DESCRIPTION

The object of the present invention is a non-invasive device for assessing the vascularity of the subcutis and the skin mantle of the breast, and its method of displaying the measured values, according to the preamble of the corresponding independent claims.

In particular, the invention subject of this patent application finds its use in the context of mastectomy and reconstruction surgery procedures, especially in the pre- and post-operative assessment of the vascularisation of the skin and subcutis layer of a tissue, notably of the breast.

Scope of application

The invention subject of this patent application finds its use in the field of production of devices suitable for detecting the distribution of blood vessels of a tissue, in particular devices able to identify the distribution in the pre- and post- surgical phases.

The healing process, which has been known for decades thanks to histological and molecular studies, is carried out in three sequential phases that are not disjointed and of variable duration, such as inflammation, synthesis or repair and remodelling or regeneration.

In the first phase, the inflammatory one, the damaged tissue is dominated by the action of inflammatory cells and of the immune system, which eliminates any potential pathogens and means the removal of damaged macromolecular structures by regulating the gradual transition to the second phase, through the modulation of macrophages from a pro- inflammatory to an anti-inflammatory state.

The synthesis of new matrix and cell proliferation, the reparative phase, fills the defect left by the initial insult and the inflammatory phase through the production of a tissue devoid of its original organization, although sufficient to repair the damage. The takeover of remodelling by the resident cells of the new tissue, the regenerative phase, allows to reorganize the extracellular matrix and the relations between the cells, resetting the particular characteristics of the lost tissue or tissues through a gradual remodelling made up of demolition and synthesis of the matrix produced during the reparative phase.

It is well known that implantable devices have an influence on the physiological evolution of the three phases outlined above; in fact, bio-inert materials stimulate an inflammatory response due to the contact with a foreign body in the tissues and this response tends to become chronic over the time, since the device is in constant connection with the tissues.

As a result, the devices made of these materials amplify the first healing phase and do not allow the physiological evolution of the subsequent ones, preventing in particular the implementation of the remodelling phase, the regenerative one, the only one able to restore the initial anatomical structure of the tissue.

Today there are few implantable devices that allow this and differ depending on the application; they are made up of bioactive materials that are chemically and structurally similar to the extracellular matrices of the tissues to be regenerated. These include hydroxyapatite minerals typical of extracellular matrices found in bones and teeth and native collagen matrices obtained by decellularization of animal tissues.

The primary requirement of the healing process is the correct supply of oxygen, nutrients and growth factors brought by the blood to the damaged site, to allow the cells metabolism involved in the process. Tissues that are damaged and have insufficient vascularization inevitably lead to necrosis and tissue death, due to lack of oxygen and nutrition.

Similarly, a bioactive material implanted in intimate contact with the skin flap also needs sufficient perfusion of adjacent tissues so that they can support its regeneration by integration and transformation into new tissue.

It is well known that a process of tissue regeneration is an alternative surgical objective to tissue repair.

Regenerative surgery

Nowadays, regenerative surgery is imposing its ratio in the scientific world.

Tissue repair involves only restoring the function of damaged tissues, while tissue regeneration promotes the recovery of the lost anatomical structure as well as of its function.

In this case, the priority is to surgically promote the regenerative process that leads to the restitutio ad integrum of the damaged tissues.

In clinical practice in breast surgery, the use of silicone implants is widely accepted, although some recent studies have pointed out the risk associated with BIA-ALCL cancer (Breast Implant-Associated Anaplastic Large Cell Lymphoma).

This tumour arises on the capsule that forms as the organism's response to the silicone foreign body. This capsule can become fibrotic, contractile, and eventually pathological due to the reaction of the tissues.

This "foreign body reaction" process is carried out by the body with a strong inflammatory response whenever, due to a surgical graft, it comes into contact with inert biomaterials such as silicone, polyurethanes, and other petroleum derivatives.

When the patient's tissue instead comes into contact with a bioactive biomaterial, for example acellular dermal matrix, the latter sends recognition signals to the organism which, thanks to the morphological identity, recognizes it as "self" and not only does not encapsulate it, but thanks to a milder inflammatory reaction transforms it into its own tissue, thus completing the regenerative process. Emphasis has often been placed on the quality of the biological matrix whenever post-operative complications such as seroma, dehiscence, tissue necrosis occurred. It was assumed that a matrix was suitable or not to support the regenerative process of tissues.

More rarely, the ability of the skin flap to support this process has been focused on.

The trauma sustained by the breast subcutis during mastectomy may be such as not to guarantee a sufficient blood supply to the actors of the repair process with consequent inhibition of the regenerative procedure.

Therefore, the objective measurement of the capacity of the skin flap to support the process is crucial, as it is determined through the measurement of blood perfusion in the flap itself and therefore the assessment of the level of vascularization of the surgical flap after mastectomy.

Often the fact of not having objective values on the vascularization of the surgical flap, leads in most cases to complications associated with a reduced perfusion (e.g., dehiscence, necrosis, extrusion, and so on).

In the breast reconstruction surgery after mastectomy, the efficacy of the muscle-sparing or pre-pectoral technique is now scientifically proven.

This technique involves the implantation of the silicone prosthesis on the subcutaneous plane and no longer under the pectoralis major muscle. Before 2012, the scientific literature on the subject called for the submuscular plane to be used for implant placement, as the unanimity of scientific studies showed a 40% risk of capsular contracture due to the reaction of the tissues of the subcutaneous plane.

It is clear nowadays that silicone, as an inert biomaterial, prevents recognition by the organism, which reacts with a strong inflammatory response and a foreign body reaction, leading to the formation of contractile capsule. Document EP2903563, owned by the writer, originally postulated the change of anatomical plane from subpectoral to subcutaneous thanks to the knowledge of the bioactive matrices' properties.

According to document EP2903563, the animal-derived matrix, acellular dermis, when implanted in contact with human tissues, sends recognition signals to the organism to the extent that it is remodelled through the phases of inflammation, repair, and regeneration.

As described in EP2903563, completely wrapping the silicone prosthesis with bioactive dermal matrix ensures that the organism recognises the biological matrix and does not come into contact with the silicone.

It is thus possible to implant a silicone prosthesis wrapped in a bioactive matrix on the subcutaneous plane avoiding the risk of capsular contracture. The advantages for the patient are to avoid the detachment of the muscle with relative pain, to obtain a much more satisfactory aesthetic result and to prevent the formation of a contractile capsule.

In order to allow bioactive membranes or ADMs to express their tissue- recognition properties and direct tissue healing towards the regeneration phase, they need some surgical techniques measures.

They must be implanted in the body in intimate contact with vascularized tissues and in a mechanical quiet state in order to be recognized by the organism as self.

Matrix anchorage points (capitonnage) between the matrix and the tissues will facilitate both a recognition interface and the obliteration of dead spaces.

These measures were postulated in the scientific work "Evaluation of a novel breast reconstruction technique using the Braxon ® acellular dermal matrix: a new muscle-sparing breast reconstruction " (Berna G, Cawthorn SJ, Papaccio G, Balestrieri N. ANZ Journal of Surgery. 2014 Aug;87(6):493-8) and subsequently taken up by extensive literature and are of value only if the upstream skin flap is well vascularized. In fact, it should be considered that removing the diseased gland (mastectomy) involves the removal of the afferent vessels that come directly from the thorax. These perforating vessels are responsible for supplying blood to both the pectoralis major and the subcutaneous network of the mammary plexus. Their inevitable removal depletes the blood supply to the skin flap, which has to rely only on peripheral vascularization.

Implanting a bioactive membrane in contact with necrotic or poorly vascularised tissues leads to dissolution of the membrane and therefore to failure of the surgical operation.

The importance of vascularisation of subcutaneous tissues is the basis of a regenerative surgery such as breast reconstruction assisted by a bioactive biological matrix on the pre-pectoral plane.

As far as the patient's eligibility is concerned, the most important exclusion criteria are vascular disorders, and the most important inclusion ones are a subcutis that is at least 0.5 cm thick and well vascularised.

According to what has been stated so far, from a clinical point of view, the good perfusion of a skin flap is a discriminating factor for the success or failure of the implantation, whereas, from a scientific point of view, an evaluation of perfusion expressed by a numerical value eliminates the distortion of subjective values and makes different clinical experiences comparable.

Description of the state-of-the-art

It is well known that the assessment of the level of vascularisation of the subcutis is performed by injection of fluorescent contrast media which, when properly illuminated, visually identify vascularised and non-vascularised areas.

Typically, this investigation is conducted through circulatory imaging, using contrast agents (for example, such as ICG and fluorescein).

However, this method has some non-negligible limitations. The first limitation found in the patient is the level of invasiveness compared to procedures without contrast agent injection.

A second limitation is the stability and tendency of the compound to aggregate. The latter, in fact, requires highly specialized and trained personnel for its storage, handling and administration. The risk is damage caused by improperly stored, handled, and administered material. A third disadvantage of the use of circulatory imaging with contrast agents is represented by the possibility of off-targets; this methodology, in fact, cannot exclude interactions with molecules or plasma/endothelial structures with consequent decrease and/or signal dilution.

Any toxicity derived from off-targets and/or aggregation and/or pre existing pathological or metabolic conditions of the patient are to be considered as additional limitations that may decrease the clearance of the dye (liver damage). This outlines the absolute necessity to adequately assess the concentration that can be administered for each individual patient.

Finally, it should be noted that this method is not universal. In fact, it is contraindicated in patients with sensitivities. If not checked beforehand it can lead to very serious allergic reactions. Non-invasive means of assessing blood perfusion in the subcutis are also known to be state-of-the-art and are generally based on measuring the oxygen saturation of the blood circulating in the blood vessels. As is well known, an oximetry device or more simply an oximeter is a medical instrument that measures the oxygen saturation (Sp02) in the blood and indicates the percentage of oxygen-bound haemoglobin present in the arterial blood.

It is well known that blood saturation (Sp02) can be expressed as the ratio between the oxygenated haemoglobin concentration Hb02 and the sum of the oxygenated haemoglobin concentration Hb02 and the non-oxygenated haemoglobin concentration (so called reduced haemoglobin) Hb. Hb0 ₂

Sp0 ₂

Hb0 ₂ + Hb

The technology on which the oximeters are based uses a red-light source, a near-infrared light source, in some cases also a green light source and one or more sensors.

The operation of the device is based on the different absorption of the two wavelengths by the two different types of haemoglobin. Respectively, Hb0 ₂ absorbs more near-infrared light, reflecting instead the red component, while Hb absorbs predominantly red light and reflects the near-infrared one.

This property combined with the difference in blood flow due to the heartbeat allows to detect the concentrations of Hb0 ₂ and thus Hb calculating the saturation.

The implementation of the measurement circuit can take place in two ways:

By transmission: by placing the light source (s) and the sensor (s) at the opposite ends of the region of interest and measuring the difference between the light emitted and the light received, thus exploiting the absorption property.

By reflection: by placing the light source (s) and the sensor (s) on the same side of the survey region and measuring the reflected light instead, taking advantage of reflection.

Typically, to calculate oxygen saturation, the oximeter uses the emission of two different signal sources - with frequencies in the red and infrared range respectively - applied to the site where the measurement is being performed.

A detector is able to measure the absorption of each of the two signals by haemoglobin: in practice, part of the emitted signals is absorbed by the haemoglobin present at the site where the measurement is being performed, while another unabsorbed part reaches the detector. The amount of signals absorbed - red and infrared - is proportional to the concentration of haemoglobin, so that when the amount of signals reaching the detector is known, the oximeter calculates the Sp02 value. In addition to known applications, such as "finger oximeters", state- of-the-art diagnostic techniques for vascularization measurement are also known, which include devices suitably refined for the measurement of the Spo2 by means of transmission technology or reflection technology (so called backscattering).

Patent application EP1054618 describes a non-invasive device for the in vivo examination and visualization of biological tissues using visible or infrared radiation.

More particularly, patent application EP1054618 describes a non- invasive technique for the non-invasive transabdominal or transthoracic exam of an internal tissue or a fetus in utero, especially a non-invasive procedure for assessing angiogenesis in tissues or organs, intended as the generation of new blood vessels.

As described in EP1054618, the non-invasive technique involves the use of a non-invasive optical system for the in vivo examination of a subject's biological tissue.

The optical system includes an optical module, a controller, and a processor. The optical module includes a series of optical input and detection ports that are positioned in a selected geometric layout, to provide a multiplicity of photon migration paths within an examined region of the biological tissue.

Each optical input port is constructed to introduce visible or infrared light emitted by a light source, while each optical detection port is constructed to receive light photons that have migrated into the area of the examined tissue by at least one of the inputs ports and supply the received light to a light detector.

The controller is designed and set up to check the operation of the light source and light detector to reveal the light that has migrated to at least one of the photon migration paths. The processor is connected to receive signals from the detector and fitted to form at least two data sets, a first one of which representing blood volume in the area of the examined tissue and a second one representing blood oxygenation in that same area.

As described in EP1054618, the optical module consists of a flat square device made of flexible rubber material in which a series of laser diodes and a series of photomultiplier tubes are embedded, according to a series of preferential geometries.

The non-invasive technique described in EP1054618 is therefore particularly unfavourable as regards the production costs of the optical module, the complexity, and the process of embedding the laser diodes and the photomultiplier tubes, as well as the high risk of affecting the results obtained in the event of the failure of a single diode or a single photomultiplier tube, thus compromising the reliability of the examination carried out according to the technique described.

Document W019226692 describes an oximeter-type device for measuring blood oxygen saturation in living tissue by reflectance spectroscopy. The device described in W019226692 includes a first series of light- emitting elements that radiate red light, a second series of light- emitting elements that radiate green light or near-infrared (NIR) light, wherein the first and the second matrix are displayed on at least one flexible substrate, and a sensor matrix disposed on said flexible substrate, wherein each sensor element is configured to detect red and green light or red and NIR light and to radiate a signal representing an amount of detected red or green or NIR light.

As with the document previously commented, the device of the oximeter type described in W019226692 is also particularly unfavourable as regards the production costs of the device itself as well as the high probability of compromising the reliability of the measurement resulting from the probability of damage to one or more sensors or one or more emitting elements associated with the flexible substrate. Description of the invention

The object of the invention which is the subject of this patent application is therefore to create a non-invasive device for measuring Sp02 of a tissue, in particular of the skin and subcutaneous mantle of a tissue, especially of the breast, which solves the disadvantages of the described state-of-the-art.

A further aim of the invention which is the subject of this patent application is to realize a non-invasive device for measuring Sp02 of a tissue, in particular of the skin and subcutaneous mantle of a tissue, especially of the breast, which allows an objective and no longer subjective assessment of the blood perfusion data of the skin flap before and after mastectomy, as a discriminating factor for breast regenerative surgery.

This and further purposes that will be apparent to the skilled in the art are achieved by a non-invasive device for assessing blood perfusion of the breast subcutis and its method of detecting and displaying the values found, according to the attached claims.

In particular, the invention, which is subject of this patent application, includes a device (400) suitable for being superimposed on the skin mantle of the breast and having on its external surface a series of through openings (1-N) positioned in a predetermined geometric pattern, suitable for the sliding insertion of a sensor device until contact with the skin to which the device is superimposed. According to the invention, which is subject of this patent application, the geometric layout of the positioning of each through opening (1-N) provides a plurality of predeterminable paths according to a suitable logic for the temporary insertion of a sensor device and for the transmission of each detected value to an appropriate processor for the graphic display of the set of detected values.

According to the invention, which is subject of this patent application, the sensor device is provided with suitable means for the detection by reflection of the saturation of the blood Sp02 of the skin mantle surface in contact with the sensor device.

According to the invention, which is subject of this patent application, a receiving device is equipped with a suitable processor for collecting the individual data detected by the sensor device.

The forms of implementation of the above have one or more of the following characteristics.

Preferentially, but not exclusively, each through opening (1-N), with which the outer surface of the device (400) is provided, has a circular section.

In a first preferred, but not exclusive, embodiment, the inner surface of the device (400), intended for contact with the skin mantle, is made of adhesive material.

In a second preferred, but not exclusive, embodiment, the surface portion defining the perimeter of the device base (400), intended for contact with the skin mantle, is made of adhesive material.

In a third preferred, but not exclusive, embodiment, the surface portion defining the perimeter of the device base (400), intended for contact with the skin mantle, has segments made of adhesive material. In a preferred, but not exclusive, embodiment, the sensor device suitable for sliding into each through opening (1-N) consists of a tubular element with a sectional area smaller than the sectional area of each through opening (1-N) and having at its distal end a sensor for measuring saturation by reflection.

In a preferred, but not exclusive, embodiment, the sensor device is internally equipped with an electrical power supply system.

In a preferred, but not exclusive, embodiment, the sensor device is internally equipped with a module for remote connection to an electronic device equipped with a suitable processor for the collection and processing of the detected data. In a preferred, but not exclusive, embodiment, the sensor device is equipped with suitable means for identifying the acquisition of the Sp02 value.

In a preferred, but not exclusive, embodiment, the sensor device is equipped with suitable means for emitting a signal to identify the acquisition of the Sp02 value.

In a preferred, but not exclusive, embodiment, the sensor device is internally equipped with a power supply module.

In a preferred, but not exclusive, embodiment, the data detected by the sensor device is sent by wireless connection from the sensor device to a receiving device equipped with a display.

In a preferred, but not exclusive, embodiment, the receiving device is a mobile device of the tablet type.

In a preferred, but not exclusive, embodiment, the receiving device is equipped with suitable means for emitting a signal to identify the successful acquisition of the data transmitted by the sensor device. The processor with which the receiving device is equipped can be set up to correlate the series of data by determining its display on a map whose references correspond to the position of each through opening (1—N).

The processor with which the receiving device is equipped can be suitably programmed to determine the insertion sequence of the sensor device in each through opening (1-N).

Other advantages and features of the present invention will become evident from the following description of the preferred embodiment and claims.

Brief description of the drawings

Figures 1,2 show three views of the device (400) according to the invention which is subject of this patent application.

Figures 3,4 show an exemplary view of the embodiment of the device (400) according to the invention which is subject of this patent application. Detailed description of the invention

With reference to the aforementioned Figures, therein is shown a particular application of a device (400) substantially consisting of an elliptical base cap made up of an hemispherical element, internally hollow, and having a base defined by a perimeter (p), a maximum height (h) from the plane defined by the base (b), which corresponds to the position of the top (403), said device (400) replicating the shape of a breast cup that completely wraps and covers the breast, possibly bearing a longitudinal line valid as a reference for the correct positioning of the device (400), by means of an element in transparent material joined to it.

According to the invention, which is subject of this patent application, the upper surface of the device (400) is defined by a pyriform square curve defining a symmetrical "water droplet" shape having an apical cusp (401) hereinafter referred to as the upper pole (401).

According to the invention, which is subject of this patent application, the device (400) has on its upper surface a series of through openings (1-N) positioned in a predetermined geometric pattern. Referring to the attached Figures, a first series (405) of through openings is made on the upper surface of the device (400) in a radial position with respect to the top (403) and at a distance (dl) from said top (403).

A second series (405.1) of through openings is made on the upper surface of the device (400) in a radial position with respect to the top (403) and at a distance (d2) from said top (403), said distance (d2) being greater than the distance (dl) of the first series of through openings (405) from the top (403).

According to the invention subject of this patent application, each series of through openings (405-405.1-405.n) is positioned radially with respect to the top (403) of the device (400) and is distant from said top (403) by a distance (d) increasing from said top (403) towards the surface the portion of the surface that defines the perimeter (p) of the device (400).

According to the invention, which is subject of this patent application, the dimensions of each through opening (1-N) are such as to allow the insertion and sliding until contact with the skin mantle of a device equipped with a sensor suitable for measuring the saturation of the skin and subcutis mantle itself to which the cap (400) is superimposed.

Description of a method of use of the device

According to the invention, which is subject of this patent application, the through openings (1-N) on the surface of the cap (400) are identified and differentiated by assigning to each of them a numerical or alphabetical reference or any other visible identifying element.

Subsequently, the cap (400), made as described above, is placed on the breast so that the upper pole (401) is positioned superior to the surface of the breast.

Once the cap (400) has been applied, the distal end of the sensor device is inserted into a first through opening (1-N) until it makes contact with the breast skin for the detection of an initial Sp02 value; then the sensor device is removed from the first through opening (1-N) and inserted again into a second through opening (2-N), until the distal end makes contact with the breast skin for a second Sp02 value, and so on until a series of Sp02 values corresponding to the number of through openings (1-N) present on the surface of the cap (400) have been collected.

According to the aforementioned method of use, the acquisition of individual Sp02 values will be carried out by means of an appropriate sending command, for example, pressing a button on the external body of the device equipped with a sensor.

Regardless of the way in which the data is sent and received and the way in which the sensor device and the receiving one are constructed, the latter will be equipped with a suitable algorithm for the reception and processing of the data and the graphic display in the form of a map characterized by a matrix of visual references, each of which corresponds to one of the through openings (1-N) of the cap (400) in which the sensor device has been inserted.

In accordance with the above, when the sensor device is inserted into a through opening (1-N) and the detected data is sent, the corresponding visual reference changes status on the map shown on the display of the receiving device.

By way of example, but not limited to, changing the status of the visual reference on the map is done by changing the colour.

Then, the map shown on the display of the receiving device indicates the subsequent visual reference, which corresponds to the next through opening (2-N) in which the sensor device has to be inserted.

If the data is acquired from the wrong opening and that is not in progression with the previous one, it is possible to cancel the last measurement and take it again at the correct point indicated by the PC/iPad/smartphone/tablet or other device.

Once the data acquisition procedure has been completed, the software will return a 2D and/or 3D map containing for each detected point of the breast the perfusion values obtained from the sensor pen and configured in the same spatial position as the template.

The numerical data obtained in this way are a novelty in the field of perfusion assessment and can also be displayed according to a chromatic scale, for example from red (very good perfusion) to blue (very bad perfusion) or by means of contour lines showing the measured value. The display of the map (s) will be supported by a legend so that the surgeon/doctor/physician can read the correctly reported numerical values.

The data can then be saved in the patient’s medical record or printed and stored in the device. In addition, having the pre- and post- mastectomy perfusion maps of tine same breast available, it will be possible to compare them directly from the software with a special command that will return a map showing the delta between the perfusion values before mastectomy and those after mastectomy, indicating the areas that have undergone a greater variation in perfusion.

The pre and post range value will be indicative for the surgeon performing the mastectomy. With the experience of the numerical response carried out by this invention, he will be able to modulate the technique of mastectomy itself (e.g., cold blade and/or low intensity electrosurgery or other devices on the market) to optimize oncological safety with regenerative surgery techniques.