Biodegradable medical device for breast reconstruction and/or augmentation

Abstract

An implantable biodegradable medical device arranged for breast reconstruction and/or augmentation, made of an interconnected porous structured polymeric matrix and belonging to the family of poly(urea urethane)s. The porous structured polymeric matrix of the medical device comprises a plurality of three dimensional channels, drilled by means of heated tools, three-dimensionally propagating through the polymeric matrix ad interconnected with the porous structure of the polymeric matrix. The polymeric matrix comprises high to-medium molecular weight hydrophobic biodegradable amorphous soft segments polyols, having average molecular weight comprised between 20000 and 60000 Da,hydrophilic polyalkoxide polyols, of average molecular weight comprised between 2000 and 15000 Da, and low molecular weight polyisocyanates and polyols, whose average molecular weights range between 15 and 200 Da.

Claims

1. An implantable biodegradable medical device arranged for breast reconstruction and/or augmentation, said device being made of an interconnected porous structured polymeric matrix and belonging to the family of poly(urea urethane)s, comprising: said polymeric matrix comprises a plurality of three dimensional channels three dimensionally propagating through the polymeric matrix and interconnected with the porous structure of said polymeric matrix, wherein said polymeric matrix comprises high to-medium molecular weight hydrophobic biodegradable amorphous soft segments polyols having average molecular weight comprised between 20,000 and 60,000 Da; hydrophilic polyalkoxide polyols, of average molecular weight comprised between 2,000 and 15,000 Da; low molecular weight polyisocyanates and polyols, whose average molecular weights range between 15 and 200 Da.

2. The medical device according to claim 1, wherein said channels are evenly spaced within the matrix and have a distance each other smaller than 5 mm.

3. The medical device according to claim 1, wherein said channels have diameters (d) of between 0.05 and 10 mm.

4. The medical device according to claim 1, wherein said hydrophobic biodegradable amorphous soft segments polyols are at least 30% of the total weight of the polymeric matrix; contain at least 10% (w/w) 1,4 Dioxane 2,5 dione (commonly named glycolide) and at least 40% (w/w) 2-oxepanone (commonly named epsilon-caprolactone); comprise a number of reactive terminal hydroxide groups which ranges between 6 and 2 per macromolecule.

5. The medical device according claim 1, wherein said hydrophilic polyalkoxide polyols comprise a number of reactive terminal hydroxide groups which ranges between 4 to 2 per macromolecule.

6. The medical device according to claim 1, wherein a weight ratio comprised between 10:1 to 1:1 is provided between the hydrophobic soft segment polyols and the hydrophilic polyalkoxide polyols.

7. The medical device according to claim 1, wherein said low molecular weight polyisocyanates and polyols are at least 40% of the total weight of the polymeric matrix.

8. The medical device according to claim 1, wherein the polymeric matrix comprises a certain content of urea groups derived from isocyanate groups convertible to urea groups, said certain content not exceeding 65.5% of said isocyanate groups convertible to urea groups.

9. A method for producing an implantable biodegradable medical device for breast reconstruction and/or augmentation, said method comprising the steps of synthesizing a PUUEE-based polymeric matrix having a soft porous structure by mixing a solution comprising high-to-medium molecular weight hydrophobic biodegradable amorphous soft segments polyols of average molecular weight from 20,000 to 60,000 Da, medium molecular weight hydrophilic polyalkoxide polyols of average molecular weight from 2,000 to 15,000 Da, low molecular weight polyisocyanates and polyols of average molecular weight from 15 to 200 Da, shaping the PUUEE-based polymeric matrix in order to obtain a matrix of desired shape. drilling, by means of heated tools, a plurality of channels three dimensionally propagating through the PUUEE based polymeric matrix and interconnected with the porous structured of the PUUEE-based polymeric matrix.

10. The method according to claim 9, wherein said hydrophobic biodegradable amorphous soft segments polyols are at least 30% of the total weight of the polymeric matrix; contain at least 10% (w/w) 1,4 Dioxane 2,5 dione (commonly named glycolide) and at least 40% (w/w) 2-oxepanone (commonly named epsilon-caprolactone); comprise a number of reactive terminal hydroxide groups which ranges between 6 and 2 per macromolecule.

11. The method according to claim 9, wherein said hydrophilic polyalkoxide polyols comprise a number of reactive terminal hydroxide groups which ranges between 4 to 2 per macromolecule.

12. The method according to claim 9, wherein a weight ratio comprised between 10:1 to 1:1 is provided between the hydrophobic soft segment polyols and the hydrophilic polyalkoxide polyols.

13. The method according to claim 9, wherein said low molecular weight polyisocyanates and polyols are at least 40% of the total weight of the polymeric matrix.

14. The method according to claim 9, wherein the polymer matrix comprises a certain content of urea groups derived from isocyanate groups convertible to urea groups, said certain content not exceeding 65.5% of said isocyanate groups convertible to urea groups.

15. The method according to claim 9, wherein said matrix has a compressive elastic modulus between 5 and 700 kPa and wherein said porous structure comprises pores having sizes (d) of between 5 and 2000 m.

16. The medical device according to claim 2, wherein said channels have diameters (d) of between 0.05 and 10 mm.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) These and further features and advantages of the present invention will appear more clearly from the following detailed description of preferred embodiments, provided by way of non-limiting examples, with reference to the attached drawings, in which components designated by same or similar reference numerals indicate components having same or similar functionality and construction and wherein:

(2) FIG. 1 shows a schematization of a spherical cap-shaped medical device according to present invention, with 4 grid-shaped channel networks positioned at different levels along the Z-axis; front view (FIG. 1a) and view from above (FIG. 1b);

(3) FIG. 2 shows a SEM micrograph of a PUUEE-based polymeric matrix, channelized according to thermal drilling technique;

(4) FIG. 3 shows a schematization of rectilinear, cylindrical channels embedded in a parallelepiped-shaped solid matrix and having constant diameters;

(5) FIG. 4 shows a schematization of a through-channel in a spherical cap-shaped scaffold with a variable diameter;

(6) FIG. 5 shows a schematization of a spherical cap-shaped scaffold with through-channels parallel to the X-axis;

(7) FIG. 6 shows a schematization of a spherical cap-shaped scaffold with through-channels parallel to the Z-axis;

(8) FIG. 7 shows a schematization of a spherical cap-shaped scaffold with through-channels parallel to the Y, X and Z-axis;

(9) FIG. 8 shows a schematization of a cylinder-shaped scaffold with two different grid-shaped channel networks at two different levels along the Z-axis;

(10) FIG. 9 shows a schematization of a spherical cap-shaped scaffold with concentric through-channels;

(11) FIG. 10 shows a schematization of a spherical cap-shaped scaffold with concentric dead-end channels;

(12) FIG. 11 shows a schematization of a cylinder-shaped scaffold with a spiral-shaped channel;

(13) FIG. 12 shows a schematization of the thermal drilling process using a hot, rectilinear needle perforating a spherical cap-shaped scaffold;

(14) FIG. 13 shows the compression stress-strain curve of PUUEE-based prosthesis, synthesized according to Example 1 of the present invention;

(15) FIG. 14 shows the weight water-uptake kinetics of PUUEE-based prosthesis, synthesized according to Example 1 of the present invention.

BEST MODES FOR CARRYING OUT THE INVENTION

(16) With reference to FIGS. 1 and 2, the medical device according to a first embodiment of the present invention is, for example, a spherical cap-shaped scaffold 10.

(17) The scaffold is preferably made of a soft polymeric matrix having a porous structure 11 (i.e. a soft polymeric foam) and belonging, preferably, to the family of poly(urea-urethane)s.

(18) More preferably, the polymeric matrix belongs to poly(urea-urethane-ester-ether)s, called PUUEE.

(19) The PUUEE-based polymeric matrix is composed by a reactive mixture comprising:

(20) 1) at least 30% (w/w) high-to-medium molecular weight hydrophobic biodegradable amorphous soft segments polyols, of average molecular weight from 20000 to 60000 Da.

(21) In particular, the hydrophobic biodegradable amorphous soft segments polyols, constituting at least 30% (w/w) of PUUEE, must contain at least 10% (w/w) 1,4-Dioxane-2,5-dione (commonly named glycolide) and at least 40% (w/w) 2-oxepanone (commonly named epsilon-caprolactone).

(22) Moreover, the number of reactive terminal hydroxide groups of said hydrophobic biodegradable amorphous soft segments polyols are ranged between 6 to 2 per macromolecule, more preferably between 4 to 2 per macromolecule.

(23) 2) medium molecular weight hydrophilic polyalkoxide polyols, of average molecular weight from 2000 to 15000 Da, as for example, polyethylene glycol (PEG), polypropylene oxide (PPO), random copolymers of ethylene glycole and propylene oxide (P(ED-co-PO).

(24) In particular, the number of reactive terminal hydroxide groups of said hydrophilic polyalkoxide polyols are ranged between 4 to 2 per macromolecule.

(25) 3) at least 40% (w/w) low molecular weight polyisocyanates and polyols, whose average molecular weights range between 15 and 200 Da.

(26) The weight ratio between the hydrophobic biodegradable soft segment polyols and the hydrophilic polyalkoxide polyols is comprised between 10:1 to 1:1, more preferably between 5:1 and 2:1, and most preferably between 4:1 and 3:1.

(27) The percentage of isocyanate functional groups involved in the syntheses of PUUEE soft foams and chemically convertible to urea groups (hard segments) ranges preferably between 50 and 65% of the total amount of isocyanate groups, more preferably between 60 and 63%.

(28) In addition, the urea content in the PUUEE foam preferably must not exceed 65.5% of the total convertible isocyanate groups.

(29) The PUUEE foam according to the present invention is a flexible foam characterized by low cross-linking degrees.

(30) This is due to its particular macromolecular structural design, mainly based on: i) the introduction and copolymerization of high-to-medium molecular weight amorphous soft segments ii) low polyurea hard segments content, and iii) as low as possible cross-linking degree, in order to avoid foam rigidity.

(31) The copolymerization of high-to-medium molecular weight amorphous soft segments (at least 30% (w/w)), whose average molecular weights are higher than 20000 Da, is such to make possible to finely tune the visco-elastic properties of the foam and to obtain flexible foams, which are characterized by low cross-linking degrees.

(32) According to a further characteristic of the present invention, the soft polymeric matrix preferably comprises a plurality of through-channels (channels) 12, which propagate in the polymeric matrix and are interconnected with its porous structure. Preferably the channels are evenly spaced within the matrix; For instance, they are placed at a substantially regular distance from each other along the X, Y, and Z-axis.

(33) According to one embodiment of the present invention, the channels are arranged in grid-shaped networks 13 positioned at different levels along a Z-axis.

(34) According to such embodiment of the present invention, the channels 12 have constant diameters d along their length (FIG. 3). According to other embodiments, the channels 14 may have variable diameters, for example a larger diameter d1 at the scaffold surface and a smaller diameter d2 inside the scaffold (FIG. 4).

(35) The physico-chemical properties of the medical device, in particular porosity degree (defined as the ratio between volume of pores and total volume), pore size, channels diameters, mechanical properties (Compressive Elastic Modulus), water uptake capacity (as defined in Example 2) and degradation kinetics in vitro, are listed in Table 1, providing, for each of these parameters, a preferable, more preferable and most preferable range of values.

(36) TABLE-US-00001 TABLE 1 Value More preferable Most preferable Parameter interval value interval value interval Porosity degree (%) 55-98 70-95 80-90 Pore size (diameter ; m) 5-2000 15-1000 50-500 Channles (diameter d; mm) 0.50-10 0.3-5 0.8-2 Mechanical properties 5-700 5-50 10-30 (Compressive Elastic Modulus; kPa) water uptake capacity 20-500 50-400 200-350 (w/w; %) degradation kinetics in 1-24 2-12 2-6 vivo (months)

(37) According to other embodiments of the present invention, the scaffold can have different sizes and shapes, which depend on the breast volume deficit after tumor resection.

(38) Also, alternative embodiments with different arrangements of the channels inside the scaffold are possible, provided that the channels are placed at a substantially regular distance along the X, Y, and Z-axis. Indeed, such an arrangement is able to promote cell penetration and homogeneous perfusion of nutrient and oxygen inside the scaffold, vascularization and tissue regeneration.

(39) According to a first of these alternative embodiments, the medical device is a spherical cup-shaped scaffold 110 with through-channels 12 parallel to the base 15 of the spherical cup, for example parallel to the X-axis, as in FIG. 5.

(40) According to a second alternative embodiment, the medical device is a spherical cap-shaped scaffold 210 with through-channels 12 perpendicular to the base 15 of the spherical cup, i.e. parallel to the Z-axis (FIG. 6).

(41) According to a third alternative embodiment, the medical device is a spherical cup-shaped scaffold 310 with through-channels 12 parallel to the X, Y and Z-axis (FIG. 7).

(42) According to a fourth alternative embodiment, the medical device is a cylindrical scaffold 410 with at least one grid-shaped channel network 13 parallel to the base 16 of the cylindrical scaffold, i.e. to the X-Y plane. For example, the scaffold 410 has two grid-shaped channel networks 13, as shown in FIG. 8.

(43) According to a fifth alternative embodiment, the medical device is a spherical cup-shaped scaffold 510 with radial through channels 12 intersecting in a common point C (FIG. 9).

(44) According to a sixth alternative embodiment, the medical device is a spherical cup-shaped scaffold 610 with radial dead-end channels 12 (FIG. 10).

(45) According to a seventh alternative embodiment, the medical device is a cylindrical scaffold 710 with at least one spiral-shaped channel 12 (FIG. 11).

(46) The invention is further illustrated by means of the following examples of a method for producing and characterizing the medical device as disclosed above.

EXAMPLES

Example 1: Synthesis of PUUEE Foam

(47) Polyol solution are prepared by mixing the following ingredients as indicated in table 2a, 2b and 2c. Hardener/catalyst solution is prepared as indicated in table 3a, 3b and 3c.

(48) The polyol and hardener solution are mixed, by means of mechanical stirring at 400-600 rpm, from one to two minutes and let to expand freely for another minute, before solidification.

(49) According to this procedure, the average pore size of the foam is inversely proportional to stirring time, before cross-linking. The longer the time of mechanical stirring the smaller the pore size. Temperature can accelerate the reaction kinetics, and can be applied to shorten cross-linking time intervals. However according to this casting strategy, which is one shot, the exothermic process characterizing the poly addition reaction between the low molecular weight molecules, involved in the formulation, is sufficient to push the conversion degree of the starting materials up to 100%.

(50) TABLE-US-00002 TABLE 2a Part per Ingredient hundred pph (w/w) Polyester triol, average number 30 molecular weight 21000 Da Polyethylene glycole, average 10 number molecular weight 6000 Da Glycerol 10 Distilled water 3 Dimethyl sulfoxide (DMSO) 44 Calcium stearate 3

(51) TABLE-US-00003 TABLE 2b Part per Ingredient hundred pph (w/w) Polyester triol, average number 40 molecular weight 24000 Da Polyethylene glycole, average 10 number molecular weight 6000 Da Glycerol 10 Distilled water 3 Dimethyl sulfoxide (DMSO) 34 Calcium stearate 3

(52) TABLE-US-00004 TABLE 2c Part per Ingredient hundred pph (w/w) Polyester triol, average number 30 molecular weight 21000 Da Polyethylene glycole, average 11 number molecular weight 4000 Da Glycerol 9 Distilled water 3 Dimethyl sulfoxide (DMSO) 44 Calcium stearate 3

(53) TABLE-US-00005 TABLE 3a Part per Ingredient hundred pph (w/w) tetramethylenediisocyanate 70 Ferric acetylacetonate 0.1 Dimethyl sulfoxide (DMSO) 30

(54) TABLE-US-00006 TABLE 3b Part per Ingredient hundred pph (w/w) Isophoronediisocyanate 85 Ferric acetylaceonate 0.1 Dimethyl sulfoxide (DMSO) 15

(55) TABLE-US-00007 TABLE 3c Part per Ingredient hundred pph (w/w) Hexamethylenediisocyanate 80 Ferric acetylacetonate 0.1 Dimethyl sulfoxide (DMSO) 20

(56) The physico-chemical properties of PUUEE foams obtained according to Example 1 (in particular porosity degree, pore size, mechanical properties, water uptake capacity and degradation kinetics in vitro) conform to those listed in Table 1, in the column Most preferable value interval.

(57) It is possible to further tune the most of the previously mentioned physico-chemical properties, in particular, mechanical properties, water uptake capacity and degradation kinetics in vitro, by changing the average molecular weight of the amorphous soft segments and the weight ratio between the hydrophilic and the hydrophobic biodegradable segments, copolymerized in the polymeric matrixes.

(58) Moreover, in the hardener/catalyst solution, the DMSO solvent can be replaced by any other organic solvent having equivalent characteristics to DMSO.

Example 2: Shaping and Channelization of PUUEE Foam

(59) A PUUEE foam with cylindrical shape is synthesized according to example 1.

(60) A hot wire is used to cut the external part of the cylinder, in order to obtain a semi-spherical caps.

(61) Once the foam has been shaped externally, a network of channels is realized inside the foam by perforating the foam with a series of hot needles. The needles are heated, electrically, at temperatures range 100-200 C., preferably between 130 and 170 C.

(62) The needles are inserted through the foam's matrix and retracted after a time interval ranging from 1 second and 20 seconds, preferably between 5 and 10 seconds.

(63) The diameter of the needle ranges 0.1 mm to 5 mm, preferably between 0.5 and 2 mm. The diameter of the resulting channels depends on both the diameter of the tool and its permanence time inside the foam, where higher permanence times produce larger channels.

(64) The network of channels is produced by perforating the foam in different areas of the spherical cap and in different directions, according to well-defined 3 dimensional pattern. In this example, the network of channels is obtained by: (1) producing parallel channels which lie in the same horizontal plane, arranged at 5 mm one from each other (X-axis); (2) producing parallel channels, arranged at 5 mm one from each other, orthogonal to and lying in the same plane of those one produced in the step 1 (Y-axis); (3) reproducing the same channels produced in steps 1 and 2 in different planes, at 5 mm distance one from each other; (4) producing channels orthogonal to those produced in steps 1 and 2, arranged at 5 mm one from each other (Z-axis).

(65) At the end of the process, a spherical cap-shaped foam with an internal three-dimensional network of channels, at a maximum distance of 5 mm one from each other, is obtained.

Example 3: Chemical and Physical Characterization of PUUEE Prosthesis

(66) Uniaxial compression test: six cylindrical specimens, of 1 cm diameter and 1 cm height were used to determine the elastic compressive modulus and compressive strength of the prosthesis.

(67) All measurements were carried out at room temperature (25 C.) on swollen samples in distilled water. The samples were compressed at the speed of 1 mm/min.

(68) Compressive elastic modulus was calculated by the slope of stress-strain curve at the deformation zone between 5 and 10%.

(69) Compressive strength was calculated as the maximum stress at deformation higher than 95%.

(70) The stress strain curve of the prosthesis obtained according to Example 1 is illustrated in FIG. 13.

(71) The prosthesis are characterized by a 30 kPa compressive elastic modulus and a compressive strength (at 95% deformation) of 1 MPa.

(72) Weight Water uptake tests: six purified and dried cylindrical samples were incubated in phosphate buffer saline solution (PBS 1). At each time point, the swollen samples were removed from PBS, blotted gently to remove excess PBS.

(73) The Weight Water uptake curve of the prosthesis obtained according to Example 1 is shown in FIG. 14.

(74) Weight water uptake was calculated according to the following formula:
Weight water uptake %=(WsW0)*100/W0 Where W0, Ws and Wd in the above equation are the initial, swollen weight respectively.

(75) In general, according to the above examples, the method for producing the medical device according to the present invention comprises the following steps:

(76) synthesizing the PUUEE-based polymeric matrix by mixing a solution comprising high-to-medium molecular weight hydrophobic biodegradable amorphous soft segments polyols of average molecular weight from 20000 to 60000 Da; medium molecular weight hydrophilic polyalkoxide polyols of average molecular weight from 2000 to 15000 Da; low molecular weight polyisocyanates and polyols of average molecular weight from 12 to 200 Da.

(77) according to the items 1-3 as disclosed above;

(78) shaping the PUUEE-based polymeric matrix in order to obtain a matrix of desired shape;

(79) realizing a plurality of channels inside the PUUEE-based polymeric matrix.

(80) The plurality of channels are obtained by means of a versatile and scalable method, which allows the channelization of porous matrices according to well-defined three-dimensional patterns and geometries, as the ones described above.

(81) The channelization technique is based on thermal drilling, i.e. on the perforation of the porous polymeric matrix by means of a heated tool 20 (FIG. 12), which is able to easily penetrate the matrix causing permanent modification of the internal morphology in those areas of the polymeric porous matrices which come in contact with the tool.

(82) For example, the perforating tool is shaped as a series of needles, mandrels or metallic sticks, whose cross-section is, for example, circular, squared or with other design and whose geometry is rectilinear or curved.

(83) The temperature of the perforating tool ranges preferably from 30 C. to 400 C., more preferably between 100 C. and 200 C., and most preferably between 130 C. and 170 C.

(84) Thanks to the high temperature of the perforating tool, the parts of polymeric matrix which come in contact with the heated tool is subjected to thermal decomposition, and this consequently leads to permanent modification of the internal morphology of the polymeric matrix. This technique is also applicable to porous scaffolds based on synthetic polymers such as polyurethanes, polyacrylates, polyesters, polyamides, vinylic polymers, polyanhydrides, polyolefines, silicones, their copolymers and mixtures, and natural origin polymers such as collagene, gelatin, hyaluronic acid, polylysine, laminin, fibronectin and their copolymers and mixtures.

(85) The channelization technique of the present invention is also suitable for stiff, porous polymeric matrixes, as the heated tool, being made of a metal alloy, is able to penetrate and shape stiff polymers, even in presence of inorganic fillers such as hydroxyapatite.

(86) The particular internal morphology of the medical device according to the present invention resembles, advantageously, the architecture of the natural biological tissues and is suitable to promote the recruitments of blood vessels (vascularization) and soft tissue restoration (instead of simply replacing the removed soft tissue).

(87) Indeed, the tailor-made synthetic polymer of the medical device according to the present invention has adequate mechanical properties (such as good elasticity, hardness, shape memory), hydrophilic character and degradation kinetics suitable for the adipose tissue regeneration in vivo.

(88) Furthermore, the particular architecture of the medical device of the present invention is obtained by means of a simple and scalable process.

(89) The casting strategy used for obtaining the soft PUUEE foam is a one shot casting strategy, which advantageously lead to cross-linked soft polyurethane foams. This is achieved thanks to the characteristic high exothermic process, resulting from the poly addition reaction of low-molecular weight polyols and polyisocyanates. The heat produced during the polymerization of low-molecular weight monomers contributes, advantageously, to the enhancement of the miscibility and reactivity of the high-to-medium molecular weight soft segments, which are necessary to obtain soft foams.

(90) In addition to the casting strategy, the characteristic softness of the PUUEE foam is obtained thanks also to a well-defined urea content (hard segments), which, according to the present invention, does not exceed 65.5% of the total convertible isocyanate groups.

(91) Furthermore, the channelization technique according to the present invention is able to re-model the porous matrix around the heated needles or mandrels. When the technique is used with the polyurethane of the present invention or with other synthetic polymers such as the ones listed above, this result is achieved without creating neither toxic nor dangerous by-product, such as oxidized substances or combustion residues, at measurable concentration, as experimentally demonstrated by the Applicant by thorough cytotoxicity

(92) Finally, despite the medical device of the present invention in particularly suitable for breast reconstruction or augmentation, it can be used, in general, for adipose tissue reconstruction, and, more in general, for soft tissue reconstruction.

(93) Of course, without prejudice to the basic principles of the invention, the details and embodiments may vary, also significantly, with respect to what has been described herein by way of example only, without departing from the scope of the invention as defined by the claims that follow.