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This paper describes the discovery of the first inhibitors of angiogenesis; the discoveries that led to the development of the first biocompatible controlled release systems for macromolecules, and findings that helped to create the field of tissue engineering. In addition, new paradigms for creating biomaterials, early work on nanotechnology in medicine and intelligent drug delivery systems are discussed. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 2449-2455, 2013. [ABSTRACT FROM AUTHOR]

Colistin is a potent antibiotic but its severe side effects including nephrotoxicity and neurotoxicity are the roadblock for their wide use in clinics. To solve this problem, we synthesized a new prodrug, mannose‐maltose‐colistin conjugate, termed MMCC that can reversibly mask the five amines of colistin that are primarily responsible for the toxicity. The deliberated design of disulfide‐based self‐immolative linker warranted the reversibly release of the pristine amines of colistin on demand without sacrificing antimicrobial efficacy. Once MMCC was delivered in cells, reducing agents cleaves the disulfide bond and release the pristine amines. The targeting ligands of maltose and mannose were grafted on colistin conjugate for targeting delivery of colistin to bacteria and macrophages, respectively. Taken together, MMCC as a new class of antimicrobial biomaterials, demonstrates its great potential for the treatment of intracellular bacterial infections. [ABSTRACT FROM AUTHOR]

Antibiotic‐loaded bone cement beads have been a reliable passive delivery system for the localized treatment of osteomyelitis; however, low, and unregulated drug release rates limit the ability of this system to maintain therapeutic concentrations. This problem is further amplified by drug‐resistant pathogens that might invade or evolve under these conditions. Furthermore, currently available bone cements are incompatible with some antibiotics. The proposed device resembles conventional bone cement beads but contains an on‐demand drug delivery magnetic sponge that provides actively controlled release of antibiotics. The slightly porous structure facilitates some drug diffusion while further drug release may be controlled remotely via magnetic actuation. Additionally, a combination of silver nitrate and gentamicin are used in the device as these agents are shown to display a synergistic antibacterial activity in vitro using checkerboard and time‐kill assays. The device releases gentamicin and silver in both actuation and diffusion modes over 7 days. The in vitro bacterial studies demonstrate the efficacy of the released agents alone, and synergistically in combination, against Methicillin‐resistant Staphylococcus aureus and Escherichia coli. The proposed device offers a facile fabrication process which allows control of the release profile by engineering hole configurations or manipulating magnetic field strength to provide the most effective therapy. [ABSTRACT FROM AUTHOR]

Inflammation and infection are two main factors predisposing a wound to become a chronic one. Degradable wound dressings involving the controlled release of suitable drugs at the ulcer site are one of the solutions to make wounds healing progress smoothly and rapidly. In this research, biodegradable dressings made of polyglycerol sebacate/polycaprolactone (PGS/PCL) containing curcumin/ciprofloxacin (CUR/CIP) and simvastatin/ciprofloxacin (SIM/CIP) were prepared by using the coaxial electrospinning method. Transmission electron microscopy for uniform core/shell structure, swelling ratio, and drug release pattern of the wound dressings were evaluated. At the in vivo study, histometric, histopathologic, and collagen expression study was performed. The PGS/PCL samples containing SIM/CIP showed a burst release pattern of CIP with a delay in the release of SIM; meanwhile, in the samples containing CUR/CIP, both drugs showed a burst release behavior. No cytotoxicity response was observed in the study groups. The in vivo study showed that wound closure was almost completed only in the SIM/CIP group after 14 days. After 14 days, in the wound treated with SIM/CIP dressing, the amount of collagen deposition and angiogenesis was higher than that of the others. These results clearly showed the effect of SIM/CIP on the improvement of the wound healing efficiency in the long term (14 days) and the effect of CUR/CIP on wound contraction in the short term (4 day). It seems, therefore, that the use of SIM and CUR simultaneously in a wound dressing could cause a synergistic effect in the wound repair. [ABSTRACT FROM AUTHOR]

Inflammation and infection are two main factors predisposing a wound to become a chronic one. Degradable wound dressings involving the controlled release of suitable drugs at the ulcer site are one of the solutions to make wounds healing progress smoothly and rapidly. In this research, biodegradable dressings made of polyglycerol sebacate/polycaprolactone (PGS/PCL) containing curcumin/ciprofloxacin (CUR/CIP) and simvastatin/ciprofloxacin (SIM/CIP) were prepared by using the coaxial electrospinning method. Transmission electron microscopy for uniform core/shell structure, swelling ratio, and drug release pattern of the wound dressings were evaluated. At the in vivo study, histometric, histopathologic, and collagen expression study was performed. The PGS/PCL samples containing SIM/CIP showed a burst release pattern of CIP with a delay in the release of SIM; meanwhile, in the samples containing CUR/CIP, both drugs showed a burst release behavior. No cytotoxicity response was observed in the study groups. The in vivo study showed that wound closure was almost completed only in the SIM/CIP group after 14 days. After 14 days, in the wound treated with SIM/CIP dressing, the amount of collagen deposition and angiogenesis was higher than that of the others. These results clearly showed the effect of SIM/CIP on the improvement of the wound healing efficiency in the long term (14 days) and the effect of CUR/CIP on wound contraction in the short term (4 day). It seems, therefore, that the use of SIM and CUR simultaneously in a wound dressing could cause a synergistic effect in the wound repair. [ABSTRACT FROM AUTHOR]

Electrospun technology becomes a valuable means of fabricating functional polymeric nanofibers with distinctive morphological properties for drug delivery applications. Nanofibers are prepared from the polymer solution, which allows the direct incorporation of therapeutics such as small drug molecules, genes, and proteins by merely mixing them into the polymeric solution. Due to their biocompatibility, adhesiveness, sterility, and efficiency in delivering diverse cargoes, electrospun nanofibers have gained much attention. This review discusses the capabilities of the electrospun nanofibers in delivering different therapeutics like small molecules, genes, and proteins to their desired target site for treating various ailments. The potential of nanofibers in administering through multiple administration routes and the associated challenges has also been expounded along with a cross‐talk about the commercial products of nanofibers for biomedical applications. [ABSTRACT FROM AUTHOR]

A benzamidine derivative from diminazene was tested for a novel activity: treatment of primary open‐angle glaucoma. This drug was incorporated into mucoadhesive polymeric inserts prepared using chitosan (Chs) and chondroitin sulfate (CS). Of current interest is the mucoadhesion, which increases the contact time with the ocular surface, resulting in improved bioavailability; also, the inserts are made to act as a prolonged release system. In the present work the inserts were prepared by the solvent casting method using different polymeric proportions (30:70, 50:50, 75:25% w/w Chs:CS and 100% Chs). Thermal analysis and infrared spectroscopy both demonstrated physical dispersion of the active drug. The most promising was the 50:50% Chs:CS which demonstrated that it was not fragile and has an in vitro release profile of up to 180 minutes. In addition, it presented greater adhesion strength in relation to the other formulations. These physicochemical results corroborate the in vivo tests performed. In this sense, we also demonstrated that the treatment with the 50:50% insert can control the intraocular pressure (IOP) for at least 3 weeks and prevents damage to the retinal ganglion cells (RGCs) compared to the placebo insert. Thus, this indicates thus that the new drug is quite viable and promising in glaucoma treatment. [ABSTRACT FROM AUTHOR]

Growth factor (GF) delivery is a common strategy for spinal cord injury repair, however, GF degradation can impede long‐term therapies. GF sequestration via heparin is known to protect bioactivity after delivery. We tested two heparin modifications, methacrylated heparin and thiolated heparin, and electrospun these with methacrylated hyaluronic acid (MeHA) to form HepMAHA and HepSHHA nanofibers. For loaded conditions, MeHA, HepMAHA, and HepSHHA fibers were incubated with soluble basic fibroblast growth factor (bFGF) or nerve growth factor (NGF) and rinsed with PBS. Control groups were hydrated in PBS. L929 fibroblast proliferation was analyzed after 24 hr of culture in either growth media or bFGF‐supplemented media. Dissociated chick dorsal root ganglia neurites were measured after 3 days of cell culture in serum free media (SFM) or NGF‐supplemented SFM (SFM + NGF). In growth media, fibroblast proliferation was significantly increased in loaded HepMAHA (α <.05) compared to other groups. In SFM, loaded HepMAHA had the longest average neurite length compared to all other groups. In SFM + NGF, HepMAHA and HepSHHA had increased neurite lengths compared to MeHA, regardless of loading (α <.01), suggesting active sequestration of soluble NGF. HepMAHA is a promising biomaterial for sequestering released GFs in a spinal cord injury environment and will be combined with GF filled microspheres for future studies. [ABSTRACT FROM AUTHOR]

An implantable scaffold‐based vaccination system is a promising platform to generate robust immune responses by modulating the immune system. However, establishment of an effective vaccine using a biodegradable, cell‐infiltrative scaffold remain challenging. Here we demonstrate a biodegradable, nanocellulose‐based immune scaffold capable of sustainably activating immune cells to elicit cellular immunity. Cell‐infiltrative nanocellulose hydrogels were used as a delivery carrier and cellular scaffold microenvironment. Nanofibrous hydrogels allowed for high cell infiltration and delivery of antigen‐loaded nanocellulose while cells degraded the hydrogel matrix. Importantly, antigen‐loaded nanocellulose hydrogels exhibited sustained activation of macrophages in vitro compared to free antigen and collagen scaffold. Histological observation revealed infiltration of macrophages and dendritic cells into the nanocellulose scaffold subcutaneously implanted in mice. In vivo fluorescence imaging indicated that the implanted scaffold released antigens at a zero‐order release profile without burst diffusion. Antigen‐loaded nanocellulose hydrogels increased interferon‐γ‐producing cells compared to free antigen injection, suggesting the enhancement of cellular immunity. Thus, nanocellulose immune scaffold may serve as a sustained‐immunostimulatory vaccine platform by providing favorable microenvironments for immune cells thus enhancing vaccine efficacy. [ABSTRACT FROM AUTHOR]

Arginine‐glycine‐aspartic acid (RGD) peptide family is known as the most prominent ligand for extracellular domain of integrin receptors. Specific expression of these receptors in various tissue of human body and tight association of their expression profile with various pathophysiological conditions made these receptors a suitable targeting candidate for several disease diagnosis and treatment as well as regeneration of various organs. For these reasons, various forms of RGD‐based integrins ligands have been greatly used in biomedical studies. Here, we summarized the last decade application progress of RGD for cancer theranostics, control of inflammation, thrombosis inhibition and critically discussed the effect of RGD peptides structure and sequence on the efficacy of gene/drug delivery systems in preclinical studies. Furthermore, we will show recent advances in application of RGD functionalized biomaterials for various tissue regenerations including cornea repair, artificial neovascularization and bone tissue regeneration. Finally, we analyzed clinically translatability of RGD peptides, considering examples of integrin ligands in clinical trials. In conclusion, prospects on using RGD peptide for precise drug delivery and biomaterial engineering are well discussed. [ABSTRACT FROM AUTHOR]

Herein, we fabricated the novel drug delivery system based on the self‐assembly of two polyelectrolytes, poly‐allylamine hydrochloride (PAH) and fucoidan, as the polycation and polyanion, respectively, under mild conditions for cancer therapeutics. Furthermore, the designed polyelectrolyte complex nanoparticles as well as the methotrexate (MTX) disodium salt‐loaded composites were systematically characterized using various techniques. The MTX loading in the nanoparticles was confirmed by zeta potential values that changed from −36.2 ± 2.2 to −28.3 ± 3.1 mV at a loading amount of 13.3 ± 1.2%. Furthermore, the obtained eventual particle sizes of nanoparticles were various with different concentrations and ratios of polyelectrolytes. The particle size also has increased from 130 ± 2.6 to 162.9 ± 2.3 nm after loading MTX. The drug release investigations in vitro at a pH value of 6.0 (acid environment) showed that the release of MTX was sustained in the conditions provided. Finally, we investigated the anticancer efficacy of MTX‐loaded nanoparticles on MCF‐7 cells and HeLa cells and the satisfactory results were obtained. Together, these self‐assembled PAH/fucoidan nanoparticles with sustained drug release property will become the promising delivery system for cancer therapeutics. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 339–347, 2019. [ABSTRACT FROM AUTHOR]

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microsphere loaded 45S5 bioactive glass (BG) based scaffolds with drug releasing capability have been developed. PHBV microspheres with a mean particle size 4 ± 2 μm loaded with daidzein were obtained by oil-in-water single emulsion solvent evaporation method and applied to the surface of BG scaffolds by dip coating technique. The morphology, in vitro bioactivity in simulated body fluid (SBF), mechanical properties and drug release kinetics of microsphere loaded scaffolds were studied. The microspheres were shown to be homogeneously dispersed on the scaffold surfaces. It was confirmed that hydroxyapatite crystals homogeneously grew not only on the surface of the scaffold but also on the surface of the microspheres within 3 days of immersion in SBF. The daidzein release from the microsphere loaded scaffolds lasted almost 1 month and was determined to be diffusion controlled. The microsphere loaded BG scaffolds with daidzein releasing capability obtained in this study are a candidate for bone tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1765-1774, 2017. [ABSTRACT FROM AUTHOR]

A scaffold capable of controlling drug release is highly desirable for bone tissue engineering. The objective of this study was to develop and characterize a highly porous biodegradable scaffold and evaluate the kinetic release behavior for the application of anti-inflammatory drug delivery. Porous scaffolds consisting of chitosan, poly(acrylic acid), and nano-hydroxyapatite were prepared using the freeze-drying method. The nanocomposite scaffolds were characterized for structure, pore size, porosity, and mechanical properties. The nanocomposite scaffolds were tested and characterized using Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive analysis of X-ray (EDS), X-ray diffraction (XRD) analysis, and tensile test instrument. The results showed that the pores of the scaffolds were interconnected, and their sizes ranged from 145 µm to 213 μm. The mechanical properties were found close to those of trabecular bone of the same density. The ability of the scaffolds to deliver naproxen sodium as a model drug in vitro was investigated. The release profile of naproxen sodium was measured in a phosphate-buffered saline solution by a ultra-violet spectrophotometer that was controlled by the Fickian diffusion mechanism. These results indicated that the chitosan- graft-poly(acrylic acid)/nano-hydroxyapatite scaffold may be a promising biomedical scaffold for clinical use in bone tissue engineering with a potential for drug delivery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2992-3003, 2016. [ABSTRACT FROM AUTHOR]

This study was undertaken to synthesize an interpolyelectrolyte complex (IPEC) of polymethacrylate (E100) and sodium carboxymethylcellulose (NaCMC) to form a polymeric hydrogel material for application in specialized oral drug delivery of sensitive levodopa. Computational modeling was employed to proffer insight into the interactions between the polymers. In addition, the reactional profile of NaCMC and polymethacrylate was elucidated using molecular mechanics energy relationships (MMER) and molecular dynamics simulations (MDS) by exploring the spatial disposition of NaCMC and E100 with respect to each other. Computational modeling revealed that the formation of the IPEC was due to strong ionic associations, hydrogen bonding, and hydrophilic interactions. The computational results corroborated well with the experimental and the analytical data. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 1077-1084, 2015. [ABSTRACT FROM AUTHOR]

Delivery of bioactive molecules is a critical step in fabricating materials for regenerative medicine, yet, this step is particularly challenging in hydrated scaffolds such as hydrogels. Although bulk photocrosslinked poly(ethylene glycol) (PEG) hydrogels have been used for a variety of tissue engineering applications, their capability as drug delivery scaffolds has been limited due to undesirable release profiles and reduction in bioactivity of molecules. To solve these problems, this article presents the fabrication of degradable PEG microgels, which are micron-sized spherical hydrogels, to deliver bioactive nerve growth factor (NGF). NGF release and activity was measured after encapsulation in microgels formed from either 3 kDa or 6 kDa PEG to determine the role of hydrogel mesh size on release. Microgels formed from 6 kDa PEG were statistically larger and had a higher swelling ratio than 3 kDa PEG. The 6 kDa PEG microgels provided a Fickian release with a reduced burst effect and 3 kDa microgels provided anomalous release over ≥20 days. Regardless of molecular weight of PEG, NGF bioactivity was not significantly reduced compared to unprocessed NGF. These results demonstrate that microgels provide easy mechanisms to control the release while retaining the activity of growth factors. As this microgel-based delivery system can be injected at the site of nerve injury to promote nerve repair, the potential to deliver active growth factors in a controlled manner may reduce healing time for neural tissue engineering applications. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 604-613, 2015. [ABSTRACT FROM AUTHOR]

ABSTRACT Preparation of hydrogels that possess an effective antibiotic release profile and better mechanical properties compared to the traditionally used collagen hydrogels has the potential to minimize post-surgical infections and support wound healing. Toward this goal, we prepared elastin-like polypeptide (ELP)-collagen composite hydrogels that displayed a significantly higher elastic modulus compared to the collagen hydrogels. We then characterized the release behavior of the collagen and ELP-collagen hydrogels loaded with varying dosages (1-5% w/w) of a commonly used broad spectrum antibiotic, doxycycline hyclate. Both collagen and ELP-collagen hydrogels showed a gradual time dependent doxycycline release over a period of 5 days. The ELP-collagen hydrogels, in general, showed a slower release of the doxycycline compared to the collagen hydrogels. The released doxycycline was found to be effective against four bacterial strains ( Escherichia coli, Pseudomonas aeruginosa, Streptococcus sanguinis, and methicillin-resistant Staphylococcus aureus) in a dose dependent manner. Combined with their improved mechanical properties, the gradual and effective drug release from the biocompatible ELP-collagen hydrogels shown here may be beneficial for drug delivery and tissue engineering applications. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 782-790, 2015. [ABSTRACT FROM AUTHOR]

The ability of silica calcium phosphate nanocomposite (SCPC75) for the controlled sequential delivery of vancomycin (Vanc) and rhBMP2 was evaluated. Fourier transform infrared spectroscopy analyses of the SCPC75 showed an increase in the bond energy of the PO4−3 due to the interactions with negatively charged moieties of Vanc. Furthermore, a decrease in the bond energy of the SiOSi functional groups was observed after rhBMP2 adsorption. In conjunction with the differences in bond site and bond energy at the ceramic/drug interface, significant differences in drug release kinetics and bioceramic dissolution rate were found. UV-vis spectrometry showed a burst release of Vanc in the first 8 h followed by a sustained release stage for up to 28 days. ELISA showed first-order release kinetics of rhBMP2 without burst release. The rhBMP2 release from SCPC75 was associated with a significantly lower rate of Ca and a higher rate of Si dissolutions when compared with Vanc release over identical time periods. Differences in the release kinetic profiles of Vanc and rhBMP2 from the SCPC75-Vanc/SCPC75-rhBMP2 scaffolds at 70/30, 50/50, or 20/80 ratios allowed for sequential drug release profiles that could be exploited to customize doses and release duration of each drug. The released rhBMP2 significantly upregulated MC3T3-E1 expression of collagen type I, osteopontin, and osteocalcin mRNA by 12.6-, 3.3-, and 2.4-fold, respectively. The released Vanc demonstrated bactericidal effects on Staphylococcus aureus in vitro. These results suggest the potential of SCPC75-Vanc-rhBMP2 scaffolds in the treatment of damaged and/or infected bone. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 4213-4223, 2014. [ABSTRACT FROM AUTHOR]

Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an 'on-off' drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The 'on-off' drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2039-2054, 2014. [ABSTRACT FROM AUTHOR]

Structurally related surfactant molecules were exploited to generate chitosan emulsions to provide systematic variation in micelle radii of curvature and size. These compositions provide precise control of chitosan particle dispersity, that is, size distribution according to three quantitative distribution parameters as well as shape distribution. This resulted in a suite of particle size distributions spanning 71 nm to 3.7 μm and a very high degree of particle sphericity, allowing the influence of particle size to be isolated in two in vivo studies relating biopolymer particle size to cellular uptake and trafficking to lymph nodes. Flow cytometry and fluorescence microscopy indicated that the three cell lines examined preferentially internalized chitosan microparticles to a greater extent than nanoparticles over a 24 h period. In an in vivo mouse model, nanoparticles initially trafficked rapidly to lymph nodes draining the site of inoculation followed by further slower uptake. Microparticles trafficked to the lymph nodes with a similar pattern except that the initial discharge was ∼50-fold less than that observed with nanoparticles indicating a profound difference in the physiological transport properties of the two particle types. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012. [ABSTRACT FROM AUTHOR]