Hydrogel-based Delivery Systems Research Articles

Hydrogel-based delivery system applied in the local anti-osteoporotic bone defects.

Osteoporosis is an age-related systemic skeletal disease leading to bone mass loss and microarchitectural deterioration. It affects a large number of patients, thereby economically burdening healthcare systems worldwide. The low bioavailability and complications, associated with systemic drug consumption, limit the efficacy of anti-osteoporosis drugs currently available. Thus, a combination of therapies, including local treatment and systemic intervention, may be more beneficial over a singular pharmacological treatment. Hydrogels are attractive materials as fillers for bone injuries with irregular shapes and as carriers for local therapeutic treatments. They exhibit low cytotoxicity, excellent biocompatibility, and biodegradability, and some with excellent mechanical and swelling properties, and a controlled degradation rate. This review reports the advantages of hydrogels for adjuvants loading, including nature-based, synthetic, and composite hydrogels. In addition, we discuss functional adjuvants loaded with hydrogels, primarily focusing on drugs and cells that inhibit osteoclast and promote osteoblast. Selecting appropriate hydrogels and adjuvants is the key to successful treatment. We hope this review serves as a reference for subsequent research and clinical application of hydrogel-based delivery systems in osteoporosis therapy.

Recent progress of Bioinspired Hydrogel-based delivery system for endometrial repair.

Endometrial injury is the main fact leading to infertility. Current treatments of endometrial injury present many problems, such as unable to achieve desired effects due to low retention and the inherent potential risk of injury. Besides, it is important to the development of bioinspired material that can mimic the natural tissue and possess native tissue topography. Hydrogel is a kind of bioinspired superhydrophilic materials with unique characteristics, such as excellent biocompatibility, biodegradability, porosity, swelling, and cross-linkage. These unique physiochemical properties of bioinspired hydrogels enable their promising application as novel delivery platform and alternative therapies for endometrial injury. In this mini review, we summarize the recent advances in bioinispred hydrogel-based delivery system for endometrial repair, including as a post-operative physical barrier and therapeutic delivery system. In addition, present status, limitations, and future perspectives are also discussed.

A TGF-α and TGF-β1 Poloxamer-based micelle/hydrogel composite: A promising novel candidate for the treatment of anosmia.

Anosmia is the inability to smell or loss of the sense of smell. It can reduce your ability to detect the smell of smoke, gas leaks, or spoiled food, as well as hinder the quality of life related to social interactions and feelings of well-being. In the current study, a drug delivery composite was designed to cure anosmia and its efficiency in delivering transforming growth factor alpha (TGF-α) and transforming growth factor beta 1 (TGF-β1) to the nasal cavity was evaluated. Bovine serum albumin (BSA) was used as a model protein for encapsulation into Poloxamers 407 micelles. For the optimization of the BSA-micelle formulation, a two-parameter five-level central composite design (CCD) was applied. The BSA-micelle was optimized with a particle size of 41 nm, drug loading of 8%, and encapsulation efficiency of 74%. Further, the BSA-micelle was characterized by FESEM, TEM, and FTIR. The analysis of release profile suggested high-paced free BSA release compared to the gradual and prolonged release of BSA-micelle/hydrogel and BSA-micelles. The cytotoxicity assay demonstrated the safety of TGF-α and TGF-β1-micelles/hydrogel. Moreover, it was observed that TGF-α and TGF-β1 within the hydrogels promote cellular viability and human olfactory ectomesenchymal stem cell OE-MSCs proliferation. In conclusion, According to the results of our study, the TGF-α and TGF-β1-micelle/hydrogel-based delivery system provides a suitable alternative for anosmia treatment.

Injectable adhesive hemostatic gel with tumor acidity neutralizer and neutrophil extracellular traps lyase for enhancing adoptive NK cell therapy prevents post-resection recurrence of hepatocellular carcinoma

Post-resection recurrence remains an intractable problem in hepatocellular carcinoma (HCC) management. Natural killer (NK) cell infusion is considered as a promising cancer therapy, but acidic tumor microenvironment (TME) and neutrophil extracellular traps (NETs) greatly counteract its efficacy. Recently, polymer hydrogels have aroused much interest in tumor combination therapy, since they load and controllably release therapeutic agents with high bioavailability and low systemic toxicity. Therefore, a biocompatible hydrogel with tumor acidity neutralizer and NETs lyase may show promise for enhancing NK infusion to prevent post-resection HCC recurrence. Herein, a dual pH-responsive hydrogel with tumor acidity neutralizer (mesoporous bioactive glass nanoparticles) and NETs lyase (Deoxyribonuclease I, DNase I) is developed and used in combination with NK cell infusion for preventing post-resection HCC recurrence. The hydrogel can be injected to surgical margin and form an adhesive gel with a rapid hemostasis. Besides, it neutralizes tumor acidity to reduce tumor infiltration of immunosuppressive cells, and releases DNase I in a pH-responsive manner to degrade NETs. Moreover, this combination therapy significantly enhances NK cell infusion to combat post-surgical HCC recurrence without systemic toxicity. This study provides proof of concept that combination of NK cell adoptive therapy and hydrogel-based delivery system can successfully prevent post-resection HCC recurrence.

Synthesis, classification and properties of hydrogels: their applications in drug delivery and agriculture.

Absorbent polymers or hydrogel polymer materials have an enhanced water retention capacity and are widely used in agriculture and medicine. The controlled release of bioactive molecules (especially drug proteins) by hydrogels and the encapsulation of living cells are some of the active areas of drug discovery research. Hydrogel-based delivery systems may result in a therapeutically advantageous outcome for drug delivery. They can provide various sequential therapeutic agents including macromolecular drugs, small molecule drugs, and cells to control the release of molecules. Due to their controllable degradability, ability to protect unstable drugs from degradation and flexible physical properties, hydrogels can be used as a platform in which various chemical and physical interactions with encapsulated drugs for controlled release in the system can be studied. Practically, hydrogels that possess biodegradable properties have aroused greater interest in drug delivery systems. The original three-dimensional structure gets broken down into non-toxic substances, thus confirming the excellent biocompatibility of the gel. Chemical crosslinking is a resource-rich method for forming hydrogels with excellent mechanical strength. But in some cases the crosslinker used in the synthesis of the hydrogels may cause some toxicity. However, the physically cross-linked hydrogel preparative method is an alternative solution to overcome the toxicity of cross-linkers. Hydrogels that are responsive to stimuli formed from various natural and synthetic polymers can show significant changes in their properties under external stimuli such as temperature, pH, light, ion changes, and redox potential. Stimulus-responsive hydrogels have a wider range of applications in biomedicine including drug delivery, gene delivery and tissue regeneration. Stimulus-responsive hydrogels loaded with multiple drugs show controlled and sustained drug release and can act as drug carriers. By integrating stimulus-responsive hydrogels, such as those with improved thermal responsiveness, pH responsiveness and dual responsiveness, into textile materials, advanced functions can be imparted to the textile materials, thereby improving the moisture and water retention performance, environmental responsiveness, aesthetic appeal, display and comfort of textiles. This review explores the stimuli-responsive hydrogels in drug delivery systems and examines super adsorbent hydrogels and their application in the field of agriculture.

Nanocarrier-hydrogel composite delivery systems for precision drug release.

Hydrogels are a class of biomaterials widely implemented in medical applications due to their biocompatibility and biodegradability. Despite the many successes of hydrogel-based delivery systems, there remain challenges to hydrogel drug delivery such as a burst release at the time of administration, a limited ability to encapsulate certain types of drugs (i.e., hydrophobic drugs, proteins, antibodies, and nucleic acids), and poor tunability of geometry and shape for controlled drug release. This review discusses two main important advances in hydrogel fabrication for precision drug release: first, the incorporation of nanocarriers to diversify their drug loading capability, and second, the design of hydrogels using 3D printing to precisely control drug dosing and release kinetics via high-resolution structures and geometries. We also outline ongoing challenges and discuss opportunities to further optimize drug release from hydrogels for personalized medicine. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Release of basic fibroblast growth factor from acoustically-responsive scaffolds promotes therapeutic angiogenesis in the hind limb ischemia model

Pro-angiogenic growth factors have been studied as potential therapeutics for cardiovascular diseases like critical limb ischemia (CLI). However, the translation of these factors has remained a challenge, in part, due to problems associated with safe and effective delivery. Here, we describe a hydrogel-based delivery system for growth factors where release is modulated by focused ultrasound (FUS), specifically a mechanism termed acoustic droplet vaporization. With these fibrin-based, acoustically-responsive scaffolds (ARSs), release of a growth factor is non-invasively and spatiotemporally-controlled in an on-demand manner using non-thermal FUS. In vitro studies demonstrated sustained release of basic fibroblast growth factor (bFGF) from the ARSs using repeated applications of FUS. In in vivo studies, ARSs containing bFGF were implanted in mice following induction of hind limb ischemia, a preclinical model of CLI. During the 4-week study, mice in the ARS + FUS group longitudinally exhibited significantly more perfusion and less visible necrosis compared to other experimental groups. Additionally, significantly greater angiogenesis and less fibrosis were observed for the ARS + FUS group. Overall, these results highlight a promising, FUS-based method of delivering a pro-angiogenic growth factor for stimulating angiogenesis and reperfusion in a cardiovascular disease model. More broadly, these results could be used to personalize the delivery of therapeutics in different regenerative applications by actively controlling the release of a growth factor.

Triple growth factor delivery promotes functional bone regeneration following composite musculoskeletal trauma

Successful bone healing in severe trauma depends on early revascularization to restore oxygen, nutrient, growth factor, and progenitor cell supply to the injury. Therapeutic angiogenesis strategies have therefore been investigated to promote revascularization following severe bone injuries; however, results have been inconsistent. This is the first study investigating the effects of dual angiogenic growth factors (VEGF and PDGF) with low-dose bone morphogenetic protein-2 (BMP-2; 2.5 µg) on bone healing in a clinically challenging composite bone-muscle injury model. Our hydrogel-based delivery systems demonstrated a more than 90% protein entrapment efficiency and a controlled simultaneous release of three growth factors over 28 days. Co-stimulation of microvascular fragment constructs with VEGF and PDGF promoted vascular network formation in vitro compared to VEGF or PDGF alone. In an in vivo model of segmental bone and volumetric muscle loss injury, combined VEGF (5 µg) and PDGF (7.5 µg or 15 µg) delivery with a low dose of BMP-2 significantly enhanced regeneration of vascularized bone compared to BMP-2 treatment alone. Notably, the regenerated bone mechanics reached ~60% of intact bone, a value that was previously only achieved by delivery of high-dose BMP-2 (10 µg) in this injury model. Overall, sustained delivery of VEGF, PDFG, and BMP-2 is a promising strategy to promote functional vascularized bone tissue regeneration following severe composite musculoskeletal injury. Although this study is conducted in a clinically relevant composite injury model in rats using a simultaneous release strategy, future studies are necessary to test the regenerative potential of spatiotemporally controlled delivery of triple growth factors on bone healing using large animal models. Statement of significanceVolumetric muscle loss combined with delayed union or non-union bone defect causes deleterious effects on bone regeneration even with the supplementation of bone morphogenetic protein-2 (BMP-2). In this study, the controlled delivery of dual angiogenic growth factors (vascular endothelial growth factor [VEGF] + Platelet-derived growth factor [PDGF]) increases vascular growth in vitro. Co-delivering VEGF+PDGF significantly increase the bone formation efficacy of low-dose BMP-2 and improves the mechanics of regenerated bone in a challenging composite bone-muscle injury model.

Application of Hydrogel-Based Delivery System in Endometrial Repair.

A receptive endometrium with proper thickness is essential for successful embryo implantation. However, endometrial injury caused by intrauterine procedures often leads to pathophysiological changes in its environment, resulting in subsequent female infertility. Among diverse treatment methods of endometrial injury, hydrogels are a class of hydrophilic three-dimensional polymeric network with biocompatibility as well as the capability of absorbing water and encapsulation, which have potential applications as a promising intrauterine controlled-release delivery system. This review summarizes recent advances in the approaches of endometrial repair and further focuses on the application of a hydrogel-based delivery system in endometrial repair, including its preparation, therapeutic loading considerations, clinical applications, as well as working mechanisms.

Injectable Anti-inflammatory Nanofiber Hydrogel to Achieve Systemic Immunotherapy Post Local Administration

Despite the great promise achieved by immune checkpoint blockade (ICB) therapy in harnessing the immune system to combat different tumors, limitations such as low objective response rates and adverse effects remain to be resolved. Here, an anti-inflammatory nanofiber hydrogel self-assembled by steroid drugs is developed for local delivery of antiprogrammed cell death protein ligand 1 (αPDL1). Interestingly, on the one hand this carrier-free system based on steroid drugs can reprogram the pro-tumoral immunosuppressive tumor microenvironment (TME) to antitumoral TME; on the other hand, it would serve as a reservoir for sustained release of αPDL1 so as to synergistically boost the immune system. By local injection of such αPDL1-loaded hydrogel, effective therapeutic effects were observed in inhibiting both local tumors and abscopal tumors without any treatment. This work presents a unique hydrogel-based delivery system using clinically approved drugs, showing promise in improving the objective response rate of ICB therapy and minimizing its systemic toxicity.

Cyclodextrin functionalized agarose gel with low gelling temperature for controlled drug delivery systems

Conventional agaroses with high gelling temperature are limited to apply to the field of drug delivery. In this study, β-cyclodextrin (βCD) functionalized agarose (CFA) with low gelling temperature was successfully prepared from ethylenediamine-functionalized agarose using mono-succinyl βCD. The gelling temperature of CFA dramatically decreased to 26.7 °C from 65 °C and the melting temperature declined from 95 °C to 66.1 °C. Upon drug loading, CFA can be used at 30 °C because of its low gelling temperature compared to agarose. CFA gel could be used both for bovine serum albumin as a full release, and for the doxorubicin (DOX) for sustained release, via inclusion complexation of βCD. Furthermore, cytotoxicity tests revealed that CFA was noncytotoxic. DOX in the CFA gel could retain the anti-cancer activity. Newly synthesized CFA with low gelling temperature offer a new means for the development of hydrogel-based delivery systems for a variety of therapeutic drugs.

γδ T cell activation in response to a keratinocyte wound signature

Abstract Epidermal resident γδ T cells are key players in the wound healing response, providing growth factors and cytokines that promote keratinocyte proliferation following recognition of damaged self. These cells are known to be unresponsive in chronic wounds and as such represent a novel target for new wound healing therapies. In this study we seek to modulate the γδ T cell response in chronic wounds through the identification, characterization, and delivery of keratinocyte-expressed proteins that comprise a “wound signature” allowing γδ T cells to recognize and respond to epithelial damage. We have identified a set of target genes though RNA-seq analysis which are upregulated following wounding in mice and correspond to membrane-bound and secreted proteins available for interactions with neighboring cells. Candidate gene expression was measured following wounding of human skin tissue, and ICAM1, CRISPLD2, and HSPA8 were shown to also be significantly upregulated in human skin wound samples. Hspa8 and ICAM-1 have been validated through in vitro assays to activate γδ T cells, and these proteins have been chosen for in vivo delivery. In order to deliver these candidate proteins into in vivo wound models we have developed a hydrogel-based delivery system with a highly tunable time frame of release. This system improves the retention of protein cargo at the wounds site post-wounding in mice and is being used to administer our candidate proteins into mouse models of non-healing wounds to assess effects on acceleration of tissue repair.

Application of furanone compounds for the modulation of biofilm formation in common wound pathogens

Chronic wounds are a significant issue in healthcare, presenting a considerable economic burden to the NHS and a serious health risk to patients. The majority of non-healing wounds have been shown to contain a biofilm which prolongs the inflammatory stage of wound healing and significantly delays wound healing. This often causes a normal wound to progress and become chronic, presenting further problems for patients including increased risk of secondary infection, further deterioration of the wound and an increase in treatment intensity. This project aims to assess the efficacy of several compounds in modulating the formation of biofilms in a number of clinically relevant pathogens when used at sub-inhibitory concentrations. The organisms used in this project include Pseudomonas aeruginosa and Staphylococcus aureus. We aim to test the efficacy of three plant derived compounds including 4-hydroxy-2,5-dimethyl-3(2 h) furanone (HDMF), 2-methyltetrahydrofuran-3-one (MTHF) and l-ascorbic acid. Future work will characterise the efficacy of these compounds when delivered to a biofilm from a hydrogel based delivery system. At sub-inhibitory concentrations in pure solution, candidate molecules tested to date showed no ability to reduce biofilm formation. Indeed, treatment with HDMF resulted in greater production of biofilm in P. aeruginosa and treatment with all compounds showed no difference in biofilm formation by S. aureus. To characterise the impact of hydrogel based delivery on compound efficacy all candidate molecules were loaded into a hydrogel and shown to be effectively released from it. Experiments to characterise the modulatory potential of these compounds when released from a hydrogel are currently underway.

Designing and enhancing the antifungal activity of corneal specific cell penetrating peptide using gelatin hydrogel delivery system.

BackgroundFungal keratitis is a major cause of corneal blindness accounting for more than one-third of microbiologically proven cases. The management of fungal keratitis is through topical or systemic antifungal medications alone or in combination with surgical treatment. Topical medications such as natamycin and voriconazole pose major challenges due to poor penetration across the corneal epithelium. To address the issue various carrier molecules like nanoparticles, lipid vesicles, and cell penetrating peptides were explored. But the major drawback such as non-specificity and lack of bioavailability remains.PurposeIn this study, we have attempted to design corneal specific cell penetrating peptide using subtractive proteomic approach from the published literature and tried to improve its bioavailability through gelatin hydrogel delivery system.Material and MethodsUsing subtractive proteomic approach two peptides VRF005 and VRF007 were identified on the basis of solubility, cell permeability and amphipathicity. The peptides were modeled for three-dimensional structure and simulated for membrane penetration. The peptides were characterized using circular dichroism spectroscopy, dynamic light scattering and native polyacrylamide gel electrophoresis. Further uptake studies were performed on primary corneal epithelial cells and the stability was analyzed in corneal epithelial tissue lysates. Insilico prediction of peptides showed it to have antifungal activity which was further validated using colony forming assay and time killing kinetics. The duration of antifungal activity of peptide was improved using gelatin hydrogel through sustained delivery.ResultsVRF005 and VRF007 showed α-helical structure and was within the allowed region of Ramachandran plot. The simulation study showed their membrane penetration. The peptide uptake was found to be specific to corneal epithelial cells and also showed intracellular localization in Candida albicans and Fusarium solani. Peptides were found to be stable up to 2 hours when incubated with corneal epithelial tissue lysate. Dynamic light scattering, and native polyacrylamide gel electrophoresis revealed aggregation of peptides. VRF007 showed antifungal activity up to 24 hour whereas VRF005 showed activity up to 4 hours. Hence gelatin hydrogel-based delivery system was used to improve the activity. Actin staining of corneal epithelial cells showed that the cells were attached on gelatin hydrogel.ConclusionWe have designed corneal specific cell penetrating peptides using subtractive proteomic approach. Bioavailability and delivery of peptide was enhanced using gelatin hydrogel system.

A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles

Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2 b (IFN α-2 b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37 °C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.

Biopolymer-based intra-articular delivery of DKK1 into the contracted rabbit knee

Post-traumatic joint contractures reduce range of motion and require surgical intervention. Repeated surgical interventions can also cause recurrent contractures, leading to a paradox that highlights the need for alternative treatment strategies. Gene expression analysis by next generation sequencing of RNA (RNA-seq) from joint tissues revealed that Wnt ligands are actively expressed in joint capsules. Therefore, we investigated the intra-articular surgical implantation of an inhibitor of fibrotic cell differentiation as a possible strategy for treating post-traumatic joint contracture. Wnt/β-catenin signaling pathway inhibitor Dickkopf 1 (DKK1) was administered into rabbit knees using oligo[(poly(ethylene glycol) fumarate)] hydrogels (OPF). In vitro experiments were used to determine the cytotoxicity of DKK1 and appropriate dosing. Contractures were induced in skeletally mature female rabbits (n=12) by disrupting knee joint capsules and immobilizing the joint by internal k-wire fixation. Surgical release was performed at 8weeks when OPF containing DKK1 (or vehicle) was administered. In vitro results indicated that >90% of DKK1 was released from OPF after 4days, and rabbit fibroblasts remained viable at 200nM (DKK1). Although not statistically significant, joint stiffness measurements were different (p<0.15) among groups (3.0N·cm/°±1.13 for control and 2.40N·cm/°±0.62 for DKK1 animals), which may be clinically relevant. Altogether, our study demonstrates feasibility of this drug delivery method (OPF+DKK1) and provides preliminary safety data for further assessment of this inhibitor of fibrosis. Further mechanistic characterization of post-traumatic joint contractures (and additional therapeutic reagents that deregulate fibrosis) will permit development of adjuvant therapies that increase joint range of motion and reduce joint stiffness: strategies easily tested using our rabbit model and hydrogel-based delivery system.

A silk hydrogel-based delivery system of bone morphogenetic protein for the treatment of large bone defects

The use of tissue grafting for the repair of large bone defects has numerous limitations including donor site morbidity and the risk of disease transmission. These limitations have prompted research efforts to investigate the effects of combining biomaterial scaffolds with biochemical cues to augment bone repair. The goal of this study was to use a critically-sized rat femoral segmental defect model to investigate the efficacy of a delivery system consisting of an electrospun polycaprolactone (PCL) nanofiber mesh tube with a silk fibroin hydrogel for local recombinant bone morphogenetic protein 2 (BMP-2) delivery. Bilateral 8 mm segmental femoral defects were formed in 13-week-old Sprague Dawley rats. Perforated electrospun PCL nanofiber mesh tubes were fitted into the adjacent native bone such that the lumen of the tubes contained the defect (Kolambkar et al., 2011b). Silk hydrogels with or without BMP-2 were injected into the defect. Bone regeneration was longitudinally assessed using 2D X-ray radiography and 3D microcomputed topography (μCT). Following sacrifice at 12 weeks after surgery, the extracted femurs were either subjected to biomechanical testing or assigned for histology. The results demonstrated that silk was an effective carrier for BMP-2. Compared to the delivery system without BMP-2, the delivery system that contained BMP-2 resulted in more bone formation (p<0.05) at 4, 8, 12 weeks after surgery. Biomechanical properties were also significantly improved in the presence of BMP-2 (p<0.05) and were comparable to age-matched intact femurs. Histological evaluation of the defect region indicated that the silk hydrogel has been completely degraded by the end of the study. Based on these results, we conclude that a BMP-2 delivery system consisting of an electrospun PCL nanofiber mesh tube with a silk hydrogel presents an effective strategy for functional repair of large bone defects.

Sustained release of 5-fluorouracil from polymeric nanoparticles.

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.

Alginate–poloxamer microparticles for controlled drug delivery to mucosal tissue

Purpose: The aim of this study was to prepare and characterize novel hydrogel-based delivery systems allowing for the controlled release of drugs to mucosal surfaces. Methods: Terbutaline sulfate and bovine serum albumin (BSA)-loaded alginate–poloxamer microparticles were prepared by a w/o-emulsion- and external gelation method. The microparticles were characterized by optical and scanning electron microscopy, laser light diffraction, atomic absorption spectroscopy, energy-dispersive X-ray analysis, via complexation with 1,9-dimethyl methylene blue and using dialysis bags as well as modified Franz diffusion cells for in vitro drug-release measurements. Results: Using heptane as organic phase, homogeneous and almost spherical microparticles were obtained with a high-loading efficiency (>90%). The resulting drug-release patterns could effectively be adjusted by varying the “alginate:poloxamer” blend ratio. In addition, the particle size, morphology, calcium and chloride content as well as alginate-release rates could be altered. Erosion was the predominant release mechanism for BSA. Special attention needs to be paid to the microparticle recovery procedure, which can significantly affect key properties such as the resulting drug-release patterns. Conclusions: The novel hydrogel-based microparticles offering mild conditions for incorporated drugs (e.g., proteins) provide an interesting potential as controlled delivery systems for mucosal surfaces.

Improving the Loading and Release of NSAIDs from pHEMA Hydrogels by Copolymerization with Functionalized Monomers

Poly(hydroxyethyl methacrylate), pHEMA, hydrogels are widely used for preparing implants, contact lenses, and other biomedical devices, which in many circumstances should load drugs to deliver them in the adjacent tissues. To enhance the potential of pHEMA hydrogels as nonsteroidal anti-inflammatory drugs (NSAIDs) delivery systems, 4-vinyl-pyridine (VP) and N-(3-aminopropyl) methacrylamide (APMA) were incorporated to the network (25–150 mM). The incorporated monomers did not change the viscoelastic properties neither the state of water, but remarkably increased the amount of ibuprofen (up to 10-fold) and diclofenac (up to 20-fold) loaded. Dried loaded pHEMA-APMA and pHEMA-VP hydrogels quickly swelled in water but ionic/hydrophobic interactions prevented the amount of drug released to be above 10%. By contrast, once the water-swollen hydrogels were transferred to pH 5.8 or 8.0 phosphate buffers or NaCl solutions, the release was prompted by competition with ions of the medium. The remaining of hydrophobic interactions and the high polymeric density of the pHEMA hydrogels contributed to sustain the release process for at least 24h for ibuprofen and almost 1 week for diclofenac. The release rate was independent of the salt content and pH in the physiological range of values, which enables the design of hydrogel-based delivery systems with predictable release rate.