Biomedical gels: structure and properties

Biomedical hydrogels are defined as biocompatible solid-liquid systems in which polymeric chains (fibers) are crosslinked to form a 3D-network swollen by a huge water amount. Their use as controlled drug release systems is in continuous growth. However, a critical step in their development is the characterization of their 3D nano/micro structure and the correlation with fabrication parameters. Indeed, hydrogels structure is complex and depends on fibers diameter, concentration, mesh/pore size and degree of crosslinking. Historically, hydrogel structure have been imaged using AFM, SEM, TEM and X-ray microscopy. Although these methods provide high-resolution images, they require a significant sample manipulation that can lead to shrinkage and collapse of the fibers structure. Moreover, information is strictly localized and poorly suited for bulk properties. The target of this thesis is to propose the combined use of not-destructive, economic and fast technologies like rheology and low field NMR (LF-NMR) to understand the macro-, micro- and nanoscopic characteristic of several hydrogels. We aim to drastically reduce the need for time-consuming, expensive measurement, rather to select optimal sample for more complex characterization. Reliability of rheological and LF NMR approach were tested to: \u2022 follow hydrogel gelation process in i) a sonicated nanocellulose solution ii) a thermo-sensitive chitosan gel. In particular, the effect of i) salt addition and sonicated time and ii) temperature on the gelation process were considered, respectively. \u2022 interpret the characteristics of cross-linked gels system relaying on polymer blends [PVP (poly-vinyl-pirrolidone) and alginate]. In particular gels mechanical strength, 3D nano/micro structure and mesh size distribution were determined. Some of these systems, suitable for liposomes delivery, were also characterized by TEM and this technique confirmed our findings. \u2022 correlate mesh size and release rate in a Diels-Alder poly(ethylene glycol) based hydrogel for controlled antibodies release. Our estimations well fitted with test of in vitro release of fluorescein isothiocyanate labeled Dextran and Bertuzimab. For what concerns biological tissues, the focus is on two innovative applications of LF-NMR relying on the different conditions experienced by water confined in three-dimensional structures. Indeed, from the LF-NMR point of view, we can distinguish between free water that is not affected by the solid surface, and bound water that undergoes the effect of solid surface: \u2022 The first application considers the analysis on the expectorate of patients affected by cystic fibrosis (CF). This pulmonary disease is mainly characterized by a dehydrated and hyper concentrated mucus in airways. We analysed these voluntary samples to reveal mucus dehydration and pathological components, which are strictly correlated to disease severity. As this approach is less expensive, faster, non-invasive and does not require highly qualified personnel, it has the potential to become a valuable monitoring tool. \u2022 The second application regards the evaluation of trabecular bone extracts from osteoporosis and osteoarthrosis patients who underwent hip replacement. These two pathological conditions differ for the quality of bone tissue, and both of them are typical of elders. Water mobility inside the trabecular network is connected to the pore size distribution characterising the bone tissue. Therefore we expected that osteoporosis samples present higher water mobility than osteoarthrosis ones. It could be a new method to rapidly and easily know the severity of osteoporosis

Dual stimuli-responsive polyurethane-based hydrogels as smart drug delivery carriers for the advanced treatment of chronic skin wounds

The design of multi-stimuli-responsive vehicles for the controlled and localized release of drugs is a challenging issue increasingly catching the attention of many research groups working on the advanced treatment of hard-to-close wounds. In this work, a thermo- and pH-responsive hydrogel (P-CHP407) was prepared from an ad hoc synthesized amphiphilic poly(ether urethane) (CHP407) exposing a significant amount of –COOH groups (8.8 ± 0.9 nmol/gpolymer). The exposure of acid moieties in P-CHP407 hydrogel led to slightly lower initial gelation temperature (12.1 °C vs. 14.6 °C, respectively) and gelation rate than CHP407 hydrogel, as rheologically assessed. Nanoscale hydrogel characterization by Low Field NMR (LF-NMR) spectroscopy suggested that the presence of carboxylic groups in P-CHP407 caused the formation of bigger micelles with a thicker hydrated shell than CHP407 hydrogels, as further proved by Dynamic Light Scattering analyses. In addition, P-CHP407 hydrogel showed improved capability to change its internal pH compared to CHP407 one when incubated with an alkaline buffer (pH 8) (e.g., pHchange_5min = 3.76 and 1.32, respectively). Moreover, LF-NMR characterization suggested a stronger alkaline-pH-induced interaction of water molecules with micelles exposing –COOH groups. Lastly, the hydrogels were found biocompatible according to ISO 10993 and able to load and release Ibuprofen: delivery kinetics of Ibuprofen was enhanced by P-CHP407 hydrogels at alkaline pH, suggesting their potential use as smart delivery systems in the treatment of chronic infected wounds

Dissolution of an ensemble of differently shaped poly-dispersed drug particles undergoing solubility reduction: mathematical modelling

The aim of this theoretical paper is to develop a mathematical model for describing the dissolution process, in a finite liquid environment, of an ensemble of poly-dispersed drug particles, in form of sphere, cylinder and parallelepiped that can undergo solubility reduction due to phase transition induced by dissolution. The main result of this work consists in its simplicity as, whatever the particular particles size distribution, only two ordinary differential equations are needed to describe the dissolution process. This, in turn, reflects in a very powerful and agile theoretical tool that can be easily implemented in electronic sheets, a widespread tool among the research community. Another model advantage lies on the possibility of determining its parameters by means of common independent techniques thus enabling the evaluation of the importance of solid wettability on the dissolution process.</p

3D human foreskin model for testing topical formulations of sildenafil citrate

: Sildenafil citrate is an approved drug used for the treatment of erectile dysfunction and premature ejaculation. Despite a widespread application, sildenafil citrate shows numerous adverse cardiovascular effects in high-risk patients. Local transdermal drug delivery of this drug is therefore being explored as an interesting and noninvasive alternative administration method that avoids adverse effects arised from peak plasma drug concentrations. Although human and animal skin represents the most reliable models to perform penetration studies, they involve a series of ethical issues and restrictions. For these reasons new in vitro approaches based on artificially reconstructed human skin or "human skin equivalents" are being developed as possible alternatives for transdermal testing. There is little information, however, on the efficiency of such new in vitro methods on cutaneous penetration of active ingredients. The objective of the current study was to investigate the sildenafil citrate loaded in three commercial transdermal vehicles using 3D full-thickness skin equivalent and compare the results with the permeability experiments using porcine skin. Our results demonstrated that, while the formulation plays an imperative role in an appropriate dermal uptake of sildenafil citrate, the D coefficient results obtained by using the 3D skin equivalent are comparable to those obtained by using the porcine skin when a simple drug suspension is applied (1.17&nbsp;×&nbsp;10-10&nbsp;±&nbsp;0.92&nbsp;×&nbsp;10-10 cm2/s vs 3.5&nbsp;×&nbsp;102&nbsp;±&nbsp;3.3&nbsp;×&nbsp;102 cm2/s), suggesting that in such case, this 3D skin model can be a valid alternative for ex-vivo skin absorption experiments

A physiologically-oriented mathematical model for the description of in vivo drug release and absorption

This paper focuses on a physiologically-oriented mathematical model aimed at studying the in vivo drug release, absorption, distribution, metabolism and elimination (ADME). To this purpose, the model accounts for drug delivery from an ensemble of non-eroding poly-disperse polymeric particles and the subsequent ADME processes. The model outcomes are studied with reference to three widely used drugs: theophylline, temazepam and nimesulide. One of the most important results of this study is the quantitative evaluation of the interplay between the release kinetics and the subsequent ADME processes. Indeed, it is usually assumed that in vivo drug release coincides with in vitro so that the effect exerted by the ADME processes is neglected. In addition, the proposed model may be an important tool for the design of delivery systems since, through proper changes, it could also account for different oral delivery systems

Oxidized Nanocarbons-Tripeptide Supramolecular Hydrogels: Shape Matters!

Short peptide hydrogels are attractive biomaterials but typically suffer from limited mechanical properties. Inclusion of other nanomaterials can serve the dual purpose of hydrogel reinforcement and of conferring additional physicochemical properties (e.g., self-healing, conductivity), as long as they do not hamper peptide self-assembly. In particular, nanocarbons are ideal candidates, and their physicochemical properties have demonstrated great potential in nanocarbon-polymer gel biomaterials for tissue engineering or drug delivery. Recently, increasing interest in supramolecular hydrogels drove research also on their enhancement with nanocarbons. However, little is known on the effect of nanocarbon morphology on the self-assembly of short peptides, which are among the most popular hydrogel building blocks. In this work, three different oxidized nanocarbons (i.e., carbon nanotube or CNT as 1D material, graphene oxide sheet or GO as 2D material, and carbon nanohorn or CNH as 3D material) were evaluated for their effects on the self-assembly of the unprotected tripeptide Leu-DPhe-DPhe at physiological conditions. Supramolecular hydrogels were obtained in all cases, and viscoelastic properties were clearly affected by the nanocarbons, which increased stiffness and resistance to applied stress. Notably, self-healing behavior was observed only in the case of CNTs. Tripeptide\u2013nanotube interaction was noted already in solution prior to self-assembly, with the tripeptide acting as a dispersing agent in phosphate buffer. Experimental and in silico investigation of the interaction between peptide and CNTs suggests that the latter acts as nucleation templates for self-assembly and reassembly. Overall, we provide useful insights for the future design of composite biomaterials with acquired properties

Potential applications of nanocellulose-containing materials in the biomedical field

Because of its high biocompatibility, bio-degradability, low-cost and easy availability, cellulose finds application in disparate areas of research. Here we focus our attention on the most recent and attractive potential applications of cellulose in the biomedical field. We first describe the chemical/structural composition of cellulose fibers, the cellulose sources/features and cellulose chemical modifications employed to improve its properties. We then move to the description of cellulose potential applications in biomedicine. In this field, cellulose is most considered in recent research in the form of nano-sized particle, i.e., nanofiber cellulose (NFC) or cellulose nanocrystal (CNC). NFC is obtained from cellulose via chemical and mechanical methods. CNC can be obtained from macroscopic or microscopic forms of cellulose following strong acid hydrolysis. NFC and CNC are used for several reasons including the mechanical properties, the extended surface area and the low toxicity. Here we present some potential applications of nano-sized cellulose in the fields of wound healing, bone-cartilage regeneration, dental application and different human diseases including cancer. To witness the close proximity of nano-sized cellulose to the practical biomedical use, examples of recent clinical trials are also reported. Altogether, the described examples strongly support the enormous application potential of nano-sized cellulose in the biomedical field

Uso sinergico della reologia e della risonanza magnetica nucleare a basso campo per caratterizzare l’espettorato di pazienti con fibrosi cistica

Hyper-concentrated and more viscous mucus presents in the lungs of patients suffering from cystic fibrosis (CF) provoke mucus stasis providing an optimal environment for bacterial growth. The sputum of CF patients has been subjected to rheological and low-field NMR investigation, providing information on i) the state of viscoelasticity (G0, h 0 ) and mucus hydration (T2avg), ii) possible correlations also with parameter of patients clinical status given by spirometry(FEV1) iii) the structure of the polymeric network in mucus. The absence of correlation among magnetic and mechanical-rheological relaxation notes that these phenomena are linked to different aspects of sputum. However, correlations exist among FEV1, T2av and rheological properties G0, h 0. Moreover, T2avg correlates with the mucociliary clearability index (MCI) and cough clearability index (CCI), two indices derived from the rheological characterization. The clinical condition of the patient can, therefore, be summarized by T2avg alone. Finally, information from the two characterizations make it possible to estimate the mesh size distribution of the polymeric network pervading sputum. This knowledge is very useful to better understand drugs penetration in mucus