroscopic techniques, like X-ray photoelectron spectroscopy, infrared, UV-visible spectroscopy, and thermal measurement (depression of melting temperature and considerable reduction in heat of fusion), using differential scanning calorimeter, followed by delayed diffusion of drug from polymer matrix. Interestingly, polymer nanohybrid exhibits long-term and excellent in vitro antitumor efficacy as opposed to pure drug or drug-intercalated LDH or only drug embedded PCL (conventional drug delivery vehicle) as evident from cell viability and cell adhesion experiments prompting a model depicting greater killing efficiency (cellular uptake) of the delivery vehicle (polymer nanohybrid) controlled by its better cell adhesion as noticed through cellular uptake after tagging of fluorescence rhodamine B separately to drug and LDH. In vivo studies also confirm the sustained release of drug in the bloodstream of albino rats using polymer nanohybrid (novel drug delivery vehicle) along with a healthy liver vis-à-vis burst release using pure drug/drug-intercalated LDHs with considerable damaged liver.

A 'turn-on' fluorescent probe for lysosomal phosphatase: a comparative study for labeling of cancer cells.

We have described the ability of a newly synthesized fluorescent probe (LP1) to detect phosphatase activity in lysosomes in cancer cells. Probe LP1 displayed a 33-fold fluorescence intensity enhancement at λem 532 nm in the presence of phosphatase in HEPES buffer (pH 4.5). The quantum yield of probe LP1 was increased by ∼21-fold upon exposure to phosphatase at acidic pH. The probe LP1 is highly chemoselective toward phosphatase (ALP/ACP) and is insensitive to interference by ubiquitous biological analytes. The high cell adhesion property and cell viability of LP1 indicate that LP1 is biocompatible and nontoxic; these two characteristic features make it a suitable candidate for phosphatase tracking in living cells. LP1 dose-dependent fluorescence images in living cells suggested that the expression of phosphatase in cancer cells (HeLa) is 2-fold higher as compared to the normal NIH-3T3 cells. The colocalization images confirmed that LP1 was exclusively localized in lysosomes. We envision that LP1 could be a potential tool in clinical diagnosis for discriminating cancer cells from normal cells depending on the expression of phosphatase in lysosomes.

Controlled drug release through regulated biodegradation of poly(lactic acid) using inorganic salts.

Biodegradation rate of poly(lactic acid) (PLA) has been regulated, both increase and decrease with respect to the biodegradation of pure PLA, by embedding meager amount of inorganic salts in polymer matrix. Biodegradation is performed in enzyme medium on suspension and film and the extent of biodegradation is measured through spectroscopic technique which is also verified by weight loss measurement. Media pH has been controlled using trace amount of inorganic salt which eventually control the biodegradation of PLA. High performance liquid chromatography confirms the hydrolytic degradation of PLA to its monomer/oligomer. Induced pH by metal salts show maximum degradation at alkaline range (with calcium salt) while inhibition is observed in acidic medium (with iron salt). The pH of media changes the conformation of enzyme which in turn regulate the rate of biodegradation. Thermal degradation and increment of modulus indicate improvement in thermo-mechanical properties of PLA in presence of inorganic salts. Functional stability of enzyme with metal salts corresponding to acidic and alkaline pH has been established through a model to explain the conformational changes of the active sites of enzyme at varying pH influencing the rate of hydrolysis leading to regulated biodegradation of PLA. The tuned biodegradation has been applied for the controlled release of drug from the polymer matrix (both sustained and enhanced cumulative release as compared to pure polymer). The cell proliferation and adhesion are influenced by the acidic and basic nature of polymeric material tuned by two different inorganic salts showing better adhesion and proliferation in calcium based composite and, therefore, suggest biological use of these composites in biomedical applications.

Functionalized Graphene Tagged Polyurethanes for Corrosion Inhibitor and Sustained Drug Delivery.

Surface functionalization of graphene oxide with sulfonate group and subsequent grafting with polyurethane chains leads to the significant improvement in the properties of polymer and modified graphene as a filler. Modification of graphene oxide is revealed through spectroscopy while grafting of polymer chain over sulfonated graphene is confirmed through 1H NMR and other techniques. Higher order of self-assembly phenomena is observed in nanohybrids as compared to pure polymer through greater interaction between polymer chain and sulfonated graphene. Significant improvement in corrosion inhibition phenomena is observed using nanohybrids at low concentration as compared to pure polymer indicating its superior efficiency as a corrosion inhibitor. Nanohybrids also exhibit better biocompatible nature in lower concentration of filler with considerable sustained release of drug vis-à-vis pure polymer suggest its potential to use as a biomaterial for tissue engineering applications.

Layered double hydroxides as effective carrier for anticancer drugs and tailoring of release rate through interlayer anions.

Hydrophobic anticancer drug, raloxifene hydrochloride (RH) is intercalated into a series of magnesium aluminum layered double hydroxides (LDHs) with various charge density anions through ion exchange technique for controlled drug delivery. The particle nature of the LDH in presence of drug is determined through electron microscopy and surface morphology. The release of drug from the RH intercalated LDHs was made very fast or sustained by altering the exchangeable anions followed by the modified Freundlich and parabolic diffusion models. The drug release rate is explained from the interactions between the drug and LDHs along with order-disorder structure of drug intercalated LDHs. Nitrate bound LDH exhibits greater interaction with drug and sustained drug delivery against the loosely interacted phosphate bound LDH-drug, which shows fast release. Cell viability through MTT assay suggests drug intercalated LDHs as better drug delivery vehicle for cancer cell line against poor bioavailability of the pure drug. In vivo study with mice indicates the differential tumor healing which becomes fast for greater drug release system but the body weight index clearly hints at damaged organ in the case of fast release system. Histopathological experiment confirms the damaged liver of the mice treated either with pure drug or phosphate bound LDH-drug, fast release system, vis-à-vis normal liver cell morphology for sluggish drug release system with steady healing rate of tumor. These observations clearly demonstrate that nitrate bound LDH nanoparticle is a potential drug delivery vehicle for anticancer drugs without any side effect.

Biodegradable poly(ε-caprolactone) as a controlled drug delivery vehicle of vancomycin for the treatment of MRSA infection.

Biodegradable poly(ε-caprolactone) (PCL) is developed as a controlled drug delivery vehicle of vancomycin (VMC) with the advantage of avoiding a second surgery. The PCL-VMC hybrid, prepared through a solution route, is used as a delivery vehicle for vancomycin for controlling MRSA osteomyelitis as well as healing the cavity simultaneously in an experimental study. An in vitro study is conducted to optimize vancomycin impregnation in the PCL-VMC hybrid. An in vitro study on drug release from the hybrid material is investigated in phosphate buffer saline showing steady and sustained release of the drug. The release kinetics is fitted with several models and a non-Fickian nature is established following the Korsmeyer-Peppas model. Spectroscopic techniques and morphology observations reveal the cause of sustained release to be the strong interaction between the drug and the polymer. The results of the antibacterial assay show that the loading of vancomycin into the PCL matrix is able to maintain the activity of the pure drug. For the in vivo study, a unicortical defect is created in the metaphysis of the distal femur in rabbits. After contaminating the defect with MRSA, the 1st group of rabbits were treated with pure polymer, the 2nd group of rabbits were treated with normal saline (PBS), the 3rd group of rabbits were treated with pure VMC and in the last group of rabbits PCL-VMC was placed. Rabbits are assessed by clinical, radiological, histological, gross examination and bacterial load assays. Infection persisted throughout the period of study for both the pure polymer and PBS treated rabbits while rabbits treated with the PCL-VMC hybrid do not show any sign of infection. The VMC treated group rabbits show mild infection for the 1st week of the study; however, the infection becomes gradually more severe with time. Serial histology confirms the formation of new bone without any inflammation and necrosis for the rabbits treated with PCL-VMC. Importantly, the PCL-VMC hybrid bioadsorbs after delivery of the drug and thereby avoids the second surgery to remove the conventional implant.