Clinical Use of Raman Spectroscopy Improves Diagnostic Accuracy for Indeterminate Thyroid Nodules.

BACKGROUND AND OBJECTIVE: Molecular analysis of thyroid fine-needle aspiration (FNA) specimens is believed to improve the management of indeterminate nodules. Raman spectroscopy (RS) can differentiate benign and malignant thyroid lesions in surgically removed tissues, generating distinctive structural profiles. Herein, the diagnostic performance of RS was tested on FNA biopsies of thyroid gland. DESIGN: Prospective, blinded, and single-center study. METHODS: We enrolled 123 patients with indeterminate or more ominous cytologic diagnoses (TIR3A-low-risk indeterminate lesion, TIR3B-high-risk indeterminate lesion, TIR4-suspicious of malignancy, TIR5-malignant). All subjects were surgical candidates (defined by international guidelines) and submitted to FNA procedures for RS analysis. We compared RS data, cytologic findings, and final histologic assessments (as reference standard) using various statistical techniques. RESULTS: The distribution of our study population was as follows: TIR3A:37, TIR3B:32, TIR4:16, and TIR5:38. In 30.9% of patients, histologic diagnoses were benign. For predicting thyroid malignancy in FNA samples, the overall specificity of RS was 86.8%, with 86.5% specificity in indeterminate cytologic categories. In patients with high-risk ultrasound categories, the specificity of RS increased to 87.5% for TIR3A, reaching 100% for TIR3B. Benign histologic diagnoses accounted for 72.9% of patients classified as TIR3A and 31.3% of those classified as TIR3B. Based on positive RS testing, unnecessary surgery was reduced to 7.4% overall (TIR3A-33.3%, TIR3B-6.7%). CONCLUSIONS: This premier use of RS for thyroid cytology confirms its role as a valuable diagnostic tool and a valid alternative to molecular studies, capable of improving the management of indeterminate nodules and reducing unnecessary surgery.

Unraveling the Effects of Carotenoids Accumulation in Human Papillary Thyroid Carcinoma.

Among the thyroid cancers, papillary thyroid cancer (PTC) accounts for 90% of the cases. In addition to the necessity to identify new targets for PTC treatment, early diagnosis and management are highly demanded. Previous data indicated that the multivariate statistical analysis of the Raman spectra allows the discrimination of healthy tissues from PTC ones; this is characterized by bands typical of carotenoids. Here, we dissected the molecular effects of carotenoid accumulation in PTC patients by analyzing whether they were required to provide increased retinoic acid (RA) synthesis and signaling and/or to sustain antioxidant functions. HPLC analysis revealed the lack of a significant difference in the overall content of carotenoids. For this reason, we wondered whether the carotenoid accumulation in PTC patients could be related to vitamin A derivative retinoic acid (RA) biosynthesis and, consequently, the RA-related pathway activation. The transcriptomic analysis performed using a dedicated PCR array revealed a significant downregulation of RA-related pathways in PTCs, suggesting that the carotenoid accumulation in PTC could be related to a lower metabolic conversion into RA compared to that of healthy tissues. In addition, the gene expression profile of 474 PTC cases previously published in the framework of the Cancer Genome Atlas (TGCA) project was examined by hierarchical clustering and heatmap analyses. This metanalysis study indicated that the RA-related pathways resulted in being significantly downregulated in PTCs and being associated with the follicular variant of PTC (FV-PTC). To assess whether the possible fate of the carotenoids accumulated in PTCs is associated with the oxidative stress response, the expression of enzymes involved in ROS scavenging was checked. An increased oxidative stress status and a reduced antioxidant defense response were observed in PTCs compared to matched healthy thyroids; this was possibly associated with the prooxidant effects of high levels of carotenoids. Finally, the DepMap datasets were used to profile the levels of 225 metabolites in 12 thyroid cancer cell lines. The results obtained suggested that the high carotenoid content in PTCs correlates with tryptophan metabolism. This pilot provided novel possible markers and possible therapeutic targets for PTC diagnosis and therapy. For the future, a larger study including a higher number of PTC patients will be necessary to further validate the molecular data reported here.

Thyroid cancer diagnosis by Raman spectroscopy.

Over the last 50 years, the incidence of human thyroid cancer disease has seen a significative increment. This comes along with an even higher increment of surgery, since, according to the international guidelines, patients are sometimes addressed to surgery also when the fine needle aspiration gives undetermined cytological diagnosis. As a matter of fact, only 30% of the thyroid glands removed for diagnostic purpose have a post surgical histological report of malignancy: this implies that about 70% of the patients have suffered an unnecessary thyroid removal. Here we show that Raman spectroscopy investigation of thyroid tissues provides reliable cancer diagnosis. Healthy tissues are consistently distinguished from cancerous ones with an accuracy of [Formula: see text] 90%, and the three cancer typology with highest incidence are clearly identified. More importantly, Raman investigation has evidenced alterations suggesting an early stage of transition of adenoma tissues into cancerous ones. These results suggest that Raman spectroscopy may overcome the limits of current diagnostic tools.

Hydration of Carboxyl Groups: A Route toward Molecular Recognition?

On Earth, water plays an active role in cellular life, over several scales of distance and time. At a nanoscale, water drives macromolecular conformation through hydrophobic forces and at short times acts as a proton donor/acceptor providing charge carriers for signal transmission. At longer times and larger distances, water controls osmosis, transport, and protein mobility. Neutron diffraction experiments augmented by computer simulation, show that the three-dimensional shape of the hydration shell of carboxyl and carboxylate groups belonging to different molecules is characteristic of each molecule. Different hydration shells identify and distinguish specific sites with the same chemical structure. This experimental evidence suggests an active role of water also in controlling, modulating, and mediating chemical reactions involving carboxyl and carboxylate groups.

Raman Spectroscopy Discloses Altered Molecular Profile in Thyroid Adenomas.

Follicular patterned nodules are sometimes complex to be classified due to ambiguous nuclear features and/or questionable capsular or vascular invasion. In this setting, there is a poor inter-observer concordance even among expert pathologists. Raman spectroscopy was recently used to separate benign and malignant thyroid nodules based on their molecular fingerprint; anyway, some histologically proved follicular adenomas were clustered as having a characteristic profile of malignant lesions. In this study, we analyzed five follicular thyroid adenomas with a malignant spectroscopic profile compared to five follicular adenomas with a benign Raman spectrum in order to assess possible molecular differences between the two groups. Morphological, immunohistochemical, and molecular analyses evidenced expression of malignancy-associated proteins in four out of five malignant clustered adenomas. The remaining malignant clustered adenoma showed a TSHR mutation previously associated with autonomously functioning follicular carcinomas. In conclusion, thyroid follicular adenomas are a group of morphologically benign neoplasms that may have altered the mutational or expression profile; cases of adenomas with altered immunophenotype are recognized as showing a profile associated with malignancy by Raman spectroscopy. This correlation warrants a more extensive evaluation and suggests a potential predictive value of spectroscopic assessment in recognizing characteristics associated with tumor progression in follicular thyroid neoplasms.

Metabolic profile of human parathyroid adenoma.

PURPOSE: Recently, it has been demonstrated that Raman spectroscopy is able to differentiate between healthy parathyroid tissues and parathyroid adenoma based on the basis of a specific molecular fingerprint. However, to our knowledge, no previous studies have been performed to evaluate the metabolic profile of parathyroid adenoma. Therefore, we designed a proof of concept study aimed to investigate the glucose/fatty acid metabolisms, in addition to the mitochondrial changes, in solitary parathyroid adenoma and in healthy parathyroid glands. METHODS: Nine females with primary hyperparathyroidism due to a solitary parathyroid adenoma and formal surgical indication for parathyroidectomy have been enrolled. At the time of surgery, the removed specimens were immediately submitted unfixed and a tissue slice of about 0.5 cm in diameter was obtained from the nodular lesion. The expression of selected metabolic enzymes and proteins has been evaluated by western blot analysis, using human parathyroid whole tissue lysates as control. RESULTS: Data obtained highlighted an increase, compared with the healthy group, of: (i) the glucose uptake by the GLUT-1 receptor and its phosphorylation by hexokinase II (HXKII); (ii) the expression of 3-phosphoglycerate dehydrogenase (3-PGDH) and glucose-6-phosphate dehydrogenase (G6PD); (iii) lipids biosynthesis; and (iv) cytochrome c expression. CONCLUSIONS: Our findings highlight for the first time the parathyroid adenoma metabolic hallmarks that could represent potential molecular targets usable for the development of new pharmacological treatments, allowing to reduce surgical parathyroidectomy.

N-Methylacetamide Aqueous Solutions: A Neutron Diffraction Study.

The hydration of N-methylacetamide (NMA) in solution has been determined by neutron diffraction with isotopic Hydrogen/Deuterium substitution (NDIS), augmented by Monte Carlo simulation. This study is representative of the hydration of the peptide bonds characteristic of proteins and might shed light on aggregation phenomena in intrinsically disordered proteins. It is found that NMA forms hydrogen bonds with water at both O and H peptide sites, although of different lengths and strengths. The comparison with the case of tripeptide glutathione evidences differences in both hydration and propensity for aggregation.

Role of Water in Sucrose, Lactose, and Sucralose Taste: The Sweeter, The Wetter?

Natural sugars combine energy supply and, except a few cases, a pleasant taste. On the other hand, exaggerated consumption may impact population health. This has busted the research for the synthesis of increasingly cheaper artificial sweeteners, with low energy content and intense taste. Here, we suggest that studies of the hydration properties of three disaccharides, namely, the natural sucrose and lactose and the artificial sucralose, may explain the difference by orders of magnitude among their sweetness. This is done by analyzing via Monte Carlo simulations the neutron diffraction differential cross sections of aqueous solutions of the three sugars and their isotopes. Our results show that the strength of the sugar-water hydrogen bond interaction is one of the factors influencing sweetness, another being the number of water molecules within the first neighboring shell of the sugar whether bonded or not.

Protection against Dehydration: A Neutron Diffraction Study on Aqueous Solutions of a Model Peptide and Trehalose.

The ability of a wide class of organisms to reversibly go through cycles of suspended life and active metabolism, depending on the turnover of drought and normal water availability conditions, represents a challenging issue. The interest in the natural mechanism for drought survival has grown over time along with the request for always more efficient conservation techniques for biological materials. Carbohydrates, such as trehalose, accumulated in the cytoplasm of drought resistant cells, are considered responsible for desiccation tolerance. Nonetheless, a detailed description of the interaction between trehalose and biomolecules is not yet established. Neutron diffraction experiments show that trehalose entraps a layer of water molecules in the first shell of a model peptide, N-methylacetamide, without direct bonding with it. This evidence contrasts the hypothesis that trehalose substitutes water and supports the opposite view, namely, of trehalose forming a protective shell which entraps a layer of water molecules at the surface of proteins, thus avoiding structural damage due to drought conditions.

Trehalose in Water Revisited.

Trehalose, commonly found in living organisms, is believed to help them survive severe environmental conditions, such as drought or extreme temperatures. With the aim of trying to understand these properties, two recent neutron scattering studies investigate the structure of trehalose water solutions but come to seemingly opposite conclusions. In the first study, which looks at two concentrations of trehalose-water mole ratios of 1:100 and 1:25, the conclusion is that trehalose hydrogen-bonds to water rather weakly and has a relatively minor impact on the structure of water in solution compared to bulk water. On the other hand, for the other, using a mole ratio of 1:38, the conclusion is that the water structure is rather substantially modified by the presence of trehalose and that the hydrogen bonding between water and trehalose hydroxyl groups is significant. In an attempt to try to understand the origin of these divergent views, which arise from similar but independent analyses of different neutron diffraction data, we have performed additional X-ray scattering experiments, which are highly sensitive to water structure, at the same trehalose-water concentrations used in the first study, and combined these with empirical potential structure refinement on the previously collected neutron data. The new analysis unequivocally confirms that trehalose does indeed have only a minor impact on the structure of water, at all three concentrations, and forms relatively weak hydrogen bonds with water. Far from being discrepant with the existing literature, our new analysis of the different datasets suggests a natural explanation for the increased glass-transition temperature of trehalose compared to other sugars and hence its enhanced effectiveness as a protectant against drought stress.

OH Stretching Dynamics in Hydroxide Aqueous Solutions.

The concept of ions being either water "structure makers" or water "breakers" seems to be inconsistent with the existence of a critical number of water molecules per ion dictating the properties of an aqueous solution, independent of the ion identity. To investigate this issue, Raman spectra of hydroxide aqueous solutions in the region of the OH stretching mode have been obtained under ambient conditions and at concentrations ranging from extreme dilution to the solubility limit. Spectra have been analyzed with a relatively model-free approach, in terms of a superposition of contributions due to the vibrations of the OH- ions, with two contributions due to the solvent. One of these latter contributions falls at wavenumbers very close to that of the OH- stretching band, sharing with it its concentration dependence of the full width at half maximum (FWHM). The other contribution due to the solvent is very broad, with increasing FWHM with increasing ion concentration. In the light of these observations, an interpretation of the Raman spectra, based on the possibility of distinguishing the self and distinct contributions, is proposed. The present analysis is supported by structural data on the same solutions and puts into evidence relevant structural and dynamical changes occurring when the number of water molecules available per solute is below ∼20, irrespective of the ion identity.

Dynamical behavior of microgels of interpenetrated polymer networks.

Microgel suspensions of an interpenetrated Polymer Network (IPN) of PNIPAM and PAAc in D2O have been investigated through dynamic light scattering as a function of temperature, pH and concentration across the Volume Phase Transition (VPT). The dynamics of the system is slowed down under H/D isotopic substitution due to different balance states between polymer/polymer and polymer/solvent interactions suggesting the crucial role played by H-bonding. The swelling behavior, reduced with respect to PNIPAM and water, has been described by the Flory-Rehner theory, tested for PNIPAM microgel and successfully expanded to higher order for IPN microgels. Moreover the concentration dependence of the relaxation time at neutral pH has highlighted two different routes to approach the glass transition: Arrhenius and super-Arrhenius (Vogel Fulcher Tammann) respectively below and above the VPT and a fragility plot has been derived. Fragility can be tuned by changing temperature: across the VPT particles undergo a transition from soft-strong to stiff-fragile.

Structure-activity relationships in carbohydrates revealed by their hydration.

One of the more intriguing aspects of carbohydrate chemistry is that despite having very similar molecular structures, sugars have very different properties. For instance, there is a sensible difference in sweet taste between glucose and trehalose, even though trehalose is a disaccharide that comprised two glucose units, suggesting a different ability of these two carbohydrates to bind to sweet receptors. Here we have looked at the hydration of specific sites and at the three-dimensional configuration of water molecules around three carbohydrates (glucose, cellobiose, and trehalose), combining neutron diffraction data with computer modelling. Results indicate that identical chemical groups can have radically different hydration patterns depending on their location on a given molecule. These differences can be linked with the specific activity of glucose, cellobiose, and trehalose as a sweet substance, as building block of cellulose fiber, and as a bioprotective agent, respectively. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.

Parent training education program: a pilot study, involving families of children with Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by severe hypotonia during the neonatal period and the first two years of life, the onset of hyperphagia with a risk of obesity during infancy and adulthood, learning difficulties and behavioral or severe psychiatric problems. This complex disease has severe consequences and difficult management issues also for patients' families. Parents of children with PWS need appropriate psychoeducational intervention in order to better manage their children with PWS. The purpose of this study was the implementation and evaluation of a PWS psychoeducational parent training program. METHODS: The Italian National Center for Rare Diseases implemented a pilot parent training program offered to parents of children with PWS. The intervention's effects was evaluated using questionnaires comprised of 11 items rated on a 7 point Likert scale. RESULTS: The intervention was offered to 43 parents. The behavior problems management, dietary restrictions, autonomy and relationships were indicated by parents as the priority topics which needed to be addressed. Evaluations, immediately post-intervention and after 6 months, were reported by parents, fulfilling specific questionnaires. 90% of parents involved in the study, appreciated the methodology, 86% felt more informed about PWS, 47-62% felt more capable to better approach behaviour's problems, 20-25% felt better about the child's health situation and future expectations. Feeling more capable to help the child autonomy and relationships were reported in 62% and 63% of parents respectively, which decreased significantly (p < 0.05) according to the evaluation 6 months after the intervention. Younger age of parents (< 44 years of age) was significantly correlated with better understanding on how to help the child's autonomy (OR: 0.05; CI: 0.04-0.8) and to better collaborate with the child's teachers (OR: 0.02; CI: 0.001-0.9). CONCLUSION: Parent training is a promising intervention for parents of children with behavior's problems. Interventions with a behaviorally oriented program, addressed to parents of PWS affected children, is a useful tool in increasing their ability to manage the problems related to the disease.

Raman, SEM-EDS and XRPD investigations on pre-Columbian Central America "estucado" pottery.

Seventeen different colored fragments from six selected pre-Columbian estucado ceramics from El Salvador have been investigated by Raman spectroscopy, scanning electron microscope coupled to an energy dispersive spectrometer (SEM/EDS) and X-ray powder diffraction (XRPD). The peculiarity of this kind of ceramics consist of the unusual presence of a white engobe, traditionally termed stucco, between the ceramic body and the decoration elements, hence the name estucado ceramics. The aim of this work was to study the unusual manufacturing technique and to identify the chemical composition of the engobe and of the pigment palette. The results showed that the stucco layer is made of clay (kaolinite) with traces of titanium oxide (anatase). Remarkably, this is the same composition of the white pigments used for the decoration layer, thus excluding an early use of natural titanium oxide as a white pigment in the estucado productions as suggested in previous investigations. Moreover, the presence of kaolinite and anatase both in the stucco and in the decoration layer suggests a cold-working or low temperature technique. The red, yellow and green decorations were realized by the use of natural ochre, while in all the blue and gray decorations Maya blue pigment was identified. Finally, an amorphous carbon pigment of vegetal origin and manganese oxide were used to obtain black pigments.

Local structure of temperature and pH-sensitive colloidal microgels.

The temperature dependence of the local intra-particle structure of colloidal microgel particles, composed of interpenetrated polymer networks, has been investigated by small-angle neutron scattering at different pH and concentrations, in the range (299÷315) K, where a volume phase transition from a swollen to a shrunken state takes place. Data are well described by a theoretical model that takes into account the presence of both interpenetrated polymer networks and cross-linkers. Two different behaviors are found across the volume phase transition. At neutral pH and T ≈ 307 K, a sharp change of the local structure from a water rich open inhomogeneous interpenetrated polymer network to a homogeneous porous solid-like structure after expelling water is observed. Differently, at acidic pH, the local structure changes almost continuously. These findings demonstrate that a fine control of the pH of the system allows to tune the sharpness of the volume-phase transition.

Improved 1,3-Propanediol Synthesis from Glycerol by the Robust Lactobacillus reuteri Strain DSM 20016.

Various Lactobacillus reuteri strains were screened for the ability to convert glycerol to 1,3- propanediol (1,3-PDO) in a glycerol-glucose co-fermentation. Only L. reuteri DSM 20016, a well-known probiotic, was able to efficiently carry out this bioconversion. Several process strategies were employed to improve this process. CO(2+) addition to the fermentation medium, led to a high product titer (46 g/l) of 1,3-PDO and to improved biomass synthesis. L. reuteri DSM 20016 produced also ca. 3 µg/g of cell dry weight of vitamin B12, conferring an economic value to the biomass produced in the process. Incidentally, we found that L. reuteri displays the highest resistance to CO(2+) ions ever reported for a microorganism. Two waste materials (crude glycerol from biodiesel industry and spruce hydrolysate from paper industry) alone or in combination were used as feedstocks for the production of 1,3-PDO by L. reuteri DSM 20016. Crude glycerol was efficiently converted into 1,3-PDO although with a lower titer than pure glycerol (-18%). Compared with the fermentation carried out with pure substrates, the 1,3- PDO produced was significantly lower (40.7 vs. 24.2 g/l) using cellulosic hydrolysate and crude glycerol, but strong increases of the maximal biomass produced (+27%) and of the glucose consumption rate (+46%) were found. The results of this study lay the foundation for further investigations to exploit the biotechnological potential of L. reuteri DSM 20016 to produce 1,3-PDO and vitamin B12 using industry byproducts.

Changes in SAM2 expression affect lactic acid tolerance and lactic acid production in Saccharomyces cerevisiae.

BACKGROUND: The great interest in the production of highly pure lactic acid enantiomers comes from the application of polylactic acid (PLA) for the production of biodegradable plastics. Yeasts can be considered as alternative cell factories to lactic acid bacteria for lactic acid production, despite not being natural producers, since they can better tolerate acidic environments. We have previously described metabolically engineered Saccharomyces cerevisiae strains producing high amounts of L-lactic acid (>60 g/L) at low pH. The high product concentration represents the major limiting step of the process, mainly because of its toxic effects. Therefore, our goal was the identification of novel targets for strain improvement possibly involved in the yeast response to lactic acid stress. RESULTS: The enzyme S-adenosylmethionine (SAM) synthetase catalyses the only known reaction leading to the biosynthesis of SAM, an important cellular cofactor. SAM is involved in phospholipid biosynthesis and hence in membrane remodelling during acid stress. Since only the enzyme isoform 2 seems to be responsive to membrane related signals (e.g. myo-inositol), Sam2p was tagged with GFP to analyse its abundance and cellular localization under different stress conditions. Western blot analyses showed that lactic acid exposure correlates with an increase in protein levels. The SAM2 gene was then overexpressed and deleted in laboratory strains. Remarkably, in the BY4741 strain its deletion conferred higher resistance to lactic acid, while its overexpression was detrimental. Therefore, SAM2 was deleted in a strain previously engineered and evolved for industrial lactic acid production and tolerance, resulting in higher production. CONCLUSIONS: Here we demonstrated that the modulation of SAM2 can have different outcomes, from clear effects to no significant phenotypic responses, upon lactic acid stress in different genetic backgrounds, and that at least in one genetic background SAM2 deletion led to an industrially relevant increase in lactic acid production. Further work is needed to elucidate the molecular basis of these observations, which underline once more that strain robustness relies on complex cellular mechanisms, involving regulatory genes and proteins. Our data confirm cofactor engineering as an important tool for cell factory improvement.

Water-peptide site-specific interactions: a structural study on the hydration of glutathione.

Water-peptide interactions play an important role in determining peptide structure and function. Nevertheless, a microscopic description of these interactions is still incomplete. In this study we have investigated at the atomic scale length the interaction between water and the tripeptide glutathione. The rationale behind this work, based on the combination between a neutron diffraction experiment and a computer simulation, is twofold. It extends previous studies on amino acids, addressing issues such as the perturbation of the water network brought by a larger biomolecule in solution. In addition, and more importantly, it seeks a possible link between the atomic length scale description of the glutathione-water interaction with the specific biological functionality of glutathione, an important intracellular antioxidant. Results indicate a rather weak hydrogen bond between the thiol (-SH) group of cysteine and its first neighbor water molecule. This -SH group serves as a proton donor, is responsible for the biological activity of glutathione, and it is involved in the formation of glutathione disulfide, the oxidized form of glutathione. Moreover, the hydration shell of the chemically identical carboxylate group on the glutamic acid residue and on the glycine residue shows an intriguing different spatial location of water molecules and coordination numbers around the two CO2(-) groups.

Development and characterization of rhVEGF-loaded poly(HEMA-MOEP) coatings electrosynthesized on titanium to enhance bone mineralization and angiogenesis.

Osteointegration of titanium implants could be significantly improved by coatings capable of promoting both mineralization and angiogenesis. In the present study, a copolymeric hydrogel coating, poly-2-hydroxyethyl methacrylate-2-methacryloyloxyethyl phosphate (P(HEMA-MOEP)), devised to enhance calcification in body fluids and to entrap and release growth factors, was electrosynthesized for the first time on titanium substrates and compared to poly-2-hydroxyethyl methacrylate (PHEMA), used as a blank reference. Polymers exhibiting negatively charged groups, such as P(HEMA-MOEP), help to enhance implant calcification. The electrosynthesized coatings were characterized by X-ray photoelectron spectroscopy and atomic force microscopy. MG-63 human osteoblast-like cell behaviour on the coated specimens was investigated by scanning electron microscopy, MTT viability test and osteocalcin mRNA detection. The ability of negatively charged phosphate groups to promote hydroxyapatite-like calcium phosphate deposition on the implants was explored by immersing them in simulated body fluid. Similar biological responses were observed in both coated specimens, while calcium-phosphorus globules were detected only on P(HEMA-MOEP) surfaces pretreated with alkaline solution. Testing of the ability of P(HEMA-MOEP) hydrogels to entrap and release human recombinant vascular endothelial growth factor, to tackle the problem of insufficient oxygen and nutrient delivery, suggested that P(HEMA-MOEP)-coated titanium prostheses could represent a multifunctional material suitable for bone restoration applications.