Date: February, 16th, 2022
Part I – GENERAL INFORMATION
Full Name: Pietro Matricardi
E-mail: pietro.matricardi@uniroma1.it
Spoken Languages: Italian (mother tongue) - English
Part II – EDUCATION
Part III – APPOINTMENTS
IIIA – Academic Appointments
IIIB – Other Academic Appointments
IIIC – Other Appointments
Part IV – TEACHING EXPERIENCE
Part V - SOCIETY MEMBERSHIPS, AWARDS AND HONORS
Part VI – OTHER ACTIVITIES
Part VII – RESEARCH ACTIVITIES
Keywords
Polysaccharide Hydrogels, Drug Delivery, Tissue Regeneration, Physico-chemical Characterization, Nanohydrogels, Liposomes, Topical Delivery
Brief Description
My research activity can be described by means of four keywords: polysaccharides, hydrogels, physico-chemical characterization, biomedical applications. The aim of the research is the development and the characterization of new polymeric matrices of soft and/or hydrogel nature, mainly based on polysaccharides, useful for applications in drug delivery and in tissue engineering.
My master degree and PhD were focused on the chemical derivatization of pectic polysaccharides and the characterization of these new polymers as a function of the main chain modifications. In particular, those researches have been devoted to the study of the a) conformational properties of those polymers, b) their interactions with metal ions, c) their solubility in organic solvents (to obtain polymers useful in products processing) and d) their gelling properties. Several polysaccharide hydrogels have been prepared by chemical crosslinking and their rheological properties were extensively studied. The work was developed in partnership with Fidia Spa, Abano Terme (Padova), with prof. S.B. Ross-Murphy, London King's College, with Polybiòs Laboratories, Padriciano (Trieste) and with Prof. Romano Lapasin, University of Trieste. During that period, I had the opportunity to develop part of the research, for short periods, in the labs of the partners.
My current research, since 2004, is mainly carried out at the Department of Chemistry and Pharmaceutical Technologies, Faculty of Pharmacy and Medicine, at Sapienza University of Rome, and in collaboration with several Italian and foreign teams.
Schematically, the subjects of my works and the main achievements can be described as follows.
• Physico-chemical characterization of polysaccharide matrices in solution and in the gel phase, with particular attention to matrices based on: scleroglucan and scleroglucan/borax, alginate and calcium alginate, dextran and dextran methacrylate derivatives. The characterization was finalized to define the nature and type of interactions that occurs between the matrix of polymers and the low molecular weight molecules used for the realization of the three-dimensional networks in the hydrogels. Particular interest was devoted to the characterization of the properties of matrices formed by the interpenetration of polysaccharide macromolecules (semi-Interpenetrated and Interpenetrated Polymer Networks – semi-IPN and IPN). The studied systems, even for possible synergistic effects in their mechanical properties, were mainly: alginate/scleroglucan; alginate/dextran derivatives; haluronan/dextran derivatives.
• Development of innovative systems for drug delivery and of new matrices for tissue engineering applications, based on alginate, hyaluronic acid, dextran and scleroglucan. These matrices prepared in solid form or as hydrogels, have been studied for their ability to carry and to deliver drugs, in different aqueous media. In this respect, we used model molecules with different chemical and physico-chemical characteristics. In particular, we studied the transport and the release properties of monolithic systems (microspheres, hydrogel tablets) in the form of polysaccharide IPNs. For some of the hydrogel matrices we have also evaluated the ability to act as a biocompatible support for applications in tissue engineering applications. Part of the research was devoted to the interaction of polysaccharides with liposomal systems.
• Development of new systems, in the form of "nano" structures based on derivatized polysaccharides to transport and deliver drugs and proteins. In particular, these nanoparticle systems were prepared by self-assembly (bottom-up and top-down mechanism) of the polysaccharide chains, which were preliminarily derivatized by hydrophobic moieties.
The various hydrogel systems developed have been characterized in terms of their chemical and physico-chemical properties. The characterizations were carried out using: HPLC, GC, GPC, capillary viscometry, polarimetry, NMR, UV / fluorimetry, SEM, TEM, optical microscopy, confocal microscopy, "in silico", rheology and dynamomechanical analysis. Various assemblies have been developed for the preparation of hydrogels for the delivery of drugs and proteins, for the production of medical devices, or suitable as scaffolds for tissue engineering applications: "implantable hydrogels"; "hydrogels as a support for nanovesicular systems"; "in situ forming hydrogels"; "beads" and "microspheres"; "antimicrobial patches for wound healing"; "nanohydrogels obtained by self-assembly".
The main results obtained from the research can be summarized as follows.
· The research evidenced that the anisotropic swelling behavior of scleroglucan/borax hydrogels, obtained after an appropriate treatment of the polymer matrices, can be related to the formation of ordered structures within the network. These structures, deeply investigated by means of different techniques, influence both the mechanical and physico-chemical properties of the hydrogels and the release behavior of molecules having different steric hindrance. The scleroglucan/borax ability to embed molecules in these ordered structures can be exploited for the immobilization of a redox protein, useful in sensor applications.
· Scleroglucan was also derivatized obtaining a carboxymethyl derivatives; the gelling abilities and the release properties, as well as the chains arrangement in solution, were modified, leading to a thermosensitive and pH responsive system. The interaction with calcium ions led to a soft matter, useful for topical applications.
· The relations among the gelling properties and the structure of guar gum hydrogels were studied as a function of temperature: a strong influence of the crosslinking density on the mechanical properties was observed. The “gel points” of the various systems were also investigated and related to the fundamental equations of the “gel point theory”.
· The research faced also the synergism in hydrogel formation. In this respect the synergistic interactions between locust bean gum and xanthan were investigated. The effect of different preparation procedures on the mechanical properties was assessed. The “hot preparation” resulted to be more effective in forming stronger hydrogels: this effect was explained in term of denaturation and refolding of macromolecules in a more complex and networked assembly.
· The hydrogel forming polysaccharide gellan was derivatized using lysine and the effect of the derivatization on the hydrogel properties (physical and chemical ones) was investigated. The moieties introduced along the polymer chains are able to interfere with the stacking of the polymer chains during the hydrogel forming process, thus leading to systems capable to modulate the release of embedded drugs. Analogously, hyaluronic acid sulphate interferes with the gellan hydrogel forming process, modulating the properties in order to fulfill some application requirements. In this case a beneficial effect was also assessed in the epidural scar prevention. The chemical derivatization was also exploited in developing hyaluronic acid hydrogels for in situ applications. In this respect, hyaluronic acid was derivatized with benzoyl cysteine and the crosslinking profile, the mechanical properties, the chondrocyte attachment and collagen production demonstrated the potentiality of the hydrogel systems as in situ forming scaffolds for cartilage regeneration. The mechanical properties of hydrogel scaffolds based on hyaluronic acid that were chemically crosslinked with α,β-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) were investigated in term of mechanical and fibroblast adhesion and proliferation. Results suggest the suitability of the investigated hydrogels as scaffolds for the regeneration of soft tissues such as skin.
· Effective hydrogels based on chitosan, obtained by chemical (tartaric acid) and physical interactions, have been studied for their application in wound healing. In this field, new dressings based on gellan fibers, PVA, borax and silver were also developed The antimicrobial effect against the bacteria more frequently present in wounds was extensively studied, confirming a synergistic antibacterial effect between silver and PVA, whereas gellan confirmed its role as a scaffold in the form of fibers with an excellent strength and fluids absorbing properties.
· The IPN technique was extensively applied in developing various hydrogel systems, demonstrating a high flexibility in modulating the overall properties, thus fulfilling the requirements of the hydrogels in such a different application, drug delivery and tissue regeneration applications. Scleroglucan and alginate are able to form IPN hydrogels, showing a synergistic effect in the mechanical properties. This property can be exploited in developing tablets able to protect the drug from acidic pH.
· The most important results in the IPN technology were obtained by “mixing” dextran methacrylate or dextran hydroxyethylmethacrylate derivatives with calcium alginate hydrogels thus forming a full chemical/physical biocompatible IPN that can be useful for in situ applications. The mechanical properties of the resulting hydrogels, as well as the degradation rate, can be tuned in a wide range of values. Most importantly, These IPNs were useful for protein delivery and in tissue engineering, in particular by allowing the formation of collagen of type II by chondrocyte cells.
· Different IPNs for different applications were also studied. Hyaluronic acid was used in combination with dextran derivatives as material for bioprinting whereas hyaluronan derivatives were used in combination with calcium alginate to form beads for protein delivery. Moreover, a new general method based on calorimetric determinations at low temperature, rheology and low field NMR was developed for the characterization of the hydrogel’s porosity.
· A very peculiar system, based on hyaluronan and gellan, was also developed for the regeneration of cartilage in osteochondral defects. In this case, the semi-IPN approach was used to form hydrogels that can act, at the same time, as filler and cap of bone/cartilage defects. In particular the triggering of the mechanical and adhesion properties of the hydrogel obtained by the disturbing effect of hyaluronan on the calcium gellan network formation was exploited to obtain a homogeneous and stable hydrogel scaffold for cell regeneration.
· The IPN research line was also extended to proteins or synthetic polymers in order to modify the long time stability of the hydrogels and their mechanical properties. This was particularly important in the development of hydrogel patches that can be used for antioxidants delivery in cardiovascular system, in order to limit the damages due to the blood reperfusion after injuries. PLA and collagen systems, after an appropriate chemical treatment, were developed specifically to form a not a hydrogel biomaterial, to be applied in tendon regeneration.
· A special hydrogel device useful for in situ applications, was based on calcium alginate microparticles, decorated with a PNIPAAM derivative. In this case the aggregation of the microparticle suspension, triggered by the temperature, was very effective in transport and delivery proteins, while protecting their activity.
· In close collaborations with other research groups, new vesicular systems were investigated. In some cases, the interactions between polysaccharide hydrogels and niosomes were studied, in order to develop topical formulation. The effect of the decoration of liposomes with polysaccharides was also studied. The properties of the hydrogel systems obtained starting from liposomes in special conditions, intended for topical or in situ applications, were also studied, and the effect of the various parameter involved, such as concentration, penetration enhancers type, active molecules embedded and temperature were evaluated.
· An emerging and very promising research field was related to the development of new nanohydrogel systems based on the self-assembling of polysaccharide chains (hyaluronan and gellan), previously derivatized with hydrophobic moieties (cholesterol, prednisolone, riboflavin – patented platform) by means of the application of a standard autoclave cycle (patented method). If the autoclave treatment is carried out in the presence of the polymers and of a thermo-stable drug, the nanohydrogel formation and loading is achieved simultaneously (patented method). In the case of not thermo-stable drugs, alternate methods have been developed. These nanohydrogels were useful for a number of different applications, being capable to carry and deliver drugs and proteins in anticancer as well as antimicrobial applications.
· To conclude the description of the research activity, I faced different topics that can be summarized briefly in: molecular imprinting, hydrogels based on cyclodextrins, hydrogels for vaginal atrophy, hydrogen storage, for cultural heritage protection, polymer prodrugs.
· The research activity allowed also the publication of review papers on hydrogels and nanohydrogel.
Part VIII – Summary of Scientific Achievements
* Calculated on the basis of the publication year.
** Number of total publications considered 85. One paper is published in a journal not yet scored.