Patent Description:
Prostate cancer is the most common cancer among European and American men. Treatment of prostate cancer commonly involves surgical therapy including radical prostatectomy. However, despite the increasing use of nerve-sparing techniques, such as robot-assisted surgery, urinary incontinence and erectile dysfunction remain major adverse consequences of radical prostatectomy.

Cavernous nerve injury caused by different factors, including mechanical traction damage to the neurovascular bundle during mobilization of the prostate, as well as post-operative inflammation of the neurovascular bundle, is the main reason for post-surgical erectile dysfunction.

Modern surgery focuses on nerve-sparing techniques which results in an increased restoration of erectile function by preserving the integrity of the neurovascular bundles.

While mechanical damage to the neurovascular bundle can be minimized by the experienced surgeon, the post-surgical inflammation remains a problem leading to nerve damage, which has to be addressed by advanced materials or structures for nerve repair.

For example, a biodegradable polyester membrane containing brain-derived neurotrophic factor and adipose-derived stem cells has been tested in a rat cavernous nerve crush injury model, and an improved erectile function was observed compared to the non-cell containing group (<NPL>).

The application of growth factors and anti-inflammatory substances to preserve and regenerate the prostatic neurovascular bundle has been further advanced by the use of dehydrated human amnion/chorion membranes as source of neurotrophic factors and cytokines (<NPL>). Document <CIT> can be seen as the closest prior art and discloses a medical device having a support structure according to the preamble of claim <NUM>.

The manufacture process and the regulatory approval and commercialization of medical devices in combination with growth factors and cellular components can be demanding and expensive processes.

Simple technical solutions, preferably based on biocompatible and biodegradable components, and capable of supporting faster recurrence of continence in patients following prostatectomy are continuously investigated. Document <CIT>, for example, discloses a composition comprising chitosan capable of ameliorating the outcome of the radical prostatectomy.

Improved technical solutions, however, are still needed in order to further facilitate nerve repair and efficiently support early return of continence and potency in patients following prostatectomy.

The object of the present disclosure is to provide a medical device capable of achieving an early increase in sexual potency and continence recovery after prostatectomy without inducing any adverse effects.

The above object is achieved thanks to the subject matter recalled specifically in the ensuing claims, which are understood as forming an integral part of this disclosure.

According to the instant disclosure, the above object is achieved by a medical device having a film support structure comprising a composition containing chitosan, the film support structure including a surface sculpturing comprising a plurality of peaks and troughs defining a plurality of grooves, wherein i) peaks have a width ranging from <NUM> to <NUM>, ii) troughs have a width ranging from <NUM> to <NUM>, and iii) the distance between a peak and a trough ranges from <NUM> to <NUM>, the grooves being arranged according to a chevron pattern.

In one or more embodiments, the medical device comprising a chitosan-based support structure herein disclosed is intended for a surgical application, specifically for being applied in contact with the prostatic neurovascular bundle of the subject undergoing prostatectomy.

Moreover, herein disclosed is a method for protecting a prostatic neurovascular bundle of a subject, wherein the medical device comprising a chitosan-based support structure is applied in contact with the prostatic neurovascular bundle of the subject undergoing prostatectomy.

One or more embodiments will now be described, purely by way of non-limiting example, with reference to the annexed drawings, in which:.

In the following description, numerous specific details are given to provide a thorough understanding of embodiments. The embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment.

The instant description concerns a medical device having a film support structure comprising a composition containing chitosan for use in preventing and/or treating impotence in a subject undergoing prostatectomy, preferably radical prostatectomy.

<FIG> shows one embodiment of the medical device object of the present description, indicated by reference number <NUM>.

The medical device <NUM> has a film support structure <NUM> comprising a composition containing chitosan, as disclosed in the following.

The film support structure <NUM> includes a surface sculpturing <NUM> including a plurality of peaks <NUM> and troughs <NUM> defining a plurality of grooves.

In one or more embodiments, the surface sculpturing <NUM> may comprise straight lines of parallel grooves.

As shown in <FIG>, according to the present description a "peak" is a feature of the geometry that sticks out (or in general protrudes) from a reference surface. Because the surface sculpturing is made of a pattern of peaks and troughs, the reference surface the peaks stick out of or protrude from is the trough (bottom) surface.

Examples of the structure of peaks and troughs are clearly shown in <FIG>, which is an enlarged schematic view of a detail of the medical device <NUM>.

Peaks <NUM> have a peak width PW ranging from <NUM> to <NUM>, preferably <NUM> to <NUM>. Troughs <NUM> have a trough width TW ranging from <NUM> to <NUM>, preferably <NUM> to <NUM>.

In one or more embodiments, peaks <NUM> and troughs <NUM> may have a length L ranging from <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM> to <NUM>. The length L is measured along a direction orthogonal to the direction along which the width is measured. For instance, the length L is measured along a direction parallel to the extension direction of a peak (or a trough), which is orthogonal to the peak (or trough) width.

A peak to trough distance D is comprised between <NUM> to <NUM>, preferably between <NUM> to <NUM>, more preferably between <NUM> to <NUM>, wherein the peak to trough distance is measured between an outermost edge or point of a peak (top) surface and an innermost edge or point of a trough (bottom) surface, and along a direction orthogonal to said peak (or trough) width and to said length. For instance, the bundle of directions along which length L, peak width PW and trough width TW are measured allows the identification of a plane to which the direction of distance D is orthogonal (e.g. plane XY for PW, TW, L, and axis Z for distance D in an orthogonal X-Y-Z reference system).

In a preferred embodiment, the thickness of the film support structure <NUM> at a peak TP may range from <NUM> to <NUM>, preferably from <NUM> to <NUM>. The thickness of the film support structure at a through TR may range from <NUM> to <NUM>, preferably from <NUM> to <NUM>.

Reference points for thickness measurement are the outermost edge or point of a peak (top) surface and the film surface opposite to the sculptured surface for thickness TP, and the innermost edge or point of a trough (bottom) surface and - again - the film surface opposite to the sculptured surface for thickness TR. Over the film, the following relationship applies at each point thereof: D = TP-TR.

In one or more embodiments, the film support structure <NUM> is a quadrangular film, as for example shown in <FIG>, having a first dimension L1 ranging from <NUM> to <NUM>, preferably <NUM> to <NUM> and a second dimension L2 ranging from <NUM> to <NUM>, preferably <NUM> to <NUM>.

In one or more embodiments, the grooves of the surface sculpturing <NUM> are arranged according to a chevron (or V-shaped) pattern.

As it can be appreciated especially in <FIG>, the chevron pattern of grooves of the surface sculpturing <NUM> has a V-angle V less than <NUM> degrees, preferably <NUM> to <NUM> degrees, more preferably <NUM> to <NUM> degrees.

The V-angle is the angle comprised between adjacent and incident features (peaks and troughs or grooves equivalently) of the chevron pattern.

In addition, a band width BW of the chevron pattern of the surface sculpturing <NUM> is <NUM> or less, preferably ranging from <NUM> to <NUM>, more preferably <NUM> to <NUM>.

By the term "band width" it is meant to designate the transverse dimension of a band-wise domain that encloses an ordinate pattern of parallel, diagonal features of the geometry of the surface sculpturing, the ordinate pattern defining in turn half (or in general a portion featuring peaks and troughs having the same orientation) of a chevron (or V-shaped) pattern.

Alternative examples falling outside the scope of the claims and herein provided for information only may apply, which are not specifically illustrated in the figures, wherein the pattern of grooves defined by peaks <NUM> and troughs <NUM> is other than a chevron pattern, for instance patterns of straight grooves, or patterns in the form of pillars and or cones.

The Inventors of the instant application surprisingly found that by virtue of its particular geometry and chemical composition, the medical device <NUM> herein disclosed is highly effective in obtaining a favourable outcome of the radical prostatectomy.

Concerning the chemical composition, the medical device <NUM> has a film support structure <NUM> characterized by a precise selection of the constituent polymer, which is chitosan.

In the experimental part that follows, the preparation of a specific embodiment of the medical device <NUM> is disclosed; the device resulted in being effective in the applications concerned.

In one or more embodiments, a high biocompatibility and bioactivity of the medical device <NUM> may be obtained by using chitosan in form of native chitosan.

In the context of the present disclosure, the expression "native chitosan" refers to the chemical structure of chitosan, i.e. a poly(N-acetyl-D-glucosamine-co-D-glucosamine) copolymer or a poly(D-glucosamine) homopolymer.

Any cross-linked or otherwise chemically modified chitosan is considered a chitosan derivative, having different properties than native chitosan. Crosslinking of chitosan, either ionically or covalently, may lead to the blockage of active functionalities of the biomaterial, namely the amine group.

In the context of the present disclosure the term "native chitosan" includes both the chitosan base and chitosan in form of a chitosan salt.

In one or more embodiments, the film support structure <NUM> of the medical device <NUM> comprises a composition containing chitosan, preferably chitosan base, in an amount at least <NUM>%, more preferably at least <NUM>%, more preferably at least <NUM>% by weight (w/w) of the composition, based on the non-aqueous components of the composition.

The film support structure <NUM> of the medical device <NUM> may comprise a composition comprising chitosan, preferably chitosan base, in an amount <NUM>% or less, more preferably <NUM>% or less, more preferably <NUM>% or less by weight (w/w) of the composition, based on the non-aqueous components of the composition.

In one or more embodiments, the composition may comprise chitosan either in form of a base and in form of a chitosan salt. Preferably, the composition comprises at least one chitosan salt in an amount of <NUM>% or less, more preferably <NUM>% or less, more preferably <NUM>% or less by weight (w/w) related to the total weight of chitosan.

The presence of chitosan in form of a salt can allow a good adhesion of the medical device <NUM> herein disclosed to the neurovascular bundle thus avoiding a premature detachment from the site of implantation. The chitosan salt is soluble in an aqueous solvent or physiological medium of neutral pH. Thus, wet tissue can etch the film support structure <NUM> of the medical device <NUM> providing for a durable contact with the prostatic neurovascular bundle.

In another example not falling within the scope of the claims, chitosan salts may be derived from the dissolution of chitosan in an aqueous solution of one or more inorganic acids, such as hydrochloric acid, and/or organic acids selected from the group consisting of monobasic or multibasic organic acids having from <NUM> to <NUM> carbon atoms and a first pKa value between <NUM> and <NUM>, such as for example acetic acid, citric acid, lactic acid, malic acid, succinic acid, mandelic acid, oxalic acid, tartaric acid, ascorbic acid, etc..

In another example, chitosan may be present in the composition in form of a chitosan base.

In another example, the composition of the film support structure <NUM> of the medical device <NUM> consists of chitosan, preferably native chitosan.

In another example, the composition comprises chitosan with a degree of acetylation of <NUM>% or less, preferably <NUM>% or less, more preferably <NUM>% or less.

In another example, the composition comprising chitosan herein disclosed is essentially free of toxic compounds.

In another example, the composition of the film support structure <NUM> of the medical device <NUM> comprises glycerol in addition to chitosan, preferably in an amount between <NUM> and <NUM> % by weight, based on the non-aqueous components of the composition.

In one or more embodiments, the composition of the film support structure <NUM> of the medical device <NUM> comprises other than chitosan also at least one polymer selected in the group consisting of synthetic polyesters, preferably homopolymers and copolymers based on glycolide, L-lactide, D,L-lactide, p-dioxanone, ε-caprolactone, natural polyesters, preferably from the group of the polyhydroxyalkanoates, such as homopolymers and copolymers based on <NUM>-hydroxybutyrate, <NUM>-hydroxybutyrate, <NUM>-hydroxyvalerate, <NUM>-hydroxyhexanoate, <NUM>-hydroxyoctanoate; polyorthoesters; polycarbonates; polyanhydrides; polyurethanes; polyphosphazenes; polyphosphoesters; polysaccharides; polypeptides; as well as derivatives, copolymers, and blends based on the abovementioned and any other group of bioresorbable polymers.

Other suitable polymers include those, which may be dissolved under physiological conditions, such as homopolymers or copolymers based on vinyl alcohol, vinyl acetate, N-vinyl pyrrolidone, ethylene glycol, propylene glycol, polysaccharides, polypeptides, as well as derivatives, copolymers, and blends based on the aforementioned and any other group of biodissolvable polymers or combinations of biodegradable and biodissolvable polymers.

Other suitable polymers include those selected from the groups of non-biodegradable and non-biodissolvable polymers, as well as their derivatives, copolymers, and blends, including combinations with biodegradable and biodissolvable polymers.

In one or more embodiments, the film support structure <NUM> of the medical device <NUM> herein disclosed may further comprise other components, such as for example at least one pharmaceutically active and/or bioactive constituent.

In one or more embodiments, bioactive constituents may be selected from the group consisting of proteins, peptides, nucleic acids, low molecular weight drugs, such as antibiotics or anti-inflammatory drugs, phosphodiesterase inhibitors, agonists or antagonists of the innate immune system, stimulating or differentiating growth factors for stimulating or differentiating growth of at least one cell sub-type, and mixtures thereof.

In another example, the film support structure <NUM> of the medical device <NUM> may further comprise biological cells, such as for example adipose-derived stem cells (ADSC) and induced pluripotent stem cells (iPSC).

The medical device <NUM> herein disclosed is intended for a surgical application, specifically for application on the prostatic neurovascular bundle of a subject undergoing prostatectomy.

In another example, the film support structure <NUM> of the medical device <NUM> is preferably in form of a solid film or a gel-like film.

In another example, the film support structure <NUM> may be in the form of a freeze-dried or solvent-dried film.

In another example, the film support structure <NUM> may be present in form of a flexible film, which may be continuous or interrupted (e.g. perforated).

In one or more embodiments, the medical device <NUM> further comprises an additional film support structure <NUM> containing a composition comprising chitosan or another polymer or polymeric composition selected from the group of biodegradable/biodissolvable, or non-biodegradable/non- biodissolvable polymers.

In one or more embodiments, the composition of the film support structure <NUM> may further comprise at least one pharmaceutically active and/or bioactive constituent or biological cells.

In one or more embodiments, the film support structure <NUM> of the medical device can have a thickness of <NUM> or less, preferably <NUM> or less, more preferably <NUM> or less.

The support structure of the medical device subject of the present invention may for example be prepared by means of the following preparation techniques: laser etching, e-beam etching, plasma etching, 3D printing, electrospinning, photolithography, stereolithography, and soft lithography.

In one or more embodiments, the medical device <NUM> herein disclosed may be applied on the prostatic neurovascular bundle of a subject.

The medical device <NUM> may present a thickness comprised between <NUM> to <NUM> at a peak TP and between <NUM> to <NUM> at a through TR.

In one or more embodiments, the surface area of the medical device <NUM> may be comprised in the range between <NUM> and <NUM><NUM>, preferable between <NUM> and <NUM><NUM>, more preferably between <NUM> and <NUM><NUM>.

Such a surface area allows covering the prostatic neurovascular bundle completely or partially and, preferably some of the surrounding tissue.

In one or more embodiments, the composition of the film support structure <NUM> herein disclosed may have a water uptake capacity of less than <NUM>%, preferably comprised between <NUM>% and <NUM>% by weight, more preferably between <NUM>% and <NUM>%.

In another example, the film support structure <NUM> may contain at least one hole (opening) extending through all the thickness of the device, which allows absorption and diffusion of physiological liquids and fast fluid exchange through the film bulk structure.

The at least one hole may have a diameter size of <NUM> or less, more preferably <NUM> or less, more preferably <NUM> or less. In a preferred embodiment, the at least one hole may have a diameter size of <NUM> or more, preferably <NUM> or more, more preferably <NUM> or more. In one or more embodiments, the diameter size of the holes of the film is between <NUM> and <NUM>.

In another example, the holes may cover an area of <NUM>% or less of the film surface, more preferably <NUM>% or less, more preferably <NUM>% or less.

In another example, a preferred flow rate of physiological fluids through the chitosan composition in form of a film containing holes is <NUM>/min/cm<NUM> or more, preferably <NUM>/min/cm<NUM> or more, more preferably <NUM>/min/cm<NUM> or more.

Thanks to this property, the accumulation of fluid underneath the composition during implantation can be reduced or prevented thus favouring its adherence to the neurovascular bundle.

In another example, the medical device <NUM> is transparent. Advantageously, this can make it easier for a physician to inspect the application to the neurovascular bundle.

In another example, the medical device <NUM>, once applied at the surgical site, may be sutured.

Advantageously, this property allows the fixation of the medical device to the surgical site and prevents dislodgement from the neurovascular bundle. In one or more embodiments, the suture retention strength based on a Prolene USP <NUM>/<NUM> suture and evaluated by a mechanical tester is <NUM> N or more, preferably <NUM> N or more when measured in the dry state, and <NUM> N or more, preferably <NUM> N or more when measured in the wet state.

The medical device subject of the present invention may for example be prepared by means of the following preparation techniques: solvent casting, molding, 3D printing, electrospinning.

Thanks to the specific combination of the particular geometric characteristics and chemical composition the medical device <NUM> herein disclosed has been found to be surprisingly effective in the recovery of potency and continence after prostatectomy.

The medical device <NUM> is able to improve the regeneration and repair of nerves specifically important for achieving a faster recurrence of potency and a reduced rate of erectile dysfunction in a subject who undergoes radical prostatectomy. In addition, the medical device <NUM> allows a faster recurrence of continence and a reduced rate of incontinence.

Moreover, thanks to the biocompatibility and to the antimicrobial and haemostatic properties of chitosan, inflammation, infection and bleeding time reduction can also be achieved. The medical device herein disclosed has the further advantage of reducing the risk of infections thanks to the antibacterial properties of chitosan.

The following examples are provided for purely illustrative purposes and should not be interpreted in a limiting sense in any way of the scope of the invention as defined by the attached claims.

Chitosan used as a starting material in the examples below was obtained in form of fine flakes from Chitinor (Norway). The degree of acetylation (DA) was determined by <NUM> NMR spectroscopy, as disclosed in <NPL>. Chitosan was analyzed in a mixture of <NUM>% DCl in D<NUM>O at a chitosan concentration of approximately <NUM>% (w/v). The spectra were recorded using a Bruker Avance III HD <NUM> spectrometer. The DA, calculated by comparing the integrated area under the peaks associated with H2-H6 of the D-glucosamine subunit with that of the methyl group, was determined as <NUM>% for chitosan as purchased, and <NUM>% for deacetylated chitosan obtained as disclosed in the following. <FIG> shows a <NUM> NMR spectrum obtained from this commercially available chitosan. <FIG> shows a corresponding <NUM> NMR spectrum obtained from chitosan deacetylated after a further hydrolysis step applied to the commercial product as described further below.

<NUM> (grams) of chitosan flakes as obtained from the supplier Chitinor were placed in a glass container and <NUM> of a <NUM>% (w/v) aqueous sodium hydroxide solution were added. The glass container was well shaken to mix the components, and placed in an oven for <NUM> hours at <NUM>. It was then removed from the oven and <NUM> (milliliters) of distilled water were added. The mixture was filtered through a <NUM> sieve. Then, chitosan was washed with distilled water until the pH of the filtrate reached approx. <NUM>, and dried, resulting in chitosan having a DA of <NUM>% as determined by <NUM> NMR spectroscopy (<FIG>).

<NUM> of chitosan having a degree of acetylation of <NUM>% were dissolved in <NUM> of a <NUM>% (w/v) aqueous acetic acid by gently shaking for <NUM>.

<NUM> of the chitosan solution was poured into a square-shaped mold, <NUM> x <NUM><NUM> (square centimetres) in size, and left in a dust-free environment for drying at room temperature.

The dried film was placed for <NUM> hours in a bath containing a solution of <NUM>% (w/v) ammonia in methanol/water <NUM>/<NUM> (v/v). The film was then removed from the bath and dried at room temperature. The resulting film has a content of approx. <NUM>% (w/w) of chitosan, based on the non-aqueous components of the film. The remaining water content of the film is less than <NUM>% (w/w). The film thickness is approx.

The film was mounted on a micropositioning stage, and a defined pattern of parallel grooves of approx. <NUM> in width separated by about <NUM> were micromachined on the film surface by using a custom-built 3D laser writing workstation with ultrashort (approx. <NUM> fs) laser pulses at a pulse repetition frequency of <NUM>. Each line of a chevron pattern of grooves with a length of <NUM> and a V-angle of <NUM> degrees was made by a single pass of the laser at a constant speed of <NUM> pm/s.

The resulting film was then cut into <NUM> x <NUM> samples, placed in sterilization bags and sterilized using ethylene oxide.

Claim 1:
Medical device (<NUM>) having a film support structure (<NUM>) for use in prostatectomy, the film support structure (<NUM>) comprising a composition containing chitosan, the film support structure (<NUM>) further including a surface sculpturing (<NUM>), said surface sculpturing (<NUM>) comprising a plurality of peaks (<NUM>) and troughs (<NUM>) defining a plurality of grooves, said peaks (<NUM>) having a peak width (PW) ranging from <NUM> to <NUM>, said troughs (<NUM>) having a trough width (TW) ranging from <NUM> to <NUM>, and wherein the distance (D) between a peak (<NUM>) and a trough (<NUM>) ranges from <NUM> to <NUM>, characterized in that the grooves of the surface sculpturing are arranged according to a chevron pattern.