Giovanni Bistoni

The clinical application of autologous bioengineered skin based on a hyaluronic acid scaffold

The aim of this work was to generate an in vitro skin substitute harbouring autologous fibroblasts, keratinocytes and melanocytes, to establish a new one-step clinical method in problems associated with skin disorders. Here we present a case of a nine-year-old girl with a congenital giant nevus treated by surgical approach, with primary co-cultures of keratinocytes, melanocytes and fibroblasts obtained from autologous skin biopsy. Generally these lesions need to be removed to avoid the risk of transformation into malignant melanoma. With this purpose we analyzed the melanocytes contained in the new skin substitute for the presence of genetic alterations correlated to increased risk for melanoma. The organotypical cultures were designed including an engineered scaffold of a non-woven mesh of hyaluronic acid (HYAFF11). This biomaterial has been previously demonstrated to be the most suitable to maintain polarity and to support the in vitro constructs. Six dermal-epidermal skin substitutes were transplanted and 14 days after surgery the re-epithelialized area was about 90%. Our results suggest that this new dermal-epidermal construct not only reduces hospitalization time and ameliorates scar retraction, but might also represent a solution for the high risk of developing a tumour derived from the original nevus.

The Effects of Zafirlukast on Capsular Contracture: Preliminary Report

Capsular contracture after breast augmentation is a distressing, troublesome event both for the patient and the surgeon. Fibrosis transforms the prosthesis into a hardened sphere, turning the initially satisfactory cosmetic result into a deformed mass. Treatment for capsular contracture can be either surgical, consisting of capsulotomy or capsulectomy with implant replacement, or pharmacologic, consisting of intracapsular instillation of steroids and antibiotics. The success rates for both types of treatment vary. Although capsular contracture is a multifactorial process, one common denominator in the successful treatment of this complication is believed to be the abatement of inflammation. Leukotriene antagonists have emerged recently as effective prophylactic agents for reactive airway diseases. Anecdotal reports have indicated that zafirlukast and montelukast effectively reverse capsular contracture. The authors investigated whether capsular contracture varies significantly over time after zafirlukast therapy by studying 20 women who had breast prostheses implanted and then experienced the development of capsular contracture. The results suggest that capsular contracture responds favorably to treatment with zafirlukast. The findings indicate that zafirlukast may reduce pain and breast capsule distortion for patients with long-standing contracture who either are not surgical candidates or do not wish to undergo surgery.

Disentanglement of Donation and Back‐Donation Effects on Experimental Observables: A Case Study of Gold–Ethyne Complexes

A charge-displacement analysis of gold-ethyne complexes shows the existence of a quantitative relationship between measurable properties and the chemical bond constituents in the Dewar-Chatt-Duncanson model. Through suitable experiments, these constituents may be disentangled and crucial insight into the nature of coordination bonds may thus be gained.

When the Tolman Electronic Parameter Fails: A Comparative DFT and Charge Displacement Study of [(L)Ni(CO)3]0/– and [(L)Au(CO)]0/+

In this study we have examined 42 [(L)M(CO)n](±/0) complexes (M = Ni and Au), including neutral ligands, such as phosphines and carbenes, and anionic ones. For each complex, the carbonyl stretching frequency (ν(CO)) and the amount of charge donated from the ligand to the metal (CT) have been computed on the basis of DFT calculations. For nickel complexes, the two observables nicely correlate with each other, as expected from the theory underlying the Tolman electronic parameter. On the contrary, for gold complexes a more complex pattern can be observed, with an apparent differentiation between phosphine ligands and carbon-based ones. Such differences have been explained analyzing the Au-L bond in terms of Dewar-Chatt-Duncanson bonding constituents (σ donation and π back-donation). Our analysis demonstrates that in linear gold(I) complexes, ν(CO) depends only on the metal-to-ligand π back-donation.

Selectively measuring π back-donation in gold(I) complexes by NMR spectroscopy.

Even though the Dewar-Chatt-Duncanson model has been successfully used by chemists since the 1950s, no experimental methodology is yet known to unambiguously estimate the constituents (donation and back-donation) of a metal-ligand interaction. It is demonstrated here that one of these components, the metal-to-ligand π back-donation, can be effectively probed by NMR measurements aimed at determining the rotational barrier of a C-N bond (ΔHr (≠) ) of a nitrogen acyclic carbene ligand. A large series of gold(I) complexes have been synthesized and analyzed, and it was found that the above experimental observables show an accurate correlation with back-donation, as defined theoretically by the appropriate charge displacement originated upon bond formation. The proposed method is potentially of wide applicability for analyzing the ligand effect in metal catalysts and guiding their design.

Charge-displacement analysis via natural orbitals for chemical valence: Charge transfer effects in coordination chemistry

We recently devised a simple scheme for analyzing on quantitative grounds the Dewar-Chatt-Duncanson donation and back-donation in symmetric coordination complexes. Our approach is based on a symmetry decomposition of the so called Charge-Displacement (CD) function quantifying the charge flow, upon formation of a metal (M)-substrate (S) bond, along the M-S interaction axis and provides clear-cut measures of donation and back-donation charges in correlation with experimental observables [G. Bistoni et al., Angew. Chem., Int. Ed. 52, 11599 (2013)]. The symmetry constraints exclude of course from the analysis most systems of interest in coordination chemistry. In this paper, we show how to entirely overcome this limitation by taking advantage of the properties of the natural orbitals for chemical valence [M. Mitoraj and A. Michalak, J. Mol. Model. 13, 347 (2007)]. A general scheme for disentangling donation and back-donation in the CD function of both symmetric and non-symmetric systems is presented and illustrated through applications to M-ethyne (M = Au, Ni and W) coordination bonds, including an explicative study on substrate activation in a model reaction mechanism.

Charge-displacement analysis of the interaction in the ammonia-noble gas complexes.

We carry out an accurate ab initio study of the interaction between ammonia and the whole series of noble gas atoms and relate the results to those of high-resolution scattering experiments that provide access to the average radial dependence of the interaction potential. The charge-displacement calculations show that charge transfer is a non-negligible, strongly anisotropic, component of the interaction, governing some basic features of the potential energy surfaces especially for the heavier systems. A comparison is made with the analogous binary complexes of H(2)O with the water-H(2) system (Belpassi, L.; et al. J. Am. Chem. Soc.2010, 132, 13046), supporting the conclusion that charge transfer plays a peculiarly special role in waters intermolecular interactions.

Understanding the Role of Dispersion in Frustrated Lewis Pairs and Classical Lewis Adducts: A Domain-Based Local Pair Natural Orbital Coupled Cluster Study

The interaction of Lewis acids and bases in both classical Lewis adducts and frustrated Lewis pairs (FLPs) is investigated to elucidate the role that London dispersion plays in different situations. The analysis comprises 14 different adducts between tris(pentafluorophenyl)borane and a series of phosphines, carbenes, and amines with various substituents, differing in both steric and electronic properties. The domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) method is used in conjunction with the recently introduced local energy decomposition (LED) analysis to obtain state-of-the-art dissociation energies and, at the same time, a clear-cut definition of the London dispersion component of the interaction, with the ultimate goal of aiding in the development of designing principles for acid/base pairs with well-defined bonding features and reactivity. In agreement with previous DFT investigations, it is found that the London dispersion dominates the interaction energy in FLPs, and is also remarkably strong in Lewis adducts. In these latter systems, its magnitude can be easily modulated by modifying the polarizability of the substituents on the basic center, which is consistent with the recently introduced concept of dispersion energy donors. By counteracting the destabilizing energy contribution associated with the deformation of the monomers, the London dispersion drives the stability of many Lewis adducts.

Relationship between the anion/cation relative orientation and the catalytic activity of nitrogen acyclic carbene–gold catalysts

We elucidate the role of the ligand in determining the ion pair structure of the [(NAC)Au(η2-3-hexyne)]+ BF4− (NAC = Nitrogen Acyclic Carbene, also known as ADC = Acyclic Diamino Carbene) catalysts and how the position of the anion influences their catalytic performance, giving a detailed relationship between the ion pair structure, determined by 19F, 1H-HOESY NMR experiments and DFT calculations, and the catalytic activity in the intermolecular alkoxylation of alkynes. From our results, it is evident that if the anion is forced to be far from the catalytic site by ancillary ligand–anion hydrogen bonding interactions, the reaction slows down. On the contrary, if the anion is located near the alkynes the reaction is accelerated, coherent with the proposed active role of the anion in catalysis. These results open new opportunities in ligand design for the gold-mediated reactions in which the anion plays an important role during the catalysis.

Quantitative assessment of the carbocation/carbene character of the gold–carbene bond

The geometric perturbation of the cyclopropyl ring in [LAu(S)](n+) (S = cyclopropyl(methoxy)carbene) complexes has been recently proposed as an indirect experimental probe of the [LAu](n+) electron-donating power, but experimental data are available only for a phosphine ligand [Brooner et al., Chem. Commun., 2014, 50, 2420, L = P(t-Bu)2(o-biphenyl)]. We broaden the study through DFT geometry optimization of a large number of systems, including anionic, neutral and cationic ligands. We combine these results with the accurate calculation, through charge displacement analysis, of the Dewar-Chatt-Duncanson components of the Au-carbene bond. The results demonstrate a linear correlation between the distortion of the cyclopropyl ring (Δd) and the Au → C π back-donation, which enables us to confidently estimate back-donation from a simple geometry optimization or, when available, from experimental data such as X-ray crystal structures. Consequently, Δd can be reliably used to quantitatively determine the position of each system in the continuum between the carbocationic and carbene extremes and the percentage of back-donation that S is able to accept (Pback). In particular, Pback results to be vanishing with cationic ligands, between 18 and 27% with neutral phosphines and carbenes and around 50% with anionic ligands. Finally, we study the effect of the heteroatom on the substrate, showing that the absolute value of the back-donation is enhanced by around 25% when the methoxy is substituted by a methyl group. Despite this, since the absence of the heteroatom also enhances the maximum capacity of the carbene to accept back-donation, the position of the systems in the continuum moves only slightly toward the carbene end.