Medical Bionics - Research Publications
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ItemDeveloping the supraparticle technology for round window-mediated drug administration into the cochlea(ELSEVIER, 2023-09)The semi-permeable round window membrane (RWM) is the gateway to the cochlea. Although the RWM is considered a minimally invasive and clinically accepted route for localised drug delivery to the cochlea, overcoming this barrier is challenging, hindering development of effective therapies for hearing loss. Neurotrophin 3 (NT3) is an emerging treatment option for hearing loss, but its therapeutic effect relies on sustained delivery across the RWM into the cochlea. Silica supraparticles (SPs) are drug delivery carriers capable of providing long-term NT3 delivery, when injected directly into the guinea pig cochlea. However, for clinical translation, a RWM delivery approach is desirable. Here, we aimed to test approaches to improve the longevity and biodistribution of NT3 inside the cochlea after RWM implantation of SPs in guinea pigs and cats. Three approaches were tested (i) coating the SPs to slow drug release (ii) improving the retention of SPs on the RWM using a clinically approved gel formulation and (iii) permeabilising the RWM with hyaluronic acid. A radioactive tracer (iodine 125: 125I) tagged to NT3 (125I NT3) was loaded into the SPs to characterise drug pharmacokinetics in vitro and in vivo. The neurotrophin-loaded SPs were coated using a chitosan and alginate layer-by-layer coating strategy, named as '(Chi/Alg)SPs', to promote long term drug release. The guinea pigs were implanted with 5× 125I NT3 loaded (Chi/Alg) SPs on the RWM, while cats were implanted with 30× (Chi/Alg) SPs. A cohort of animals were also implanted with SPs (controls). We found that the NT3 loaded (Chi/Alg)SPs exhibited a more linear release profile compared to NT3 loaded SPs alone. The 125I NT3 loaded (Chi/Alg)SPs in fibrin sealant had efficient drug loading (~5 μg of NT3 loaded per SP that weights ~50 μg) and elution capacities (~49% over one month) in vitro. Compared to the SPs in fibrin sealant, the (Chi/Alg)SPs in fibrin sealant had a significantly slower 125I NT3 drug release profile over the first 7 days in vitro (~12% for (Chi/Alg) SPs in fibrin sealant vs ~43% for SPs in fibrin sealant). One-month post-implantation of (Chi/Alg) SPs, gamma count measurements revealed an average of 0.3 μg NT3 remained in the guinea pig cochlea, while for the cat, 1.3 μg remained. Histological analysis of cochlear tissue revealed presence of a 125I NT3 signal localised in the basilar membrane of the lower basal turn in some cochleae after 4 weeks in guinea pigs and 8 weeks in cats. Comparatively, and in contrast to the in vitro release data, implantation of the SPs presented better NT3 retention and distribution inside the cochlea in both the guinea pigs and cats. No significant difference in drug entry was observed upon acute treatment of the RWM with hyaluronic acid. Collectively, our findings indicate that SPs and (Chi/Alg)SPs can facilitate drug transfer across the RWM, with detectable levels inside the cat cochlea even after 8 weeks with the intracochlear approach. This is the first study to examine neurotrophin pharmacokinetics in the cochlea for such an extended period of times in these two animal species. Whilst promising, we note that outcomes between animals were variable, and opposing results were found between in vitro and in vivo release studies. These findings have important clinical ramifications, emphasising the need to understand the physical properties and mechanics of this complex barrier in parallel with the development of therapies for hearing loss.
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ItemPharmacokinetics and biodistribution of supraparticle-delivered neurotrophin 3 in the guinea pig cochlea(ELSEVIER, 2022-02)Hearing loss is the most prevalent sensory disorder affecting nearly half a billion people worldwide. Aside from devices to assist hearing, such as hearing aids and cochlear implants, a drug treatment for hearing loss has yet to be developed. The neurotrophin family of growth factors has long been established as a potential therapy, however delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We previously demonstrated that direct delivery of exogenous neurotrophin-3 (NT3) in the guinea pig cochleae via a bolus injection was rapidly cleared from the inner ear, with almost complete elimination 3 days post-treatment. Here, we explored the potential of suprapaticles (SPs) for NT3 delivery to the inner ear to achieve sustained delivery over time. SPs are porous spheroid structures comprised of smaller colloidal silica nanoparticles that provide a platform for long-term controlled release of therapeutics. This study aimed to assess the pharmacokinetics and biodistribution of SP-delivered NT3. We used a radioactive tracer (iodine 125: 125I) to label the NT3 to determine the loading, retention and distribution of NT3 delivered via SPs. Gamma measurements taken from 125I NT3 loaded SPs revealed high drug loading (an average of 5.3 μg of NT3 loaded per SP weighing 50 μg) and elution capacities in vitro (67% cumulative release over one month). Whole cochlear gamma measurements from SP-implanted cochleae harvested at various time points revealed detection of 125I NT3 in the guinea pig cochlea after one month, with 3.6 and 10% of the loaded drug remaining in the intracochlear and round window-implanted cochleae respectively. Autoradiography analysis of cochlear micro-sections revealed widespread 125I NT3 distribution after intracochlear SP delivery, but more restricted distribution with the round window delivery approach. Collectively, drug delivery into the inner ear using SPs support sustained, long-term availability and release of neurotrophins in the inner ear.
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ItemGel-Mediated Electrospray Assembly of Silica Supraparticles for Sustained Drug Delivery(AMER CHEMICAL SOC, 2018-09-19)Supraparticles (SPs) composed of smaller colloidal particles provide a platform for the long-term, controlled release of therapeutics in biomedical applications. However, current synthesis methods used to achieve high drug loading and those involving biocompatible materials are often tedious and low throughput, thereby limiting the translation of SPs to diverse applications. Herein, we present a simple, effective, and automatable alginate-mediated electrospray technique for the assembly of robust spherical silica SPs (Si-SPs) for long-term (>4 months) drug delivery. The Si-SPs are composed of either porous or nonporous primary Si particles within a decomposable alginate matrix. The size and shape of the Si-SPs can be tailored by controlling the concentrations of alginate and silica primary particles used and key electrospraying parameters, such as flow rate, voltage, and collector distance. Furthermore, the performance (including drug loading kinetics, loading capacity, loading efficiency, and drug release) of the Si-SPs can be tuned by changing the porosity of the primary particles and through the retention or removal (via calcination) of the alginate matrix. The structure and morphology of the Si-SPs were characterized by electron microscopy, dynamic light scattering, N2 adsorption-desorption analysis, and X-ray photoelectron spectroscopy. The cytotoxicity and degradability of the Si-SPs were also examined. Drug loading kinetics and loading capacity for six different types of Si-SPs, using a model protein drug (fluorescently labeled lysozyme), demonstrate that Si-SPs prepared from primary silica particles with large pores can load significant amounts of lysozyme (∼10 μg per SP) and exhibit sustained, long-term release of more than 150 days. Our experiments show that Si-SPs can be produced through a gel-mediated electrospray technique that is robust and automatable (important for clinical translation and commercialization) and that they present a promising platform for long-term drug delivery.
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ItemMesoporous Silica Supraparticles for Sustained Inner-Ear Drug Delivery(Wiley, 2014)Mesoporous silica supraparticles (MS-SPs) are prepared via self-assembly of mesoporous silica nanoparticles under capillary force action in confined droplets. The MS-SPs are effective carriers for sustained drug delivery. Animal studies show that these particles are suitable for chronic intracochlear implantation, and neurotrophins released from the MS-SPs can efficiently rescue primary auditory neurons in an in vivo sensorineural hearing loss model.
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ItemMold-Templated Inorganic-Organic Hybrid Supraparticles for Code livery of Drugs(AMER CHEMICAL SOC, 2014-11)This paper reports a facile and robust mold-templated technique for the assembly of mesoporous silica (MS) supraparticles and demonstrates their potential as vehicles for codelivery of brain-derived neurotrophic factor (BDNF) and dexamethasone (DEX). The MS supraparticles are assembled using gelatin as a biodegradable adhesive to bind and cross-link the particles. Microfabricated molds made of polydimethylsiloxane are used to control the size and shape of the supraparticles. The obtained mesoporous silica-gelatin hybrid supraparticles (MSG-SPs) are stable in water as well as in organic solvents, such as dimethyl sulfoxide, and efficiently coencapsulate both BDNF and DEX. The MSG-SPs also exhibit sustained release kinetics in simulated physiological conditions (>30 days), making them potential candidates for long-term delivery of therapeutics to the inner ear.
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ItemDrug delivery: mesoporous silica supraparticles for sustained inner-ear drug delivery (small 21/2014).(Wiley, 2014-11)Mesoporous silica supraparticles (MS-SPs) self-assembled from mesoporous silica nanoparticles are reported on page 4244 by F. Caruso and co-workers. The MS-SPs are effective carriers for the sustained delivery of brain-derived neurotrophic factor. Animal studies show that the MS-SPs can be implanted into the cochlea and deliver neurotrophins to prevent the progressive loss of the auditory neurons that normally occurs with deafness.