This application claims U.S. provisional patent application No.: 60/471,518 and International patent application No. PCT/US03/33750, filed on 23/10/2003, the disclosures of each of which are incorporated herein by reference in their entirety.
Detailed description of the invention
Certain embodiments of the invention include reticulated, bio-sustainable elastomeric products that are also compressible and capable of exhibiting elasticity upon recovery, such products having a wide variety of applications, and being useful, for example, as long-term tissue engineering implants for use in bioimplants, particularly those implanted into the human body, particularly where dynamic packing and/or expansion is desired, such as in soft tissue-related orthopedic applications; it is also used for tissue proliferation, support and repair; for therapeutic purposes; for cosmetic, reconstructive, urinary tract, gastroesophageal purposes; or for pharmaceutically active agents, such as drug delivery. Other embodiments relate to reticulated, biodurable elastomeric products for in vivo delivery via catheters, endoscopes, arthroscopes, laparoscopes, cystoscopes, syringes and other suitable delivery devices, and which can be satisfactorily implanted or exposed to tissue and body fluids for extended periods of time, e.g., at least 29 days.
As recognized by the present invention, there is a medical need for a non-toxic implantable device that can be delivered to a site in a patient's body, such as a site in a patient's body, and occupy that site for an extended period of time without causing harm to the host. In one embodiment, such implantable devices are ultimately integrated, e.g., ingrown into tissue. Various biodegradable porous polymeric materials have been proposed for tissue proliferation and repair.
It would be desirable to create implantable devices suitable for use as tissue engineering scaffolds or in other corresponding substrates to support in vivo propagation applications of cells, for example, in a number of orthopedic applications, particularly in the repair of attachment, regeneration, proliferation, support and ingrowth of organ soft tissue. Without being bound by any particular theory, the high pore content and high reticulation are believed to allow the implantable device to at least partially, in some cases sufficiently, and in some cases completely, in-grow and proliferate cells and tissues, such as fibroblasts, fibrous tissue, synovial cells, bone marrow somatic cells, stem cells, and/or fibrochondrocytes. These ingrown and proliferating tissues then provide the functions of the original tissue being repaired and replaced, such as the ability to withstand stress. However, prior to the advent of the present invention, materials and/or products were not available to meet the needs of such implantable devices.
Broadly speaking, certain embodiments of the reticulated, biopersistent elastic product of the present invention comprises, or consists essentially of, if not all, a highly permeable reticulated matrix formed of a biopersistent polymeric elastomer that is resiliently compressible and thus capable of returning to its original shape when delivered to a biological site. In a specific embodiment, the chemical characteristics of the elastomeric matrix are clear. In another embodiment, the physical properties of the elastomeric matrix are clear. In another embodiment, the chemical and physical characteristics of the elastomeric matrix are both clear.
Certain embodiments of the present invention are capable of supporting cell growth and allowing cell in-growth and in-vivo proliferation, and thus are useful as in-vivo biological implantable devices, e.g., as tissue engineering scaffolds to provide substrates required for cell proliferation in vitro and in vivo.
In a particular embodiment, the reticulated elastomeric matrix of the present invention promotes cellular ingrowth by providing a surface for cell attachment, migration, proliferation, and/or coating deposition (e.g., collagen). In another embodiment, any type of tissue can be grown into the implantable device comprising the reticulated elastomeric matrix of the present invention, including, for example, epidermal tissue (including squamous, cubic, and columnar epidermal tissue, and the like), connective tissue (including, for example, cellulite, dense regular and irregular tissue, reticulated tissue, adipose tissue, cartilage, and bone), and muscle tissue (including, for example, skeletal muscle, smooth muscle, and cardiac muscle), or combinations thereof, such as microtubule tissue. In another embodiment of the invention, an implantable device comprising the reticulated elastomeric matrix of the invention allows tissue ingrowth to occupy substantially the entire interconnected pore volume.
In one embodiment, the present invention provides an implantable device that is sufficiently resiliently compressible to be delivered by a "delivery device," i.e., a device with a chamber for containing a resilient implantable device, which is delivered to a target site, such as with a catheter, endoscope, arthroscope, laparoscope, cystoscope, or syringe, and then released at the site. In another embodiment, the resilient implantable device so delivered returns to substantially its original shape after delivery to a biological site and has sufficient biopersistence and biocompatibility to be suitable for long-term implantation.
The structure, morphology and properties of the elastomeric matrices of the invention may be designed or varied over a wide range of properties for different functional or therapeutic uses, and such design or variation may be achieved by varying the starting materials and/or processing conditions.
Without being bound by any theory, it is an object of the present invention to provide a lightweight, durable structure that fills a biological volume or cavity and is sufficiently porous throughout the volume that the structure can be made by one or more of the following methods: occlusion, embolization, cellular ingrowth, cellular proliferation, tissue regeneration, tissue attachment, drug delivery, enzymatic action of immobilized enzymes, and other useful methods, including those described in the present specification and, in particular, in the claimed priority applications.
In a particular embodiment, the elastomeric matrix of the present invention has sufficient elasticity to allow it to substantially recover, e.g., to at least 50% of its size in a relaxed configuration, e.g., a low compression set, e.g., at 25 ℃ or 37 ℃, after being compressed for implantation into the human body; and have sufficient strength and flow-through properties to enable the use of the matrix in controlled release of pharmaceutically active ingredients (e.g., drugs) and other medical applications. In one embodiment, the elastomeric matrix of the present invention has sufficient elasticity to allow it to substantially return to, for example, at least 60% of its size in a relaxed configuration after being compressed for implantation into the human body, and in one embodiment, the elastomeric matrix of the present invention has sufficient elasticity to allow it to substantially return to, for example, at least 90% of its size in a relaxed configuration after being compressed for implantation into the human body.
In this application, the term "bio-durable" describes an elastomer or other product that is stable in a biological environment for an extended period of time. Such products, when exposed to biological environments, do not exhibit significant fracture or degradation, erosion, or significant degradation of mechanical properties associated with their use, for a period of time commensurate with the use of the implantable device. The time of implantation may be weeks, months or years; the life of the host product into which the elastomeric product of the invention has been integrated (e.g., grafted or repaired); or the lifetime of the patient host into which the elastomeric product is implanted. In one embodiment, the desired exposure time is considered to be at least about 29 days. In another specific embodiment, the desired exposure time is considered to be at least 29 days. In a specific embodiment, the implantable device has a biodurability of at least 2 months. In another embodiment, the implantable device has a biodurability of at least 6 months. In another embodiment, the implantable device has a biodurability of at least 12 months. In another embodiment, the implantable device has a biodurable force of greater than 12 months. In another embodiment, the implantable device has a biodurability of at least 24 months. In another embodiment, the implantable device has a biodurability of at least 5 years. In another embodiment, the implantable device has a biodurable capacity of greater than 5 years.
In a particular embodiment, the bio-sustainable product of the invention is also biocompatible. In the present application, the term "biocompatible" is meant to indicate that the product elicits little, if any, adverse biological reactions when implanted in a host patient. The same applies to the "biocompatible" property, as applies to the "bio-persistable".
A possible biological environment is understood to be in vivo, e.g. in a patient host implanted with the product or topically administered with the product, e.g. in a mammalian host, such as a human or other primate, a pet or sport animal, a domestic or food animal, or a laboratory animal. All such uses are considered to be within the scope of the present invention. As used herein, a "patient" is an animal. In a specific embodiment, the animal is a bird, including but not limited to a chicken, turkey, duck, goose, quail, or mammal. In another embodiment, the animal is a mammal, including but not limited to cows, horses, sheep, goats, pigs, cats, dogs, mice, rats, hamsters, rabbits, guinea pigs, monkeys, and humans. In another embodiment, the animal is a primate or a human. In another specific embodiment, the animal is a human.
In one embodiment, the structural material for the cellular elastomer of the present invention is a synthetic polymer, particularly, but not exclusively, an elastomeric polymer resistant to biodegradation, e.g., in one embodiment, polycarbonate polyurethane, polycarbonate urea-urethane, polyether polyurethane, poly (carbonate-co-ether) urea-urethane, silicone, etc.; in another embodiment, are polycarbonate urea-urethanes, poly (carbonate-co-ether) urea-urethanes, and polysiloxanes. These elastomers are generally hydrophobic, but according to the present invention may be treated to have a less hydrophobic or to some extent hydrophilic surface. In another embodiment, such elastomers may be manufactured with a less hydrophobic or somewhat hydrophilic surface.
The reticulated biodurable elastic product of the present invention may be described as possessing a "macrostructure" and a "microstructure," which terms have the general meaning described below.
"macrostructures" refers to the physical characteristics of an article or object made from the biodurable elastic product of the present invention as a whole, such as: the periphery is described in terms of geometric bounds of the article or object, regardless of the hole or void. "macrostructural surface area" refers to the outermost surface area, although the pores are densely packed therein, without regard to the surface area inside the pores. "macrostructural volume" or simply "volume" occupied by an article or object refers to the "volume" defined by the surface area of the macrostructure (or simply "macro"), and "bulk density" refers to the mass per unit volume of the article or object itself, which is distinct from the density of the structural material.
"microstructure" refers to internal structural features of the bio-sustainable elastomeric material from which the product of the invention is composed, such as pore size, pore surface area (i.e., the total area of material surfaces in the pores), and the structure of struts and cross-sections (which make up the solid structure of embodiments of the elastomeric product of the invention).
Referring to fig. 1, a schematic depiction of a particular morphology of reticulated foam is shown for convenience. FIG. 1 is a simplified illustration of the microstructural features and composition of certain specific products of the invention. This figure is neither an idealized representation of a particular elastomeric product of the present invention nor a detailed representation of a particular specific product. Other features and compositions of the microstructure will be apparent from the description, or may become apparent from one or more methods of making a porous elastomeric product according to the invention described in this application.
Form of the composition
A porous, bio-durable elastomeric matrix 10 is shown, generally described, with individual components that may be uniquely shaped or with extended, continuous or amorphous entities. The matrix 10 comprises a reticulated solid phase 12 formed of a suitable bio-durably elastic material interspersed with (or formed thereby) a continuous interconnected pore phase 14, the latter of which is a primary feature of the reticulated structure.
In one embodiment, the elastomeric material comprising elastomeric matrix 10 may be a mixture or blend of materials. In another embodiment, the elastic material is a single synthetic polymeric elastomer, as will be described in further detail below.
The porous phase 14 is typically filled with air or gas prior to use. During use, the porous phase 14 is in many, but not all, cases filled with a liquid, such as a biological or body fluid.
As shown in FIG. 1, the solid phase 12 of the flexible matrix 10 has an organic structure comprising a plurality of relatively thin struts 16 extending between and interconnecting a plurality of cross segments 18. The intersection 18 is the basic structural site where three or more struts 16 meet. Four or five or more struts 16 meet at one intersection 18, or at some point two intersections 18 can be seen to merge into another. In one embodiment, the struts 16 extend in three dimensions above and below the plane of the paper between the cross sections 18, with no particular preference for one plane. Thus, any given strut 16 may extend from the cross portion 18 in any direction relative to other struts 16 connected to the cross portion 18. The struts 16 and cross-over portions 18 generally have a curved profile and form a plurality of pores 20 or interstitial spaces in the solid phase 12 therebetween. The struts 16 and cross-over portions 18 form an interconnected, continuous solid phase.
As shown in FIG. 1, the structural components of the solid phase 12 of the elastomeric matrix 10, i.e., the struts 16 and intersections 18, appear to possess some lamellar structure as if some were cut from a single lamellar sheet, but it is understood that this appearance is due in part to the difficulty in describing complex three-dimensional structures in two-dimensional patterns. Both the post 16 and the cross-section 18 have, and in some cases possess, a non-laminar profile including circular, elliptical, non-circular cross-sectional shapes and cross-sections that vary in area depending on the particular configuration, e.g., along the longest dimension, they become progressively smaller or larger in cross-section.
Many of the pores 20 have walls formed of a structural material, also referred to as "windows" or "panes," such as walls 22. Such cell walls are somewhat disadvantageous in that they may impede the passage of fluids and/or tissue proliferation and propagation through the pores 20. In another embodiment, the cell walls 22 may be removed using a suitable treatment step, such as reticulation as discussed below.
In addition to the boundary ends of the macrostructured surface, in the embodiment shown in FIG. 1, the solid phase 12 of the elastomeric matrix 10 comprises few, if any, free ends, terminal ends, or protruding "strut-like" structures extending from the struts 16 or cross-sections 18, but not connected to other struts or cross-sections.
However, in an alternative embodiment, a large number of small fibers (not shown) are present in the solid phase 12, such as about 1 to 5 fibers per strut 16 or cross-section 18. In certain applications, such fibers may be useful, as they provide additional surface area.
The struts 16 and cross-over portions 18 may be considered to define the shape and structure of the pores 20, which pores 20 make up the pore phase 14 (or vice versa). A plurality of holes 20, open to and communicating with at least two holes 20 due to the absence of at least part of the cell wall, can be clearly identified. At the intersection portion 18, three or more holes 20 meet and communicate with each other. In certain embodiments, the void phase 14 is continuous or substantially continuous throughout the elastomeric matrix 10, meaning that few, if any, closed cells are present. Such closed cells, the interior space of each of which is not connected to any other cell, e.g., cell walls 22 separating them from adjacent cells, represent a loss of useful volume and can impede the access of useful fluids to the interior struts 16 and cross-section structures 18 of the elastomeric matrix 10.
In a particular embodiment, the closed cells, if present, occupy less than 30% of the volume of the elastomeric matrix. In another embodiment, the closed cells, if present, occupy less than 25% of the volume of the elastomeric matrix. In another embodiment, the closed cells, if present, occupy less than 20% of the volume of the elastomeric matrix. In another embodiment, the closed cells, if present, occupy less than 15% of the volume of the elastomeric matrix. In another embodiment, the closed cells, if present, occupy less than 10% of the volume of the elastomeric matrix. In another embodiment, the closed cells, if present, occupy less than 5% of the volume of the elastomeric matrix. In another embodiment, the closed cells, if present, occupy less than 2% of the volume of the elastomeric matrix. The presence of closed pores may be distinguished by their effect on reducing the volumetric flow rate of liquid through the elastomeric matrix 10 and/or reducing the growth and proliferation of cells into the elastomeric matrix 10.
In another embodiment, the elastomeric matrix 10 is reticulated. In another embodiment, the elastomeric matrix 10 is substantially reticulated. In another embodiment, the elastomeric matrix 10 is fully reticulated. In another embodiment, a plurality of cell walls 22 of the elastomeric matrix 10 are removed. In another embodiment, a majority of the cell walls 22 of the elastomeric matrix 10 are removed. In another embodiment, substantially all of the cell walls 22 of the elastomeric matrix 10 are removed.
In another embodiment, the solid phase 12 may be reticulated, which comprises a continuous network of solid structures, such as the network of struts 16 and cross-members 18, without any significant ends, spacers, or interruptions, except at the edges of the elastomeric matrix. In this network, a hypothetical line can pass completely through the material of the solid phase 12 from one point of the network to any other point of the network.
In another embodiment, the pore phase 14 is also a continuous network of interstitial or interconnected gas or liquid flow channels extending throughout the structure of the solid phase 12 of the elastomeric matrix 10, defined thereby and opening to all of its outer surfaces. In another embodiment, as described above, there are few, substantially no, or no occluded or closed pores that are not connected to at least one other pore 20 in the pore network. In addition, in a pore phase network, there is also a hypothetical line that may pass completely through the pore phase 14 from one point of the network to any other point of the network.
In accordance with the objects of the present invention, in one embodiment, the microstructure of the elastomeric matrix 10 is configured to allow or promote cell adhesion to the surface of the solid phase 12, the formation of a neointima thereon and the ingrowth and proliferation of cells and tissue into the pores 20 of the pore phase 14 when the elastomeric matrix 10 is at a suitable in vivo site for a period of time.
In another embodiment, such cell or tissue ingrowth and proliferation, for some purpose, may include fibrosis. This initiation and promotion of ingrowth or proliferation occurs not only at the outer surface layers of the pores 20, but also within the innermost of the elastomeric matrix 10 and throughout the elastomeric matrix 10. Thus, in this particular embodiment, the space occupied by the elastomeric matrix 10 is completely filled with both the ingrowth and proliferation cells and tissue in the form of fibrosis, scar or other tissue, in addition to the space occupied by the elastomeric solid matrix 12. In another embodiment, the implantable device of the present invention functions to keep the ingrowth tissue alive, for example, by prolonging the presence of supporting microvessels.
Thus, with particular regard to the morphology of the void phase 14, in one embodiment, the elastomeric matrix 10 is reticulated with open interconnected pores. Without being bound by any particular theory, it is believed that this allows the interior of the elastomeric matrix 10 to be naturally infused with bodily fluids (e.g., blood) in order to maintain the cell population by providing nutrients thereto and removing waste therefrom, even though the cell population is resident within the interior of the elastomeric matrix 10. In another embodiment, the elastomeric matrix 10 is reticulated with open interconnected pores having a range of sizes. In another embodiment, the elastomeric matrix 10 is reticulated with open interconnected pores having a distribution of different size ranges.
Depending on the particular application for which the elastomeric matrix 10 is to be used, it may be desirable to select various physical and chemical parameters of the elastomeric matrix 10 (particular parameters are described below) to promote cellular ingrowth and proliferation.
It will be appreciated that such a structure of the elastomeric matrix 10 that may provide internal cell infusion is liquid permeable, which may also provide a pathway for liquids to and through the interior of the matrix for purposes other than cell infusion, such as for example, elution of pharmaceutically active agents (e.g., drugs or other biologically useful materials). Such materials are optionally safe for the interior surfaces of the elastomeric matrix 10.
In another embodiment of the invention, if the macrostructural surface is sealed, for example by a bioabsorbable membrane, to contain a gas within the implantable product that is released after the membrane is gradually ablated to provide a local therapeutic or other effect, then the gaseous phase 12 can be filled with or contacted with a deliverable treatment gas, such as a sterilant, e.g., ozone, or a wound repair agent, e.g., nitric oxide.
Useful embodiments of the present invention include slightly randomized structures, as shown in FIG. 1, with the shape and size of the struts 16, cross-over portions 18, and holes 20 varying completely; and more ordered structures which also exhibit the three-dimensional interconnection characteristics of the solid and pore phases, structural complexity and high liquid permeability. Such more ordered structures can be prepared by the process of the present invention as further described below.
Porosity of the coating
The void phase 14 may occupy as little as 50% of the volume of the elastomeric matrix 10, the void phase 14 volume referring to the volume provided by the interstitial spaces of the elastomeric matrix 10 prior to any optional coating or layer applied to the surface of the internal pores. In one embodiment, the volume of the void phase 14, as defined, is from about 70% to about 99% of the volume of the elastomeric matrix 10. In another embodiment, the volume of the void phase 14 is from about 80% to about 98% of the volume of the elastomeric matrix 10. In another embodiment, the volume of the void phase 14 is from about 90% to about 98% of the volume of the elastomeric matrix 10.
In this specification, when the pore is spherical or substantially spherical, its largest transverse dimension is equal to the diameter of the pore. When the hole is non-circular, such as ellipsoidal, tetrahedral, its largest transverse dimension is equal to the largest distance within the hole from one face of the hole to the other, e.g., the major axis of an ellipsoidal hole or the length of the longest face of a tetrahedral hole. In this specification, "average diameter or other largest transverse dimension" refers to the arithmetic mean diameter of an ellipsoid or near ellipsoid, or the arithmetic mean largest transverse dimension of a non-spherical body.
In particular embodiments associated with orthopedic applications and the like, the pores 20 have an average diameter or other largest transverse dimension of at least about 10 microns in order to promote cellular ingrowth and proliferation, and also to provide sufficient liquid permeability. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of at least about 20 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of at least about 50 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of at least about 150 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of at least about 250 micrometers. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension greater than 250 micrometers. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension greater than 250 micrometers. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of at least about 450 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension greater than about 450 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension greater than 450 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of at least about 500 microns.
In particular embodiments associated with orthopedic applications and the like, the pores 20 have an average diameter or other largest transverse dimension of no greater than about 600 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of no greater than about 450 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of no greater than about 250 micrometers. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of no greater than about 150 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of no greater than about 20 microns.
In particular embodiments related to orthopedic applications and the like, the pores 20 have an average diameter or other largest transverse dimension of from about 10 microns to about 50 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of from about 20 microns to about 150 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of about 150 microns to about 250 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of from about 250 microns to about 500 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of about 450 microns to about 600 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of from about 10 microns to about 500 microns. In another embodiment, the pores 20 have an average diameter or other largest transverse dimension of about 20 microns to about 600 microns.
In another embodiment, implantable devices made from elastomeric matrix 10 may contain pores ranging in size from small, e.g., 20 microns, to large, e.g., 500 microns, in a single device. In another embodiment, such variations may be present across a cross-section of the entire material or across a sub-section of the cross-section. In another embodiment, such changes may be present in a systematic gradual manner. In another embodiment, such changes may be present in a stepwise manner. For example, the pore size distribution is about 20 microns to about 70 microns at one end of the implantable device and about 300 microns to about 500 microns at one end of the implantable device. This change in the size distribution of the pores can take place in one or more continuous transitions or in one or more discrete steps, i.e. a transition from one pore size distribution to another can be either gradual in the case of a gradual transition or else marked in the case of discrete steps. As regards the orientation of the pores, a similar transition can also occur in the orientation of the pores, from more oriented pores to less oriented pores or even non-oriented pores, over the entire cross-section or a sub-section of the cross-section. Differences in pore size distribution and/or pore orientation throughout the cross-section of implantable devices made from the elastomeric matrix 10 may allow the implantable devices to be designed to optimally perform in terms of cell type, cell attachment, cell ingrowth, and/or cell proliferation. Alternatively, a different pore size distribution and/or pore orientation throughout the cross-section of an implantable device made from the elastomeric matrix 10 may allow the implantable device to be designed to optimally perform in terms of cell type, cell attachment, cell ingrowth, and/or cell proliferation.
Cells are known to adhere, proliferate and differentiate along and on the structural contours formed by the pore size distribution. The orientation of the cells and the morphology of the cells may result in a constructed or newly formed tissue that substantially replicates or mimics the anatomical features of the actual tissue (e.g., tissue to be replaced). When an implantable device (without prior cell seeding) is implanted at a tissue repair and regeneration site, preferred cell morphology and orientation results due to continuous or stepwise changes in pore size distribution (with or without pore orientation). When the implantable device is implanted at a tissue repair and regeneration site in a patient (e.g., humans and animals) after receiving an in vitro culture of cells, preferred cell morphology and orientation may also result due to continuous or stepwise changes in pore size distribution. These continuous or stepwise changes in pore size (with or without pore direction) distribution are important features of tissue engineering scaffolds for many orthopedic applications, particularly for attachment, repair, regeneration, proliferation and/or support of soft tissue surrounding the spine, shoulder, knee, hand or joint, and for prosthetic organ growth applications.
Pore size, pore size distribution, surface area, gas permeability and liquid permeability can all be determined by conventional methods well known in the art. Some assays have been summarized, for example, by A.Jena and K.Gupta, "Advanced technology for Evaluation of Port Structure Processes engineering of Filtration Media to Optimize them Design and Performance", www.pmjapp.com/papers/index.Html and the publication "A Novel Business Process technology for Evaluation of Port Volume, Port Size and Liquid Performance". Instruments used to perform these measurements include a thin film Porosimeter, a liquid extrusion Porosimeter (liquid extrusion Porosimeter), each of which is commercially available from port Materials, Inc.
Size and shape
The elastomeric matrix 10 can be easily manufactured in any desired size and shape. It is an advantage of the present invention that the elastomeric matrix 10 is suitable for mass production from bulk stock by subdividing, e.g., cutting, stamping, laser cutting, compression molding. In one embodiment, the bulk material may be subdivided with a heated surface. Another advantage of the present invention is that the shape and configuration of the elastomeric matrix 10 can be varied over a wide range and can be readily formed into a desired anatomical shape.
The size, shape, configuration and other relevant details of the elastomeric matrix 10 may be customized for a particular application or patient, or may be mass produced on a standardized basis. However, mass production is economical. Thus, the elastomeric matrix 10 may be contained in kits containing elastomeric implantable device pieces of varying sizes and shapes. In addition, as described elsewhere in this specification and disclosed in the priority application, multiple, e.g., two, three, or four, individual elastomeric matrices 10 may be used as implantable device systems for a single target biological site, adjusted in size or shape or both to act synergistically to treat a single target site.
The practitioner (who may be a surgeon or other doctor or veterinarian, researcher, etc.) performing the procedure may then select one or more implantable devices for a particular purpose, such as that described in the claimed priority application.
For example, the elastomeric matrix 10 may have a minimum dimension as small as 0.5 mm and a maximum dimension as large as 100 mm, or even larger. In one embodiment, however, elastomeric matrix 10 of this size for implantation is expected to have an elongated shape, such as a cylinder, rod, tube, or elongated prism shape, or a folded, coiled, spiral, or other more compact configuration. Likewise, the dimension as small as 0.5 mm may be the transverse dimension of the elongated shape or ribbon or sheet of the implantable device.
In alternative embodiments, such elastomeric matrices 10 may be used, for example, for orthopedic applications, having a spherical, cubic, tetrahedral, toroidal, or other shape with substantially no dimension elongated compared to other dimensions, and a diameter or other maximum dimension between about 0.5 mm and 500 mm. In another embodiment, the elastomeric matrix 10 having such a shape has a diameter or other maximum dimension of about 3 mm to about 20 mm.
For most implantable device applications, the size of the elastomeric matrix 10 macrostructure includes the following specific embodiments: compact shapes such as spheres, cubes, pyramids, tetrahedrons, cones, cylinders, trapezoids, parallelepipeds, ellipsoids, spindle bodies, tubes or cylinders; and many less regular shapes having a transverse dimension of from about 1 mm to about 200 mm (in another embodiment, the transverse dimension is from about 5 mm to about 100 mm); a sheet or tape-like shape having a maximum thickness of about 0.5 mm to about 20 mm (in another embodiment, about 1 mm to about 5 mm) and a lateral dimension of about 5 mm to about 200 mm (in another embodiment, about 10 mm to about 100 mm).
For treatment in orthopaedic applications, the present invention has the advantage of enabling the efficient use of the above-described implantable elastomeric matrix components without the need to closely follow the shape of the site of orthopaedic application, which is often complicated and difficult to simulate. Thus, in one embodiment, the implantable elastomeric matrix component of the present invention has a significantly different and simpler configuration, such as described in the claimed priority application.
Moreover, in a particular embodiment, the implantable device, or implantable device system (if multiple are used), of the present invention does not completely fill the orthopedic application site, even when fully expanded in situ. In a particular embodiment, the implantable device of the present invention is smaller in size than the site of orthopedic application when fully expanded, and provides sufficient space within the site of orthopedic application to ensure vascularization, cellular ingrowth and proliferation, and to provide sufficient space for possible passage of blood to the implantable device. In another embodiment, the implantable device of the present invention is larger in size than the site of orthopedic application when fully expanded. In another embodiment, the implantable device of the present invention is smaller in volume than the site of orthopedic application after being fully expanded. In another embodiment, the implantable device of the present invention is substantially as large in volume as the site of orthopedic application after being fully expanded. In another embodiment, the implantable device of the present invention is larger in volume than the site of orthopedic application after it is fully expanded. In another embodiment, the expanded implantable device of the present invention may be further expanded, such as by expansion in one dimension of 1-20%, by absorption and/or absorption of moisture or other body fluids after placement at the site of orthopedic application.
Some useful implantable devices can have a shape that approximates the contour of a portion of the target orthopedic application site. In one embodiment, the implantable device is formed into a relatively simple convex, dished, hemispherical, or semi-ellipsoidal shape and size to treat a plurality of different sites in different patients.
In another particular embodiment, it is contemplated that such implantable devices for orthopedic applications and the like, once implanted, do not completely fill, cover, or span the biological site in which they reside before their pores are filled with biological fluids, bodily fluids, and/or tissues; although not required, in many cases, at least one dimension of the single implanted elastomeric matrix 10 does not exceed 50% of the entrance to the biological site, or covers 50% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 75% of the entrance to the biological site, or covers 75% of the damaged tissue in need of repair or replacement. In another embodiment, at least one of the dimensions of the single implanted elastomeric matrix 10 as described above does not exceed 95% of the entrance to the biological site, or covers 95% of the damaged tissue in need of repair or replacement.
In another embodiment, such an implantable device for orthopedic applications and the like, once implanted, does not completely fill, cover, or span the biological site in which it resides before its pores are filled with biological fluids, bodily fluids, and/or tissues; although not required, in many cases, at least one dimension of the single implanted elastomeric matrix 10 does not exceed 100% of the entrance to the biological site, or covers 100% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 98% of the entrance to the biological site, or covers 98% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 102% of the entrance to the biological site, or covers 102% of the damaged tissue in need of repair or replacement.
In another embodiment, such an implantable device for orthopedic applications and the like, once implanted, does not completely fill, cover, or span the biological site in which it resides before its pores are filled with biological fluids, bodily fluids, and/or tissues; although not required, in many cases, at least one dimension of the single implanted elastomeric matrix 10 does not exceed 105% of the entrance to the biological site, or covers 105% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 125% of the entrance to the biological site, or covers 125% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 150% of the entrance to the biological site, or covers 150% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 200% of the entrance to the biological site, or covers 200% of the damaged tissue in need of repair or replacement. In another embodiment, at least one dimension of the single implanted elastomeric matrix 10 as described above does not exceed 300% of the entrance to the biological site, or covers 300% of the damaged tissue in need of repair or replacement.
In another embodiment, it is contemplated that such implantable devices for orthopedic applications and the like do not completely fill, cover, or span the biological site in which they reside, even if their pores are filled with biological fluids, bodily fluids, and/or tissues over a period of time; although not required, in many cases, the volume of a single implanted elastomeric matrix 10 does not exceed 50% of the entrance to the biological site, or covers 50% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled aperture as described above has a volume that does not exceed 75% of the entrance to the biological site, or covers 75% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled aperture as described above has a volume that does not exceed 95% of the entrance to the biological site, or covers 95% of the damaged tissue in need of repair or replacement.
In another embodiment, such implantable devices for orthopedic applications and the like also do not completely fill, cover, or span the biological site in which they reside when their pores are filled with biological fluids, bodily fluids, and/or tissues over a period of time; although not required, in many cases, the volume of a single implanted elastomeric matrix 10 does not exceed 100% of the entrance to the biological site, or covers 100% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled aperture as described above has a volume that does not exceed 98% of the entrance to the biological site, or covers 98% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled aperture as described above has a volume that does not exceed 102% of the entrance to the biological site, or covers 102% of the damaged tissue in need of repair or replacement.
In another embodiment, such implantable devices for orthopedic applications and the like also do not completely fill, cover, or span the biological site in which they reside when their pores are filled with biological fluids, bodily fluids, and/or tissues over a period of time; although not required, in many cases the volume of a single implanted elastomeric matrix 10 does not exceed 105% of the entrance to the biological site, or covers 105% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled hole as described above has a volume that does not exceed 125% of the entrance to the biological site, or covers 125% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled aperture as described above has a volume that does not exceed 150% of the entrance to the biological site, or covers 300% of the damaged tissue in need of repair or replacement. In another embodiment, a single implanted elastomeric matrix 10 having a filled aperture as described above has a volume that does not exceed 150% of the entrance to the biological site, or covers 300% of the damaged tissue in need of repair or replacement.
Elastomeric and elastomeric matrix implantable devices with distinct properties
In one particular embodiment, the elastomers used as the structural material of the elastomeric matrix 10, alone or in combination in a mixture or solution, are well-characterized synthetic elastomeric polymers having suitable mechanical properties, chemical, physical or biological properties that are well characterized and thus considered to be biodurable and suitable for use in vivo implantable devices in patients, particularly mammals, and especially humans. In another embodiment, the elastomer used as the structural material of the elastomeric matrix 10 has been sufficiently characterized in its chemical, physical, biological properties to be considered biodurable and suitable for use in an implantable device in a patient, particularly a mammal, especially a human.
Physical Properties of elastomeric matrices
The elastomeric matrix 10 may have any suitable bulk density (also referred to as specific gravity) and other properties. For example, in one embodiment, the bulk density may be about 0.005g/cc to about 0.15g/cc (about 0.31 lb/ft) as determined according to the test method described in American society for testing and materials Standard D35743To about 9.4lb/ft3). In one embodiment, the bulk density may be about 0.008g/cc to about 0.127g/cc (about 0.5 lb/ft)3To about 8lb/ft3). In one embodiment, the bulk density may be about 0.015g/cc to about 0.115g/cc (about 0.93 lb/ft)3To about 7.2lb/ft3). In one embodiment, the bulk density may be from about 0.024g/cc to about 0.104g/cc (about 1.5 lb/ft)3To about 6.5lb/ft3)。
The elastomeric matrix 10 may have any suitable micro-surface area and other properties. One of ordinary skill in the art can, for example, roughly estimate the frequency of the pores, e.g., the number of linear pores per millimeter, from the average lateral micron diameter of the pores, from the exposed surface of the porous material, and from the frequency of the pores, the microscopic surface area can be roughly estimated.
Other physical attributes will be or become apparent to one of ordinary skill in the art.
Mechanical Properties of elastomeric matrices
In one embodiment, the reticulated elastomeric matrix 10 has sufficient structural integrity to be self-supporting and self-standing in vitro. However, in another embodiment, structural supports, such as ribs or struts, may be mounted on the elastomeric matrix 10.
The reticulated elastomeric matrix 10 has sufficient tensile strength to withstand normal manual or mechanical handling during and after processing steps in the intended application where it is required or desired not to tear, break, shatter, split or otherwise break apart, shed pieces or particles, or lose their structural integrity. The tensile strength of the starting material should not be so high as to interfere with the fabrication or other processing of the elastomeric matrix 10.
Thus, for example, in one embodiment, the tensile strength of the reticulated elastomeric matrix 10 is about 700kg/m2To about 350,000kg/m2(about 1psi to about 500 psi). In one embodiment, the tensile strength of the reticulated elastomeric matrix 10 is about 700kg/m2To about 70,000kg/m2(about 1psi to about 100psi)
Sufficient ultimate tensile elongation is also desirable. For example, in another embodiment, the reticulated elastomeric matrix 10 has an ultimate tensile elongation of at least about 25%. In another embodiment, the elastomeric matrix 10 has an ultimate tensile elongation of at least about 200%.
One particular embodiment for use in practicing the present invention is a reticulated elastomeric matrix 10 that is sufficiently flexible and resilient, i.e., elastically compressible, that it can be first compressed from a relaxed configuration to a first compact configuration at room temperature (e.g., 25 ℃) for in vitro delivery through a delivery device, such as a catheter, endoscope, syringe, cystoscope, trocar or other suitable introducer device, and then expanded in situ to a second, working configuration. Moreover, in another embodiment, the reticulated elastomeric matrix, after having been compressed to between about 5% and 95% of its original size, such as between 19/20 and 1/20 of its original size, also has the stated elastic compressibility. In another embodiment, the reticulated elastomeric matrix, after having been compressed to about 10-90% of its original size, such as 9/10 to 1/10 of its original size, also has the elastic compressibility described. In this specification, a reticulated elastomeric matrix 10 has "elastic compressibility," i.e., "elastically compressible," if at least one dimension of the second, working configuration is at least 50% of the size of the relaxed configuration in vitro. In another embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 80% the size of the relaxed configuration in vitro. In another embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 90% of the size of the relaxed configuration in vitro. In another embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 97% the size of the relaxed configuration in vitro.
In another embodiment, the reticulated elastomeric matrix, after having been compressed to about 5-95% of its original volume, for example, 19/20 to 1/20% of its original volume, also has the stated elastic compressibility. In another embodiment, the reticulated elastomeric matrix, after having been compressed to about 10-90% of its original volume, for example, 9/10 to 1/10% of its original volume, also has the stated elastic compressibility. In this specification, "volume" is the volume delineated by the outermost three-dimensional contour of the elastomeric matrix. In another specific embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 50% the size of the relaxed configuration in vivo. In another specific embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 80% the size of the relaxed configuration in vivo. In another specific embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 90% of the size of the relaxed configuration in vivo. In another specific embodiment, the reticulated elastomeric matrix 10 has an elastic compressibility such that at least one dimension of the second, working configuration is at least about 97% the size of the relaxed configuration in vivo.
In another embodiment, the reticulated elastomeric matrix 10 described above expands from the first, compact configuration to the second, working configuration in a very short time, such as, in one embodiment, recovering about 95% in 90 seconds or less, and in another embodiment, recovering in 40 seconds or less, each maintaining a 75% compressive deformation for up to 10 minutes. In another embodiment, expansion from the first compact configuration to the second working configuration occurs in a short period of time, e.g., recovery of about 95% in one embodiment in 180 seconds or less, and recovery in another embodiment in 60 seconds or less, each maintaining 75% compression set for up to 30 minutes. In another embodiment, the elastomeric matrix 10 recovers at least about 97% of its volume in the relaxed configuration in about 10 minutes after maintaining a 75% compressive deformation for 30 minutes.
In one embodiment, the reticulated elastomeric matrix 10 has a compressive strength of about 700kg/m at 50% compression set2To about 350,000kg/m2(about 1psi to about 500 psi). In one embodiment, the reticulated elastomeric matrix 10 has a compressive strength of about 700kg/m at 50% compression set2To about 70,000kg/m2(about 1psi to about 100 psi). In one embodiment, the reticulated elastomeric matrix 10 has a compressive strength of about 7,000kg/m at 75% compression set2To about420,000kg/m2(about 10psi to about 600 psi). In one embodiment, the reticulated elastomeric matrix 10 has a compressive strength of about 7,000kg/m at 75% compression set2To about 140,000kg/m2(about 10psi to about 200 psi).
In another embodiment, the reticulated elastomeric matrix 10 has a compression set of no more than 30% when compressed to 50% of its thickness at about 25 ℃ (i.e., according to ASTM D3574). In another embodiment, the reticulated elastomeric matrix 10 has a compression set of no more than about 20%. In another embodiment, the reticulated elastomeric matrix 10 has a compression set of no more than about 10%. In another embodiment, the reticulated elastomeric matrix 10 has a compression set of no more than about 5%.
In another embodiment, the tear strength of the reticulated elastomeric matrix 10 is from about 0.18 kilograms per linear centimeter to about 8.9 kilograms per linear centimeter (about 1 pound per linear inch to about 50 pounds per linear inch) as determined according to the determination method described in ASTM Standard D3574. In another embodiment, the tear strength of the reticulated elastomeric matrix 10 is from about 0.18 kilograms per linear centimeter to about 1.78 kilograms per linear centimeter (about 1 pound per linear inch to about 10 pounds per linear inch) as determined by the determination method described in ASTM Standard D3574.
Table 1 summarizes the mechanical and other properties suitable for use in particular embodiments of the reticulated elastomeric matrix 10. Other suitable mechanical properties will be apparent, or will be apparent, to those of ordinary skill in the art.
Table 1: properties of the reticulated elastomeric matrix 10
| Properties | Typical value |
| Specific gravity/bulk density | 0.31-9.4lb/ft3(0.005-0.15G/cc) |
| Tensile strength | 1-500lb/ft3(700-350,000kg/m2) |
| Ultimate tensile elongation | ≥25％ |
| Compressive strength at 50% compression | 1-500psi(700-350,000kg/m2) |
| Compressive strength at 75% compression | 10-600psi(7,000-420,000kg/m2) |
| Compression set of 50%, 22 hours, 25 deg.C | ≤30％ |
| Tear strength | 1-50 pounds per linear inch (0.18-8.90 kilograms per linear centimeter) |
The mechanical properties of the porous Materials described herein can be measured, if not otherwise stated, according to ASTM D3574-01 entitled "Standard Test Methods for Flexible Cellular Materials-Slab, bound Molded Urethane Foams" or other Methods deemed suitable by one of ordinary skill in the art.
Moreover, good handleability is also desirable for post-polymerization shaping and manufacturing if the elastomer used to make the elastomeric matrix 10 is subjected to a porosity treatment after the polymerization reaction rather than during the polymerization reaction. For example, in one embodiment, the elastomeric matrix 10 has a low viscosity.
Biological durability and biocompatibility
In a particular embodiment, the elastomer is sufficiently bio-durable to be suitable for long-term implantation in a patient, such as an animal or human. The biodurable elastomer and elastomeric matrix have chemical, physical and/or biological properties and thus can provide a reasonably expected biodurability, that is, the elastomer will exhibit sustained stability for a period of at least 29 days when implanted into an animal, such as a mammal. The predetermined time for long-term implantation may vary depending on the particular application. For many applications, longer implantation times are required, and for such applications, a biodurable time of at least 6, 12, 24 months or 5 years is desirable. An elastomer is particularly advantageous in that it is bio-durable throughout the life of the patient. In the treatment of, for example, spinal defects, with a particular embodiment of the elastomeric matrix 10, bio-persistence over 50 years is beneficial because such a condition may be expected to be useful in relatively young patients, most likely in people over the age of 30.
In another embodiment, the time of implantation is at least sufficient for the cells to begin in-growth and proliferation, e.g., at least about 4-8 weeks. In another embodiment, the properties of the elastomer have been well characterized, in order to be suitable for long-term implantation, as chemical, physical and/or biological properties that provide a reasonably expected biopersistence, that is, the elastomer exhibits a sustained biopersistence when implanted for an extended period of time.
Without being bound by any theory, the bio-durability of the elastomeric matrix of the present invention can be improved by: a biodurable polymer is selected as the polymeric component of the flowable material used in the sacrificial molding or lyophilization process for preparing the reticulated elastomeric matrix of the present invention. Moreover, other considerations for improving the biopersistence of an elastomeric matrix prepared by processes including polymerization, crosslinking, foaming, and reticulation include selecting the starting components for biopersistence and the desired ratios of these components such that the elastomeric matrix retains the biopersistence of these components. For example, the bio-durability of the elastomeric matrix can be increased by minimizing the possibility of the presence and formation of chemical bonds and groups, such as ester groups, that are susceptible to hydrolysis, such as under conditions of temperature and pH of the patient's body fluids. As another example, after crosslinking and foaming, it is preferred to perform the curing step for about 2 hours or more to minimize the presence of free amino groups in the elastomeric matrix. Moreover, it is important to minimize degradation that occurs during the preparation of the elastomeric matrix by methods well known to those of ordinary skill in the art, for example, degradation that occurs as a result of exposure to shear forces or heat that occurs during mixing, decomposition, crosslinking, and/or foaming.
As described above, the biodurable elastomers and elastomeric matrices are stable in biological environments for extended periods of time. Such products, when they are exposed to the stresses of the biological environment and/or the body, do not show significant signs of fracture, degradation, corrosion, nor significant deterioration of the mechanical properties associated with their use, during the corresponding time of their use. However, minor cracking, splitting or loss of toughness and hardness, sometimes also referred to as ESC or environmental stress cracking, does not affect many of the orthopedic and other applications described herein. Many in vivo applications, such as when elastomeric matrix 10 is used in the treatment of sites of orthopedic applications, expose it to little, if any, mechanical stress and, thus, are less likely to cause mechanical failure that could lead to serious patient consequences. Thus, in the application to which the present invention is directed, the absence of ESCs may not be a prerequisite for suitable elastomers to be bio-sustainable, as the properties of elastomers become less important as endothelialisation, embedding and intracellular growth and proliferation proceeds.
Moreover, in some implant applications, it is contemplated that elastomeric matrix 10 may become muralized (walled-off) or embedded by tissue, scar tissue, etc., or completely integrated into, for example, a tissue to be repaired or a lumen to be treated, after a period of time, for example, 2 weeks to 1 year. Under such conditions, the chances of exposure of the elastomeric matrix 10 to moving or circulating biological fluids are reduced. Thus, the likelihood of biochemical degradation or release of unwanted, potentially harmful, products into the host organ is reduced (if not eliminated).
In another embodiment, the elastomeric matrix has good biopersistence and good biocompatibility, so that the elastomer induces few, if any, adverse reactions in vivo. To this end, in another embodiment of the use of the present invention, the elastomer or other material is free of biologically harmful or dangerous substances or structures that would induce adverse or negative effects in vivo when implanted at the target site for the desired time of implantation. Thus, such elastomers should be completely free or contain only very small, biologically tolerable amounts of cytotoxins, mutagens, carcinogens and/or teratogens. In another particular embodiment, the biological properties of the bio-sustainability of the elastomer used to make the elastomeric matrix 10 include at least one of the following: is resistant to biological degradation; no or very low cytotoxicity, hemotoxicity, carcinogenicity, mutagenicity, or teratogenicity.
Elastomeric matrices prepared from polymerized, crosslinked and foamed elastomers
In another embodiment, the present invention provides porous biopersistent elastomers (which can be used to make the biopersistent reticulated elastomeric matrix 10 described herein) and methods of polymerization, crosslinking, and foaming thereof. In another embodiment, reticulation is then performed.
More specifically, in another embodiment, the present invention provides a method of making a biopersistent elastomeric polyurethane matrix comprising synthesizing the matrix from a polycarbonate polyol component and an isocyanate component by polymerization, crosslinking, and foaming (thereby forming pores), followed by reticulation of the foam to provide a reticulated product. This product, known as a polycarbonate polyurethane, is a polymer containing carbamate groups, for example, formed from the hydroxyl groups of the polycarbonate polyol component and the isocyanate groups of the isocyanate component. In this embodiment, the method employs a controlled chemical reaction to produce a reticulated elastomeric product having good biopersistence. According to the invention, the polymerization is carried out by using a chemical reaction to produce a foam product and avoid the presence of biologically harmful or toxic components therein.
In one embodiment, the above process employs at least one polyol component as a starting material. In this application, the term "polyol component" includes molecules having an average of about two hydroxyl groups per molecule, i.e., difunctional polyols or diols, as well as those molecules having an average of more than 2 hydroxyl groups per molecule, i.e., polyols or multifunctional polyols. Examples of polyols may contain on average about 2 to 5 hydroxyl groups per molecule. In one embodiment, the process uses a difunctional polyol component as a starting material. In this embodiment, because the hydroxyl functionality of the diol is about 2, it cannot be provided with so-called "soft segment" crosslinking of the soft segment. In another embodiment, the process employs a polyfunctional polyol as a polyol component starting material in an amount sufficient to provide a controlled degree of soft segment crosslinking. In another embodiment, the method provides sufficient soft tissue crosslinking to produce a stable foam. In another embodiment, the soft segment is generally comprised of a relatively low molecular weight polyol component, in another embodiment the molecular weight is from about 350 to about 6,000 daltons, and in another embodiment from about 450 to about 4,000 daltons. Thus, these polyols are generally liquids or solids with a low melting point. The soft segment polyol terminates in a hydroxyl group, or a primary or secondary group. In another embodiment, the soft segment polyol component has about 2 hydroxyl groups per molecule. In another embodiment, the soft segment polyol component contains more than 2 hydroxyl groups per molecule. To produce soft segment crosslinking, some polyols require more than two hydroxyl groups per polyol molecule.
In one embodiment, the average number of hydroxyl groups per molecule in the polyol component is about 2. In another embodiment, the average number of hydroxyl groups per molecule in the polyol component is greater than about 2. In another embodiment, the average number of hydroxyl groups per molecule in the polyol component is greater than 2. In one embodiment, the polyol component comprises a plurality of tertiary carbon bonds.
In a specific embodiment, the polyol component is a polyether polyol, a polyester polyol, a polycarbonate polyol, a hydrocarbon polyol, a polysiloxane polyol, a poly (ether-co-ester) polyol, a poly (ether-co-carbonate) polyol, a poly (ether-co-hydrocarbon) polyol, a poly (ether-co-siloxane) polyol, a poly (ester-co-carbonate) polyol, a poly (ester-co-hydrocarbon) polyol, a poly (ester-co-siloxane) polyol, a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, a poly (hydrocarbon-co-siloxane) polyol, or a mixture thereof.
Polyether polyols are oligomers, for example, alkylene oxides such as ethylene oxide or propylene oxide, which polymerize with ethylene glycol or polyhydric alcohols, which result in hydroxyl functionalities greater than 2, allowing soft tissue crosslinking. Polyether polyols are oligomers, such as oligomers of the reaction product of a carboxylic acid and a glycol or triol, such as ethylene adipate, propylene adipate, butylene adipate, diethylene adipate, phthalate, polycaprolactone and castor oil. When the reactants include materials having a hydroxyl functionality greater than 2, such as polyols, soft segment crosslinking may occur.
The polyol of the polycarbonate type is generally produced by reacting a carbonate monomer with one type of alkyl diol or a plurality of types of diols, in each of which the carbon chain length between two hydroxyl groups is different. The carbon chain length between two adjacent carbonic acids is the same as the carbon chain length of the original diol. For example, difunctional polycarbonate polyols can be prepared by reacting 1, 6-hexanediol with a carbonate salt, such as with sodium bicarbonate to produce the polycarbonate type polyol 1, 6-hexanediol carbonate. Commercially available such reaction products have molecular weights between 500 and 5,000. If the polycarbonate polyol is a solid at 25 ℃, it is usually melted before further processing. Alternatively, in another embodiment, the liquid polycarbonate polyol can be prepared from a mixture of alkyl diols, such as all ternary or binary mixtures of 1, 6-hexanediol, cyclohexyldimethanol, and 1, 4-butanediol. Without being bound by any theory, it is believed that this mixture of alkyl diols disrupts the crystallinity of the product polycarbonate polyol, rendering it liquid at 25 ℃, thus turning the foam containing it into a relatively soft foam.
Soft segment crosslinking may occur when the reactants used to prepare the polycarbonate polyol include materials having a hydroxyl functionality greater than 2, such as polyhydroxy alcohols. In preparing the polycarbonate polyol component, a polycarbonate polyol having an average number of hydroxyl groups per molecule of greater than 2, such as a polycarbonate triol, can be prepared by using a material such as n-hexanetriol. To prepare a liquid polycarbonate triol component, a mixture containing other hydroxyl-containing materials, such as cyclohexyltriol and/or butanetriol, is reacted with a carbonate and n-hexanetriol.
Commercial polycarbonate polyols are generally produced by free radical polymerization of diolefins with vinyl monomers, and are therefore typical difunctional hydroxyl terminated materials.
The polysiloxane polyols are oligomers, for example, oligomers containing hydroxy-terminated alkyl-and/or aryl-substituted siloxanes, such as dimethylsiloxanes, biphenylsiloxanes or methylphenylsiloxanes. In preparing the polysiloxane polyol component, polysiloxane polyols having a number of hydroxyl groups per molecule of greater than 2, such as polysiloxane triols, can be prepared by using, for example, methylhydroxymethylsiloxane.
The specific type of polyol is not limited to those formed from a single monomer unit. For example, polyols of the polyethylene type can be prepared from mixtures of ethylene oxide and propylene oxide.
In addition, in another embodiment, a copolymer or co-polyol may be prepared from any of the above polyols by methods well known in the art. Thus, polyol copolymers of the following binary components may be used: poly (ether-co-ester) polyols, poly (ether-co-carbonate) polyols, poly (ether-co-hydrocarbon) polyols, poly (ether-co-siloxane) polyols, poly (ester-co-carbonate) polyols, poly (ester-co-hydrocarbon) polyols, poly (ester-co-siloxane) polyols, poly (carbonate-co-hydrocarbon) polyols, poly (carbonate-co-siloxane) polyols, and poly (hydrocarbon-co-siloxane) polyols. For example, poly (ether-co-ester) polyols can be prepared by copolymerizing polyether units formed from ethylene oxide with polyester units containing ethylene adipate. In another embodiment, the copolymer is a poly (ether-co-carbonate) polyol, a poly (ether-co-hydrocarbon) polyol, a poly (ether-co-siloxane) polyol, a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, a poly (hydrocarbon-co-siloxane) polyol, or a mixture thereof. In another embodiment, the copolymer is a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, a poly (hydrocarbon-co-siloxane) polyol, or a mixture thereof. In another embodiment, the copolymer is a poly (carbonate-co-hydrocarbon) polyol. For example, poly (carbonate-co-hydrocarbon) polyols can be prepared by polymerizing 1, 6-hexanediol, 1, 4-butanediol, and hydrocarbon-type polyols with a carbonate.
In another embodiment, the above polyol component is a polyether polyol, a polycarbonate polyol, a hydrocarbon polyol, a polysiloxane polyol, a poly (ether-co-carbonate) polyol, a poly (ether-co-hydrocarbon) polyol, a poly (ether-co-siloxane) polyol, a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, a poly (hydrocarbon-co-siloxane) polyol, or a mixture thereof. In another embodiment, the polyol component is a polycarbonate polyol, a hydrocarbon polyol, a polysiloxane polyol, a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, a poly (hydrocarbon-co-siloxane) polyol, or a mixture thereof. In another embodiment, the polyol component is a polycarbonate polyol, a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, a poly (hydrocarbon-co-siloxane) polyol, or a mixture thereof. In another embodiment, the polyol component is a polycarbonate polyol, a poly (carbonate-co-hydrocarbon) polyol, a poly (carbonate-co-siloxane) polyol, or a mixture thereof. In another embodiment, the polyol component is a polycarbonate polyol.
Moreover, in another embodiment, mixtures, blends and/or mixed blends of polyols and co-polyols can also be used in the elastomeric matrix of the present invention. In another embodiment, the molecular weight of the polyol is varied. In another embodiment, the polyol functionality is varied.
In another embodiment, because neither the difunctional polycarbonate polyol nor the difunctional hydrocarbon polyol itself is capable of inducing soft segment crosslinking, higher functionality is introduced into the mixture by the use of a crosslinker component having a hydroxyl group functionality greater than 2. In another embodiment, higher functionality is introduced by using an isocyanate component having an isocyanate group functionality greater than 2.
Polycarbonate diols having molecular weights of about 500 to about 5,000 daltons are readily available commercially, as POLY-CD CD220 from Arch chemical company (Norwalk, CT) and PC-1733 from Stahl USA, Inc. (Peabody, MA). Commercial hydrocarbon polyols are available from Sartomer (Exton, Pa.). Commercial polyethers are readily available, e.g. E.g. having a functionality of 3SGP430 andseries are available from BASF corporation (Wyandotte, MI),available from Dow chemical company (Midland, Mich.),andfrom BayAvailable from er corporation (Leverkusen, Germany) and Huntsman corporation (Madison Heights, MI). Commercially available polyester polyols are readily available, e.g. from BASFDow' sPolycaprolactone and VORANOL, BAYCOLL A and Bayer and HuntsmanAnd (4) series. Commercial silicone polyols are readily available, as available from Dow.
The above process also employs at least one isocyanate component and optionally at least one crosslinking agent to provide so-called "hard segments". In the present spirit, the term "isocyanate component" includes molecules containing an average of about 2 isocyanate groups per molecule and molecules containing an average of more than about 2 isocyanate groups per molecule. The isocyanate groups of the isocyanate component may be reacted with the hydrogens of the other components, for example, with the hydrogen of the hydroxyl group of the polyol component, the crosslinking agent and/or the hydrogen of the hydroxyl group of water linked to oxygen or the hydrogen of the amino group linked to nitrogen.
In one embodiment, the average number of isocyanate groups per molecule in the isocyanate component is about 2. In one embodiment, the average number of isocyanate groups per molecule in the isocyanate component is greater than about 2. In a specific embodiment, the average number of isocyanate groups per molecule in the isocyanate component is greater than 2.
The isocyanate index, which is a quantity well known in the art, refers to the molar ratio of the number of isocyanate groups available for reaction in the formulation to the number of groups capable of reacting with those isocyanate groups in the formulation (e.g., diols, polyols, crosslinking agents, and water-when water is present). In one embodiment, the isocyanate index is from about 0.9 to about 1.1. In another embodiment, the isocyanate index is from about 0.9 to about 1.02. In another embodiment, the isocyanate index is from about 0.98 to about 1.02. In another embodiment, the isocyanate index is from about 0.9 to about 1.0. In one embodiment, the isocyanate index is from about 0.9 to about 0.98.
Examples of diisocyanates include aliphatic diisocyanates, isocyanates containing aromatic groups (so-called "aromatic isocyanates"), or mixtures thereof. Aliphatic diisocyanates include tetramethylene diisocyanate, cyclohexylamine-1, 2-diisocyanate, cyclohexylamine-1, 4-diisocyanate, cyclohexyl diisocyanate, isophorone diisocyanate, methylene-cis- (p-cyclohexyl isocyanate) ("H)12MDI "), or mixtures thereof. Aromatic isocyanates include p-phenylene diisocyanate, 4 '-diphenylmethane diisocyanate ("4, 4' -MDI"), 2, 4 '-diphenylmethane diisocyanate ("2, 4' -MDI"), 2, 4-toluene diisocyanate ("2, 4-TDI"), 2, 6-toluene diisocyanate ("2, 6-TDI"), m-tetramethylxylene diisocyanate, or mixtures thereof.
Examples of isocyanates containing an average of more than 2 isocyanate groups per molecule include the adduct of cyclohexyl diisocyanate and water, the former containing about 3 isocyanate groups and being commercially available, for example, from Bayer corporation, and the trimolecular condensate of cyclohexyl diisocyanateThe latter contains about 3 isocyanates and is commercially available, for example from Bayer
In one embodiment, the isocyanate component comprises a mixture of at least about 5% by weight 2, 4 '-MDI and the balance 4, 4' -MDI. In another embodiment, the isocyanate component comprises a mixture of at least 5% by weight of 2, 4 '-MDI and the remainder 4, 4' -MDI. In another embodiment, the isocyanate component comprises a mixture of about 5 to about 50 weight percent 2, 4 '-MDI with the balance being 4, 4' -MDI. In another embodiment, the isocyanate component comprises a mixture of 5 to about 50 weight percent 2, 4 '-MDI with the remainder being 4, 4' -MDI. In another embodiment, the isocyanate component comprises a mixture of about 5 to about 40 weight percent 2, 4 '-MDI with the balance being 4, 4' -MDI. In another embodiment, the isocyanate component comprises a mixture of 5 to about 40 weight percent 2, 4 '-MDI with the remainder being 4, 4' -MDI. In another embodiment, the isocyanate component comprises a mixture of 5 to about 35 weight percent 2, 4 '-MDI with the remainder being 4, 4' -MDI. Without being bound by any theory, it is believed that the use of higher levels of 2, 4 ' -MDI in the 4, 4 ' -MDI mixture results in a softened elastomeric matrix because the asymmetric 2, 4 ' -MDI structure disrupts the crystalline phase of the hard segment.
The stable diisocyanate includes MDI, such as125M, Dow CoCertain products of the series and ISONATE 50 OP; isocyanates containing mixtures of 4, 4 '-MDI and 2, 4' -MDI, e.g. Huntsman9433 and9258 and Bayer MONDUR MRS 2 and MRS 20; TDLs, such as those of Lyondell Corp. (Houston, TX); isophorone, e.g. of Degussa (Germany)H12MDI, such as DESMODUR W from Bayer; and various diisocyanates available from BASF corporation.
Suitable isocyanate components containing an average of more than about 2 isocyanate groups per molecule include the following modified diphenylmethane-diisocyanates:1088 (isocyanate functionality of about 3), ISONATE 143L (isocyanate functionality of about 2.1), PAPI27 (isocyanate functionality of about 2.7), PAPI 94 (isocyanate functionality of about 2.3), PAPI580N (isocyanate functionality of about 3), PAPI 20 (isocyanate functionality of about 3.2), all available from Dow.
Examples of chain extenders include diols, diamines, alkanols, or mixtures thereof. In one embodiment, the chain extender is an aliphatic diol containing from 2 to 10 carbon atoms. In another embodiment, the diol chain extender is selected from the group consisting of ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 1, 4-butanediol, 1, 5-pentanediol, diethylene glycol, triethylene glycol, or mixtures thereof. In another embodiment, the chain extender is a diamine containing from 2 to 10 carbon atoms. In another embodiment, the diamine chain extender is selected from the group consisting of ethylenediamine, 1, 3-butanediamine, 1, 4-butanediamine, 1, 5-pentanediamine, 1, 6-hexanediamine, 1, 7-heptanediamine, 1, 8-octanediamine, isophorone diamine, or mixtures thereof. In another embodiment, the chain extender is an alkanol having 2 to 6 carbon atoms. In another embodiment, the alkanol chain extender is selected from diethanolamine, triethanolamine, isopropanolamine, dimethylethanolamine, methyldiethanolamine, diethylethanolamine, or mixtures thereof.
Commercially available chain extenders include those available from Huntsman corporationDiamine series, triamine series and polyether amine series, CreanoOf vaOf isophorone diamine, air products Corp (Allentown, Pa.)The diamine series, the ethanolamines, diethylethanolamines, and isopropanolamines of Dow, and various chain extenders of Bayer, BASF, and UOP Corp. (Des Plaines, IL).
In a specific embodiment, a small amount of optional components are present to allow crosslinking to occur, such as multifunctional hydroxyl compounds or other crosslinking agents with a functionality greater than 2 (e.g., glycerol). In another embodiment, the optional multifunctional crosslinker is present in an amount just sufficient to result in a stable foam, i.e., a foam that does not collapse to form a non-foam. Further, alternatively, the multifunctional adducts of aliphatic and cycloaliphatic isocyanates may be combined with aromatic diisocyanates to produce crosslinking. Further, alternatively, the multifunctional adducts of aliphatic and cycloaliphatic isocyanates may be combined with aliphatic diisocyanates to produce crosslinking.
Optionally, the above process uses at least one catalyst, which in certain embodiments is selected from blowing catalysts, such as tertiary amines; gel catalysts, such as dibutyl tin dilaurate; or a mixture thereof. In addition, it is well known in the art that tertiary amine catalysts also have a gelling effect, that is, they can be used as blowing and gelling catalysts. Examples of tertiary amine catalysts include those of Toyo Soda Co. (Japan) Of the series, Texaco Chemical Co. (Austin, TX)Series, Th.GoldschmidtCo. (Germany)Andof the series, Rohm and Haas (Philadelphia, PA)Series, Kao Corp. (Japan)Series and QUINCAT series by enterprise chemical Co. Examples of organotin catalysts (organotin catalysts) include those of Witco Corporation (Middlebury, CT)Andof the series, Cosan Chemical Co. (Carlstadt, N.J.)Andseries, Air ProductsAndand (4) series.
In certain embodiments, the above methods employ at least one surfactant. Examples of surfactants include Goldschmidt' s2370, DC 5241 from Dow Coming (Midland, MI), and other non-ionic silicones, such as Dow Corning, air products and General Electric (Waterford, NY) polydimethylsiloxanes.
In certain embodiments, the above methods employ at least one pore opener. Examples of pore openers include Goldschmidt' s501。
The crosslinked polyurethane can be prepared by a prepolymer method, a single plug method, or the like. Specific embodiments regarding the prepolymer are as follows: first, a prepolymer is prepared by a conventional method using at least one isocyanate component (e.g., MDI) and at least one multifunctional soft segment material having a functionality of about 2 (e.g., polyether type soft segment having a functionality of about 3); the prepolymer, optionally at least one catalyst (such as dibutyltin dilaurate), and at least one multifunctional chain extender (such as 1, 4-butanediol) are then mixed in a mixing vessel to cure or crosslink the mixture. In another embodiment, the crosslinking is carried out in a mold. In another embodiment, crosslinking and foaming, i.e. the formation of cells, are carried out together. In another embodiment, the crosslinking and foaming are carried out together in a mold.
Alternatively, a so-called "single plug method" may be used. Embodiments of the single plug process do not require a separate prepolymer preparation step. In one embodiment, starting materials, such as those described above, are mixed in a mixing vessel and then foamed and crosslinked. In another embodiment, the components are heated prior to mixing. In another embodiment, the crosslinking is carried out in a mold. In another embodiment, the crosslinking and foaming are carried out together in a mold. In another embodiment, all components except the isocyanate are mixed in a mixing vessel. The isocyanate is then added (for example with high-speed stirring), whereupon crosslinking and foaming take place. In another embodiment, this foam mixture is poured into a mold and allowed to foam.
In another embodiment, the polyol component is mixed with an isocyanate and other optional additives such as viscosity modifiers, surfactants, and/or pore openers to form a first liquid. In another embodiment, the polyol component is a liquid at the mixing temperature. In another embodiment, the polyol component is a solid and the mixing temperature is increased so that the polyol component is a liquid prior to mixing, such as by heating to increase the mixing temperature. Next, the blowing agent and other optional additives, such as a gelling catalyst and/or a blowing catalyst, are mixed to form a second liquid. The first liquid and the second liquid are then mixed in a mixer, followed by foaming and crosslinking thereof.
In another embodiment, any or all of the methods of the present invention can be used to produce a density greater than 3.4lb/ft3(0.054 g/cc). In this embodiment, no or minimal cross-linking agents are used, such as glycerol; the isocyanate component has a functionality of 2 to 2.3; the isocyanate component consists essentially of MDI; the mass percent of 4, 4' -MDI is more than 55% of the isocyanate component. The polyol component has a molecular weight of about 1,000 to 2,000 daltons. The amount of blowing agent (e.g., water) is adjusted to achieve a density greater than 3.4lb/ft3(0.054 g/cc). Reducing the amount of blowing agent can reduce the number of urea linkages in the material. Any reduction in hardness and/or tensile strength and/or compressive strength resulting from lower crosslinking and/or fewer urea linkages can be compensated for by using difunctional chain extenders, such as butanediol, and/or increasing the density of the foam. Reducing the degree of crosslinking, and thus the foam toughness and elongation at break, results in more effective reticulation because the resulting higher density foam material is better able to withstand the sudden effects that may be produced by the reticulation process with minimal, if any, damage to the struts 16.
In one embodiment, the present invention provides a method for preparing flexible polyurethane capable of being reticulated from a polycarbonate polyol component and an isocyanate component as starting materialsA method for making a durable substrate. In another embodiment, a porous biopersistent elastomer polymerization process is provided for preparing an elastomeric polyurethane matrix, the process comprising combining a polycarbonate polyol component and an aliphatic isocyanate component, such as H12MDI, and mixing.
In another embodiment, the above foam is substantially free of isocyanurate linkages. In another embodiment, the foam is free of isocyanurate linkages. In another embodiment, the foam is substantially free of biuret linkages. In another embodiment, the foam is free of biuret linkages. In another embodiment, the foam is substantially free of allophanate linkages. In another embodiment, the foam is free of allophanate linkages. In another embodiment, the foam is substantially free of isocyanurate and biuret linkages. In another embodiment, the foam is free of isocyanurate and biuret linkages. In another embodiment, the foam is substantially free of isocyanurate linkages and allophanate linkages. In another embodiment, the foam is free of isocyanurate linkages and allophanate linkages. In another embodiment, the foam is substantially free of allophanate linkages and biuret linkages. In another embodiment, the foam is free of allophanate and biuret linkages. In another embodiment, the foam is substantially free of allophanate linkages, biuret linkages and isocyanurate linkages. In another embodiment, the foam is free of allophanate, biuret, and isocyanurate linkages. Without being bound by any particular theory, it is believed that the absence of allophanate, biuret and/or isocyanurate linkages results in lower crosslinking of the hard segments and thus provides a higher degree of flexibility to the elastomeric matrix.
In certain embodiments, additives, such as surfactants and catalysts, may be added that are beneficial to the resulting stable foam. By limiting the amount of these additives to the minimum amount required while maintaining the functionality of each additive, its effect on product toxicity can be controlled.
In one embodiment, elastomeric substrates are prepared having various densities, for example, densities of 0.005 to about 0.15g/cc (about 0.31 to about 9.4 lb/ft)3) The elastomeric matrix of (a). The density can be controlled, for example, by the blowing agent or amount of blowing agent, the isocyanate index, the isocyanate component content of the composition, the exotherm of the reaction, and/or the pressure of the foaming environment.
Examples of blowing agents include water and physical blowing agents, for example, volatile organic chemicals such as hydrocarbons, ethanol, and acetone, and various fluorocarbons and environmentally friendly alternatives thereof, such as hydrofluorocarbons, chlorofluorocarbons, and hydrochlorofluorocarbons. Water reacts with isocyanate groups to produce carbon dioxide which can act as a blowing agent. Also, in certain embodiments, a combination of blowing agents, such as water in combination with a fluorocarbon, may be used. In another embodiment, water is used as the blowing agent. Commercial fluorocarbon blowing agents are available from Huntsman, e.i. dupont DE Nemours and co. (Wilmington, DE), allied m Chemical (Minneapolis, MN) and Honeywell (Morristown, NJ).
In the present application, the amounts of the other components present in the formulation are calculated by mass per 100 parts by mass of the polyol (e.g. polycarbonate polyol, polysiloxane polyol) in the preparation of the elastomeric matrix by foaming and crosslinking as follows: 10 to 90 parts (or grams) of an isocyanate component having an isocyanate index of about 0.85 to about 1.10 (e.g., MDI or mixtures thereof, H12MDI), about 0.5 to about 6.0 parts (or grams) of a blowing agent (e.g., water), about 0.1 to about 2.0 parts (or grams) of a blowing catalyst (e.g., a tertiary amine), about 0.1 to about 8.0 parts (or grams) of a surfactant, and about 0.1 to about 8.0 parts (or grams) of a cell opener. Of course, for a particular formulation, the actual amount of isocyanate component used is related to and depends on the size of the isocyanate index. Further, in the preparation of the elastic base by foaming and crosslinking, the formulation is made for every 100 parts by mass of the polyolThe amounts of the other components present in (a) are calculated by mass as follows: up to about 20 parts (or grams) of a chain extender, up to about 20 parts (or grams) of a crosslinker, up to about 0.5 parts (or grams) of a gel catalyst (e.g., a tin-containing compound), up to about 10 parts (or grams) of a physical blowing agent (e.g., a hydrocarbon, ethanol, acetone, fluorocarbon), and up to about 15 parts (or grams) of a viscosity modifier.
For the purposes of the present invention, the substrate may then be reticulated with appropriate properties as determined by testing, for example, acceptable compression set at body temperature, ventilation, tensile strength and compression properties.
In another embodiment, the gel catalyst, such as a tin catalyst, is omitted, or optionally replaced with another catalyst, such as a tertiary amine. In a specific embodiment, the tertiary amine catalyst comprises one or more non-aromatic amines. In another embodiment, the chemical reaction is conducted such that the tertiary amine catalyst (if used) can be incorporated into the polymer by reaction and such catalyst residues are avoided. In another embodiment, the gel catalyst is omitted and, instead, a higher foaming temperature is used.
In another embodiment, to enhance biopersistence and biocompatibility, the components used in the polymerization process are selected to avoid or minimize the presence of biologically undesirable or biologically vulnerable species in the elastomeric matrix end product.
An alternative embodiment of the invention involves the partial or complete replacement of water as blowing agent by water-soluble spheres, fillers or particles which can be removed after complete cross-linking of the matrix by, for example, washing with water, extraction or dissolution.
Further process of the invention
Referring to fig. 2, a schematic block flow diagram illustrates the overall process of an alternative embodiment of the method of the present invention, wherein an implantable device comprising a bio-sustainable porous reticulated elastomeric matrix 10 may be prepared from raw elastomers or elastomeric agents by one or another different process route.
In the first route, the elastomers prepared using the process of the present invention by employing, for example, a blowing agent during the preparation process contain a large number of pores, as described herein. Specifically, the starting material 40 may comprise, for example, a polyol component, an isocyanate, an optional crosslinking agent, and any other desired additives such as surfactants, etc., which may be used to synthesize a desired elastomeric matrix with or without significant foaming or other cell-generating activity in a synthesis step 42. Suitable starting materials are selected to provide the desired mechanical properties and to enhance biocompatibility and biodurability. In step 48, the elastomeric polymer produced in step 42 is characterized (as described above) for chemical and purity, physical and mechanical properties, and optionally biological properties, resulting in a well-defined elastomeric matrix 50. Alternatively, the characterization data may be used to control or modify step 42 to improve the process or the product, as shown by path 51.
Alternatively, the well-characterized elastomer 50 is prepared from the starting material 40 and supplied by a commercial vendor 60 for use in a production facility. Such elastomers are synthesized according to known methods and subsequently processed into porous materials. An example of this type of elastomer isAn 80A aromatic polyurethane elastomer and a CARBOTHANE PC 3575A aliphatic polyurethane elastomer. The elastomer 50 may be made porous, such as by using a blowing agent in the polymerization reaction or in a post-polymerization step. In a post-polymerization step (e.g., starting from a commercially available exemplary elastomer), the blowing agent can enter the starting material (e.g., by absorption and/or adsorption, optionally under the influence of high temperature and/or pressure) to form an elastomeric matrix containing cells before the blowing gas is released from the blowing agent. In a specific embodiment, the pores are interconnected. Each otherThe number of connections can depend on the following factors: such as the temperature applied to the polymer, the pressure applied to the polymer, the concentration of gas in the polymer, the concentration of gas at the surface of the polymer, the rate of gas release, and/or the manner of gas release.
If desired, in step 52, the elastomeric polymerization agent used in starting material 40 may be selected to avoid the production of harmful by-products or residues, which may be purified if necessary. The polymer synthesis, step 54, is then carried out using the selected and purified starting materials, and avoids the production of harmful by-products or residues. The elastomeric polymer produced in step 54 is then characterized in step 56, as described in step 48, to produce a high quality, well characterized elastomer 50. In another embodiment, the results of these characterizations are fed back into the process control program, as shown by path 58, to facilitate the production of high quality, well characterized elastomers 50.
In one embodiment, the present invention provides reticulated biopersistent elastomeric matrices comprising polymeric components designed specifically for biomedical implantation. The elastomeric matrix comprises a bio-durable polymeric material and is prepared by a process that avoids chemical alteration of the polymer, avoids the formation of unwanted by-products, and avoids residues containing harmful unreacted starting materials. In some cases, foams containing polyurethane and prepared by known techniques may not be suitable for long-term intravascular, orthopedic, and related applications because, for example, there are harmful unreacted starting materials or harmful by-products. In one embodiment, the elastomeric matrix is prepared from a commercially available bio-durably polymeric elastomeric material and avoids chemically altering the starting elastomeric material during the process of preparing the porous and reticulated elastomeric matrix.
In another embodiment, the chemical characteristics of the bio-sustainability of the elastomer used to make the elastomeric matrix 10 include one or more of the following: good oxidation stability; the compounds are free or substantially free of readily biodegradable chemical bonds, e.g., certain polyether linkages or readily hydrolyzable ester linkages, which may be introduced by incorporating a polyether or polyester polyol component into the polyurethane; the chemical characteristics of the product are clear, the product is relatively refined or purified and is free or basically free of harmful impurities, reactants and byproducts; oligomers and the like; molecular weight is clear (unless the elastomer is crosslinked); and is soluble in biocompatible solvents (unless, of course, the elastomer is crosslinked).
In another embodiment, the process-related characteristics of the bio-sustainability of the elastomer used to make the elastomeric matrix 10 (referring to the process used to make the elastomer of the solid phase 12) include one or more of the following: the method is repeated; process control of product consistency; and avoiding or substantially removing harmful impurities, reactants, by-products, oligomers, etc.
In certain embodiments, the pore generation, reticulation and other post-polymerization processes of the present invention are carefully designed and controlled, as described below. To this end, in certain embodiments, the process of the present invention avoids the introduction of harmful residues or adversely affecting the desirable biodurable properties of the starting materials. In another embodiment, the starting material may be further processed and/or characterized to improve, produce, or demonstrate characteristics associated with bio-sustainability. In another particular embodiment, the essential characteristics of the elastomer may be characterized as suitable, and these process features may be employed or controlled to enhance the biodurability in accordance with the teachings of the present specification.
Reticulation of elastomeric matrices
The elastomeric matrix 10 can be subjected to various post-processing treatments to enhance its utility, some of which are described herein and others of which are known to those of ordinary skill in the art. In one embodiment, reticulation of the elastomeric matrix 10 of the present invention (if not already part of the manufacturing process) can be used to remove at least a portion of the internal "windows" present, i.e., the residual cell walls 22 shown in FIG. 1. Reticulation tends to increase porosity and liquid permeability.
Porous or foam materials having some broken cell walls are generally known as "open cell" materials or foams. In contrast, porous materials known as "reticulated" or "at least partially reticulated" are numerous, i.e. at least 40% of the cell walls present in the same porous material, not exclusively consisting of closed pores, are at least partially removed. When the cell walls are at least partially removed by reticulation, adjacent reticulated pores are open, interconnected and in communication with each other. Wherein more, i.e., at least about 65% of the cell walls are removed, is considered "further reticulated". If most, i.e. at least 80% or almost all, i.e. at least 90% of the cell walls are removed, the remaining porous material is considered to be "substantially reticulated" or "fully reticulated", respectively. It should be understood that, according to usage in the art, a mesh material or foam is one that contains an at least partially open interconnected network of pores.
"reticulation" generally refers to the process of at least partially removing the cell walls, not just by breaking or tearing them apart by crushing methods. Moreover, unreasonable crushing can result in fragments that need to be removed by further processing. In another embodiment, the reticulation process substantially completely removes at least a portion of the cell walls. Reticulation may be achieved, for example, by at least partially dissolving away the cell walls, known as "solution reticulation" or "chemical reticulation"; or by at least partially melting, burning, or blasting away the cell walls, respectively referred to as "combustion reticulation", "thermal reticulation", or "knocking reticulation". The molten material produced by melting the cell walls may build up on the pillars. In one embodiment, such a step is used in the process of the present invention to reticulate the elastomeric matrix 10. In another embodiment, any residual gas in the pores of the elastomeric matrix 10 may be evacuated by a process using a vacuum prior to reticulation. In another embodiment, reticulation is accomplished by a plurality of reticulation steps. In another embodiment, two reticulation steps are employed. In another embodiment, the first combustion reticulation is followed by a second combustion reticulation. In another embodiment, combustion reticulation is followed by chemical reticulation. In another embodiment, chemical reticulation is followed by combustion reticulation. In another embodiment, the first chemical reticulation is followed by a second chemical reticulation.
In related embodiments for orthopedic applications and the like, the elastomeric matrix 10 can be reticulated to provide an interconnected pore structure having an average diameter or other largest transverse dimension of at least about 10 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension of at least about 20 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension of at least about 50 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension of at least about 150 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension of at least about 250 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension greater than about 250 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension greater than 250 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension of at least about 450 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension greater than about 450 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension greater than 450 microns. In another embodiment, the elastomeric matrix 10 can be reticulated to provide pores having an average diameter or other largest transverse dimension of at least about 500 microns.
In related embodiments for orthopedic applications and the like, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of no greater than about 600 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of no greater than about 450 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of no greater than about 250 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of no greater than about 150 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of no greater than about 20 microns.
In related embodiments for orthopedic applications and the like, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 10 microns to about 50 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 20 microns to about 150 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 150 microns to about 250 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 250 microns to about 500 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 450 microns to about 600 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 10 microns to about 500 microns. In another embodiment, the elastomeric matrix can be reticulated to provide pores having an average diameter or other largest transverse dimension of from about 10 microns to about 600 microns.
Optionally, the reticulated elastomeric matrix may be purified, for example, by solvent extraction, either before or after reticulation. In one embodiment, any such solvent extraction process, such as extraction with isopropanol or other purification methods, is a relatively mild process that is carried out to avoid or minimize possible adverse effects on the mechanical or chemical properties of the elastomeric matrix that are necessary to achieve the objectives of the present invention.
One embodiment employs chemical reticulation wherein the elastomeric matrix is reticulated in an acid bath containing a mineral acid. Another embodiment employs chemical reticulation wherein the elastomeric matrix is reticulated in a caustic bath containing an inorganic base. Another embodiment employs solvent reticulation, wherein a non-residue volatile solvent is used in the process. Another embodiment employs solvent reticulation, wherein the temperature is raised above 25 ℃. In another embodiment, the elastomeric matrix containing the polycarbonate polyurethane is reticulated with a solvent selected from tetrahydrofuran ("THF"), dimethylacetamide ("DMAC"), dimethylsulfoxide ("DMSO"), dimethylformamide ("DMF"), N-methyl-2-pyrrolidone (also known as meta-pyrrolidone), or mixtures thereof. In another embodiment, the elastomeric matrix comprising the polycarbonate polyurethane is solvent reticulated with THF. In another embodiment, the elastomeric matrix comprising the polycarbonate polyurethane is solvent reticulated with N-methyl-2-pyrrolidone. In another embodiment, the elastomeric matrix comprising a polycarbonate polyurethane is chemically reticulated with a strong base. In another embodiment, the strong base has a pH of at least about 9.
In any of these embodiments of chemical reticulation or solvent reticulation, the reticulated foam described above may optionally be rinsed. In any of these embodiments of chemical reticulation or solvent reticulation, the reticulated foam may be dried.
In one embodiment, combustion reticulation may be employed, in which a flammable gas, such as a mixture of hydrogen and oxygen or a mixture of oxygen and methane, may be ignited, such as by an electrical flash. In another embodiment, the combustion reticulation is performed within a pressure chamber. In another embodiment, the pressure within the pressure chamber is substantially reduced, such as to below about 50-150 microns Hg, by applying a vacuum at least 2 minutes before the hydrogen, oxygen, or mixture thereof is introduced. In another embodiment, the pressure within the pressure chamber is substantially reduced over a plurality of cycles, for example, the pressure is substantially reduced, then a non-reactive gas such as argon or nitrogen is introduced, and then the pressure is substantially reduced before hydrogen, oxygen, or a mixture thereof is introduced. The temperature at which reticulation occurs may be influenced by the maintenance temperature of the chamber and/or the hydrogen/oxygen ratio within the chamber. In another embodiment, the combustion reticulation is followed by an annealing period. In any of these embodiments of combustion reticulation, the reticulated foam optionally may be flushed. In any of these embodiments of combustion reticulation, the reticulated foam optionally may be dried.
In one embodiment, a reticulation procedure is performed to provide an elastic matrix configuration suitable for cellular ingrowth and proliferation into the interior of the matrix. In another embodiment, a reticulation procedure is performed to provide an elastomeric matrix configuration suitable for cellular ingrowth and proliferation throughout the elastomeric matrix configured for implantation, as described herein.
The term "configuration" and like terms are used to indicate the arrangement, shape and size of the various structures to which the term refers. Thus, a structure referred to as a "configuration" is intended to refer to the entire spatial geometry selected or designed to serve a purpose-related structure or portion of a structure.
Elastic matrix in net form prepared by freeze-drying method
In a specific embodiment, the biopersistent reticulated elastomeric matrix of the present invention may be prepared by freeze-drying a flowable polymeric material. In another embodiment, the polymeric material comprises a solution of a solvent-soluble, bio-sustainable elastomer dissolved in a solvent. The flowable polymeric material is subjected to a lyophilization step which comprises solidifying the flowable polymeric material to form a solid, for example, by cooling the solution, and then removing the non-polymeric material, for example, by raising the solvent from the solid under reduced pressure, to provide an at least partially reticulated elastomeric matrix. The at least partially reticulated elastomeric matrix has a bulk density less than the density of the starting polymeric material. In another embodiment, a solution of the biodurable elastomer in a solvent is sufficiently, but not necessarily, completely cured and the solvent is then sublimed from the material to provide an at least partially reticulated elastomeric matrix. By selecting a suitable solvent or solvent mixture to dissolve the polymer, with the assistance of agitation or heating, a homogeneous solution suitable for lyophilization can be obtained by a suitable mixing procedure. In another embodiment, the solution is cooled to a temperature below the freezing temperature of the solution. In another embodiment, the solution is cooled to a temperature above the apparent glass transition temperature of the solid and below the freezing temperature of the solution.
Without being bound by any particular theory, it is believed that during lyophilization, the polymer solution separates in a controlled manner into one of two distinct morphologies: 1) a continuous phase (i.e., solvent) and another phase dispersed in the continuous phase; or 2) two bicontinuous phases. In each case, subsequent removal of the solvent phase produces a porous structure with a range of pore sizes. The holes are usually interconnected. Their shape, size and orientation are all dependent on the nature of the solution and the conditions of the lyophilization process in conventional methods. For example, the lyophilized product has a range of pore sizes that can be varied by methods known in the art by varying, for example, the freezing temperature, the rate of freezing, the density of the crystalline nuclei, the concentration of the polymer, the molecular weight of the polymer, and the type of solvent.
In general, in one embodiment, suitable elastomeric materials for use in lyophilization are well characterized and include elastomers that: which have the desirable mechanical properties described in this specification, and which have chemical properties that are favorable to biopersistence such that they provide sufficient biopersistence for reasonable expectation.
A particular advantage of thermoplastic elastomers such as polyurethanes is their chemical properties in relation to their good biological sustainability. In a particular embodiment, such thermoplastic polyurethane elastomers include polycarbonate polyurethanes, polyester polyurethanes, polyether polyurethanes, polysiloxane polyurethanes, polyurethanes with so-called "hybrid" soft segments, or mixtures thereof. In another embodiment, the thermoplastic polyurethane elastomer comprises polycarbonate polyurethane, polyether polyurethane, polysiloxane polyurethane, mixed soft segment polyurethane, or mixtures thereof. In another embodiment, the thermoplastic polyurethane elastomer comprises polycarbonate polyurethane, polyether polyurethane, mixed soft segment polyurethane, or mixtures thereof. Mixed soft segment polyurethanes are well known in the art and include, for example, polycarbonate-polyester polyurethanes, polycarbonate-polyether polyurethanes, polycarbonate-polysiloxane polyurethanes, polyester-polyether polyurethanes, polyester-polysiloxane polyurethanes, and polyether-polysiloxane polyurethanes. In another embodiment, the thermoplastic polyurethane elastomer contains at least one diisocyanate, at least one chain extender, and at least one diol in the isocyanate component, and may be prepared with any combination of diisocyanates, difunctional chain extenders, and diols, as described in detail above.
In one embodiment, the thermoplastic elastomer has an average molecular weight of about 30,000 to about 500,000 daltons. In another embodiment, the thermoplastic elastomer has an average molecular weight of about 50,000 to about 250,000 daltons.
In one embodiment, some suitable thermoplastic polyurethanes for use in the present invention are suitably characterized in the present specification, and include: polyurethanes with mixed soft segments containing polysiloxane and polyether and/or polycarbonate components, as disclosed by Meijs et al in U.S. patent No.6,313,254; and those disclosed by DiDomenico et al in U.S. Pat. Nos. 6,149,678, 6,111,052 and 5,986,034. In another embodiment, the optional therapeutic agent may be added to a suitable block of other elastomers for use in the practice of the present invention.
Some commercially available thermoplastic elastomers suitable for practicing the present invention include the polycarbonate polyurethane series available from Polymer technology Group Inc. (Berkeley, Calif.). For example, polycarbonate polyurethane polymersThe products of grades with very clear properties of 80A, 55D and 90D are said to have good mechanical properties, no cytotoxicity, mutagenicity, carcinogenicity and non-hemolytic. Another commercially available elastomer suitable for the practice of the present invention is a biopersistent medical grade polycarbonate aromatic polyurethane thermoplastic elastomer A series available from CardioTech International, Inc. Another commercially available elastomer suitable for the practice of the present invention is a thermoplastic polyurethane elastomerSeries, particularly the 2363 series, and more particularly those designated 81A and 85A, are available from Dow chemical company (Midland, Mich.). Other commercially available elastomers suitable for practicing the present invention include those of Viasys Healthcare (Wilmington, MA)Andthese commercial polyurethane polymers are reported to be linear, uncrosslinked polymers, and as such, they are soluble, easy to analyze, and easy to characterize.
Solvents for use in the practice of the present invention for lyophilization include, but are not limited to, THF, DMAC, DMSO, DMF, cyclohexylamine, ethanol, dioxane, N-methyl-2-pyrrolidone, and mixtures thereof. Generally, in one particular embodiment, the amount of polymer in the solution is from about 0.5% to about 30% by mass of the solution, depending on the solubility of the polymer in the solvent and the desired final properties of the reticulated elastomeric matrix. In another embodiment, the amount of polymer in the solution is from about 0.5% to about 15% by mass of the solution.
In addition, additives, such as buffer substances, may be present in the polymer-solvent solution. In one embodiment, the additive does not react with the polymer or solvent. In another embodiment, the additive is a solid material, a buffer substance, a reinforcing material, a porous decorative agent, or a pharmacologically active agent that promotes tissue regeneration or continued growth.
In another embodiment, the polymer solution may contain various inserts mixed with the solution, such as films, sheets, foams, tissues, woven fabrics, non-woven fabrics, bonded or woven textile structures, or implants that do not have a smooth surface. In another embodiment, the solution can be prepared with a structural insert, such as an orthopedic, urological or vascular implant. In another specific embodiment, the inserts comprise at least one biocompatible material and may be non-absorbable and/or absorbable.
The type of morphology of the pores formed during the removal of the non-polymeric material and thereafter remaining in the reticulated elastomeric matrix is a function of such variables as, for example, the thermodynamics of the solution, the solidification rate and the temperature at which the solution cools, the concentration of polymer in the solution, and the type of nuclei (e.g., uniform or non-uniform). In a specific embodiment, the freeze dryer of the polymer solution cools to-70 ℃. In another embodiment, the lyophilizer of the polymer solution is cooled to-40 ℃. In a specific embodiment, the freeze dryer comprises a rack on which the polymer solution is placed, which is cooled to-70 ℃. In another embodiment, the rack is cooled to-40 ℃. The cooling rate of the coagulated polymer solution may be from about 0.2 deg.C/min to about 2.5 deg.C/min.
At the beginning of the lyophilization process of a particular embodiment, the polymer solution described above is placed in molds, and the molds are placed into a lyophilizer. The mold walls are cooled in the freeze dryer, for example, as they contact the freeze drying shelves. The temperature of the freeze dryer is reduced at the required cooling rate until the final cooling temperature is obtained. For example, in a freeze dryer, molds are placed on a freezing rack and the heat transfer surface moves from the freeze dryer rack up through the mold walls into the polymer solution. The rate at which this transfer surface advances affects the nucleation and orientation of the frozen structure. This rate depends on, for example, the cooling rate and the thermal conductivity of the mold. When the temperature of the solution is below the gel-forming and/or freezing point of the solvent, the solution may be divided into a continuous phase and a dispersed phase, or bicontinuous phase, as described above. The morphology of the phase separation system was fixed during the freezing step of the lyophilization process. When the frozen material is exposed to reduced pressure, the pores are initially created by sublimating the solvent.
Without being bound by any particular theory, it is generally believed that the higher the concentration of the polymer solution, the higher the viscosity (possibly due to higher concentration or higher molecular weight of the polymer) or the higher the cooling rate, the smaller the pores formed in the freeze-dried product, while the lower the concentration of the polymer solution, the viscosity (possibly due to lower concentration or lower molecular weight of the polymer) or the slower the cooling rate, the larger the pores formed in the freeze-dried product.
The lyophilization process is further illustrated in example 17.
Producing features of internal bore
Within the pores 20, the elastomeric matrix 10 optionally has other features than the voids or gas-filled spaces described above. In a particular embodiment, the elastomeric matrix 10 may have as part of its microstructure features referred to herein as "pores," i.e., features of the elastomeric matrix 10 that are located "within pores. In one embodiment, the interior surfaces of the pores 20 may be "coated intrapore," i.e., coated or treated to impart a degree of desired characteristics to these surfaces, such as hydrophilicity. The coating or treatment medium may have the additional ability to transfer or bind the active component, thereby allowing the active component to be preferentially delivered to the pores 20. In a particular embodiment, such a coating medium or treatment may be used to facilitate covalent bonding of the material to the surface of the internal pores, such as described in the claimed priority application. In another embodiment, the coating comprises a biodegradable polymer and an inorganic component, such as hydroxyapatite. The hydrophilic treatment may be achieved by exposing the elastomer to a hydrophilic environment, such as an aqueous solution, during placement of the elastomer, or by chemical or radiation treatment of the prepared reticulated elastomeric matrix 10 by other methods known in the art.
Furthermore, one or more coatings may be created intrapore by contacting the film in a liquid coating solution or molten state to form a biocompatible polymer under suitable conditions that allow the formation of a biocompatible polymer film. In a particular embodiment, the polymer used for such a coating is a film-forming biocompatible polymer having a molecular weight high enough not to be soft or tacky. The polymer is also bound to the solid phase 12. In another embodiment, the binding force is such that: the polymer film does not break or move during handling or application of the reticulated elastomeric matrix 10.
Suitable biocompatible polymers include polyamides, polyolefins (e.g., polypropylene, polyethylene), non-absorbable polyesters (e.g., polyethylene terephthalate), and bioabsorbable aliphatic polyesters (e.g., lactic acid, glycolic acid, lactide, glycolide, p-dioxanone, trimethylene carbonate, epsilon-caprolactone, or mixed homopolymers and copolymers thereof). Also, biocompatible polymers include film-forming bioabsorbable polymers including aliphatic polyesters, poly (amino acids), copoly (ether-esters), polyalkylene oxalates, polyamides, poly (iminocarbonates), polyorthoesters, polyoxaesters (including polyoxaesters containing amino groups), polyurethanes, polyanhydrides, polyphosphazenes, biomolecules, and mixtures thereof. In the present invention, the aliphatic polyesters include lactide (including d-, 1-and meso-lactide of lactic acid), epsilon-caprolactone, glycolide (including glycolic acid), hydroxybutyrate, hydroxyvalerate, p-dioxanone, trimethylene carbonate (and its alkyl derivatives), 1, 4-dioxan-2-one, 1, 5-dioxan-2-one, 6, 6-methyl-1, 4-dioxan-2-one, or mixtures thereof.
Biocompatible polymers also include film-forming biocompatible polymers having relatively low chronic tissue reaction, such as polyurethanes, silicones, poly (meth) acrylates, polyesters, polyalkyl oxides (such as polyethylene oxide), polyvinyl alcohol, polyethylene glycol, and polyvinylpyrrolidone, and hydrogels such as those formed from crosslinked polyvinylpyrrolidone and polyesters. Other polymers may also be used as biocompatible polymeric materials provided that they are capable of being dissolved, cured or polymerized. Such polymers and copolymers include polyolefins, polyisobutylene, and copolymers of ethylene-alpha-olefins; acrylic polymers (including methacrylates) and copolymers; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile; a polyvinyl ketone; polyaromatic vinyls such as polystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers of ethylene monomers and copolymers of ethylene with alpha-olefins, such as ethylene-methyl acrylate copolymers and ethylene-vinyl acetate copolymers; acrylonitrile-styrene copolymers; an ABS resin; polyamides, such as nylon-66 and polycaprolactam; an alkyd resin; a polycarbonate; polyformaldehyde; a polyimide; a polyether; an epoxy resin; a polyurethane; artificial fibers; rayon triacetate; cellophane; cellulose and its derivatives, such as cellulose acetate, cellulose acetate butyrate, cellulose nitrate, cellulose propionate and ether cellulose (e.g. carboxymethyl cellulose, hydroxyalkyl cellulose); or a mixture thereof. In the present invention, the polyamide includes polyamides corresponding to the following general formula:
-N(H)-(CH2)n-C (O) -and-N (H) -CH2)x-N(H)-C(O)-(CH2)y-C(O)-
Wherein N is an integer between about 4 and about 13, x is an integer between about 4 and about 12, and y is an integer between about 4 and about 16. It should be understood that the above list of materials is exemplary only and not limiting.
Devices made from reticulated elastomeric matrix 10 are typically coated with a polymer, optionally containing a pharmaceutically active agent such as a therapeutic agent or drug, by simple dipping or spraying of the coating. In one embodiment, the coating is a solution and the polymer is present in the coating solution in an amount of about 1% to about 40% by weight. In another embodiment, the polymer is present in the coating solution in an amount of about 1% to about 20% by weight. In another embodiment, the polymer is present in the coating solution in an amount of about 1% to about 10% by weight.
Proper balancing of viscosity, polymer deposition level, wetting rate and evaporation rate of the solvent that completely coats the solid phase 12 need to be considered in selecting a solvent or solvent mixture for the coating solution, as is well known in the art. In one embodiment, a suitable solvent is selected to render the polymer soluble in the solvent. In another embodiment, the solvent is substantially completely removed from the coating. In another embodiment, the solvent is non-toxic, non-carcinogenic, and environmentally friendly. The mixed solvent system facilitates control of viscosity and evaporation rate. In all cases, the solvent should not react with the coated polymer. Solvents include, but are not limited to, acetone, N-methylpyrrolidone ("NMP"), DMSO, toluene, dichloromethane, chloroform, 1, 1, 2-trichloroethane ("TCE"), various fluorochloroalkanes, dioxane, ethyl acetate, THF, DMF, and DMAC.
In another embodiment, the film forming coating polymer is a thermoplastic polymer that is melted into the pores 20 of the elastomeric matrix 10, forming a coating on at least a portion of the solid phase material 12 of the elastomeric matrix 10 when cooled or solidified. In another embodiment, the processing temperature of the thermoplastic coating polymer in the molten state is above 60 ℃. In another embodiment, the processing temperature of the thermoplastic coating polymer in the molten state is above 90 ℃. In another embodiment, the thermoplastic covering polymer in the molten state has a processing temperature above 120 ℃.
In yet another embodiment of the present invention, as described in detail below, a portion or all of the pores 20 of the elastomeric matrix 10 are coated or filled with an intracellular growth promoting agent. In another embodiment, the accelerator is foamed. In another embodiment, the accelerator is present in the form of a thin layer. The enhancer may be a biodegradable material that enhances the in vivo growth of cells into the elastomeric matrix 10. The promoter comprises naturally occurring materials which are enzymatically hydrolyzed or water-labile in the human body, such as fibrin, fibrinogen, collagen, elastin, hyaluronic acid and absorbable biocompatible polysaccharides such as chitosan, starch, fatty acids (and esters thereof), glucose-polysaccharides and hyaluronic acid. In certain embodiments, the pore surfaces of elastomeric matrix 10 are coated or infused, as described above, with or with an enhancer in place of or in addition to the biocompatible polymer to enhance cellular ingrowth and proliferation.
In one embodiment, the coating or infusion is performed to ensure that the product is a "combined elastic implantable device," i.e., the reticulated elastomeric matrix and coating described herein remain sufficiently elastic after being compressed so that it can be delivered by a delivery device such as a catheter, syringe, or endoscope. Some embodiments of such a combined elastic implantable device are illustrated in a non-limiting manner with collagen as an example, but it should be understood that other materials may be substituted for collagen, as described above.
One embodiment of the invention is a method of making a combined elastic implantable device comprising:
a) injecting an aqueous collagen slurry into the pores of a reticulated porous elastomer, such as the pores of an elastomeric matrix 10, which elastomeric matrix 10 optionally may be a biodurable elastomeric product;
b) removing water, optionally by lyophilization, to produce a collagen coating on at least a portion of the pore surfaces of the reticulated porous elastomer, wherein optionally the collagen coating comprises a network of interconnected pores.
The collagen may be injected by pressing, such as by compressing an aqueous collagen slurry, suspension or solution into the pores of the elastomeric matrix. The collagen may be of type I, II, or III or mixtures thereof. In a specific embodiment, the collagen type comprises at least 90% type I collagen. The collagen concentration is about 0.3% to about 2.0% (by mass), and the pH of the slurry, suspension or aqueous solution is adjusted to about 2.6 to about 5.0 upon lyophilization. Alternatively, the collagen may be injected into the elastomeric matrix by dipping the elastomeric matrix into a collagen slurry.
The porous phase 14 of the resilient implantable device of the above combination is somewhat reduced in volume as compared to the uncoated reticulated elastomer. In a specific embodiment, the combined elastic implantable device maintains good liquid permeability and sufficient porosity for the ingrowth and proliferation of fibroblasts or other cells.
Optionally, the lyophilized collagen may be cross-linked to control the rate of enzymatic degradation of the collagen coating in vivo and/or to control the ability of the collagen coating to bind to the elastomeric matrix 10. The collagen is crosslinked by methods well known in the art, such as heating in a vacuum vessel, heating in a sufficiently dry inert gas, contacting the collagen with formaldehyde vapor, or using glutaraldehyde. Without being bound by any particular theory, it is believed that when the combined elastomeric implantable device is implanted, the tissue forming agents, such as fibroblasts, having a high affinity for collagen, are more likely to invade the collagen-coated elastomeric matrix 10 than an uncoated matrix. Without being bound by any particular theory, it is further believed that as the enzymes of collagen degrade, new tissue invades and fills the space left by the degraded collagen, while also penetrating and filling other available space in the elastomeric matrix 10. The collagen coating or filling of the elastomeric matrix 10 is believed, without being bound by any particular theory, to have an additional benefit on its structural integrity resulting from the reinforcing effect within the pores 20 of the elastomeric matrix 10, which provides greater stiffness and structural stability to the various configurations of the elastomeric matrix 10.
Methods for preparing collagen-coated composite elastic implantable devices are illustrated in examples 5 and 11. Other methods will be apparent to those of ordinary skill in the art.
Coated implantable devices
In certain applications, at least a portion of the outer or macroscopic surface of a device made from the elastomeric matrix 10 is coated or fused to present a smaller macroscopic surface area (since the internal surface area of the pores below the surface cannot be present). Without being bound by any particular theory, it is believed that this reduced surface area makes it more likely and easier to deliver and transport through long tortuous pathways within the delivery device. Surface coatings or fusions alter the "porosity of the surface," i.e., at least partially reduce the percentage of pores that open to the surface; or to the extent that the pores of the coated or fused surface are completely closed, i.e., the surface is not porous, since substantially no pores remain on the coated or fused surface. However, surface coating or fusing still allows the internal interconnected pore structure of the elastomeric matrix 10 to remain open to the interior and other uncoated or unfused surfaces, e.g., the portions of the coated or fused pores not located on the surface remain interconnected with other pores, and those pores remaining open to the surface promote cellular ingrowth and proliferation. In one embodiment, the coated and uncoated surfaces are at right angles to each other. In another embodiment, the coated and uncoated surfaces are at an acute angle to each other. In another embodiment, the coated and uncoated surfaces are adjacent. In a specific embodiment, the coated and uncoated surfaces are not adjacent. In one embodiment, the coated and uncoated surfaces are in contact with each other. In a specific embodiment, the coated and uncoated surfaces do not contact each other.
In other applications, one or more of the macroscopic surfaces of the implantable device made from the reticulated elastomeric matrix 10 may be coated, fused, or melted to improve its adhesion efficiency to the attachment means (e.g., anchors or sutures) so that the attachment means will not be torn or pulled from the implantable device. Without being bound by any particular theory, as discussed above, it is believed that additionally anchoring contact to macroscopic surfaces on the implantable device inhibits tearing or pull-out by reducing voids and increasing resistance.
The fusion and/or selective melting of the macro skin of the elastomeric matrix 10 may be accomplished by several different methods. In one embodiment, the elastomeric matrix 10 is cut into a size and shape suitable for the manufacture of the final implantable device using a knife or blade that is heated to an elevated temperature, such as described in example 18. In another embodiment, a suitably shaped and sized device is cut from a larger piece of elastomeric matrix 10 using a laser cutting device, during which the surfaces in contact with the laser beam are fused. In another embodiment, a cold laser cutting device is used to cut a device of appropriate shape and size. In another embodiment, a device of suitable size and shape can be manufactured by a thermal compression process using a hot mold. A slightly larger elastomeric matrix 10 cut from a larger piece may be placed in a heated mold. The mold closes the cut pieces to reduce their overall size to the appropriate size and sets and fuses the surfaces in contact with the hot mold, as described in example 9. In each of the embodiments described above, in one embodiment, the treatment temperature for both sizing and sizing is greater than about 15 ℃. In another embodiment, the treatment temperature for both sizing and sizing is greater than about 100 ℃. In another embodiment, the treatment temperature for both sizing and sizing is greater than about 130 ℃. In another embodiment, the macroscopic surface layer and/or the parts that are not fused during the fusion of the macroscopic surfaces are protected from exposure by covering them.
The coating of the macroscopic surface may be made of biocompatible polymers, including biodegradable and non-biodegradable polymers. Suitable biocompatible polymers include those disclosed in the preceding section. It is to be understood that the material list is illustrative only and not limiting. In one embodiment, the pores of the surface are closed by the use of an absorbable polymer melt coating on the shaped elastomeric matrix. The elastomeric matrix and the coating together comprise the device. In another embodiment, the device is formed by occluding pores in the surface by coating a solution of an absorbable polymer onto a shaped elastic matrix. In yet another embodiment, the coated substrate and the elastomeric substrate together occupy a volume greater than the volume occupied by the uncoated elastomeric substrate alone.
The coating of the elastomeric matrix 10 can be carried out, for example, by dipping or spraying the polymer into a coating solution containing the polymer or the polymer mixed with the pharmaceutically active agent. In one embodiment, the coating solution has a polymer content of about 1% to about 40% by weight. In another embodiment, the coating solution has a polymer content of about 1% to about 20% by weight. In another embodiment, the coating solution has a polymer content of about 1% to about 10% by weight. In another embodiment, the macroscopic surface layer and/or the part thereof not solution coated is protected from exposure by covering it with a solution coating. The solvent or solvent mixture used to coat the solution is selected as described in the previous section (i.e., the section "create internal pore characteristics").
In one embodiment, the coating of the elastomeric matrix 10 may be performed by a method comprising: melt film-forming coating polymers and apply these melted polymers to the elastomeric substrate 10 by dip coating, such as described in example 10. In another embodiment, the coating of the elastomeric matrix 10 may be performed by a method comprising: the molten film forms the coating polymer and then the molten polymer is applied as a thin layer of molten polymer to the core formed by the elastomeric matrix 10 using a die in a process such as extrusion or co-extrusion. In both embodiments, the molten polymer coats the macroscopic surface and spans or blocks the pores on the surface, but does not appreciably penetrate into the interior of the pores. Without being bound to any particular theory, it is believed that this is because the molten polymer has a high viscosity. Thus, the network character of both the portion of the elastomeric matrix remote from the macroscopic surface and the portion of the macroscopic surface of the elastomeric matrix not in contact with the molten polymer is retained. Upon cooling and solidification, the molten polymer forms a solid coating on the elastomeric matrix 10. In one embodiment, the molten thermoplastic coating polymer is treated at a temperature of at least about 60 ℃. In another embodiment, the molten thermoplastic coating polymer has a processing temperature of at least about 90 ℃. In another embodiment, the molten thermoplastic coating polymer has a processing temperature of at least about 120 ℃. In another embodiment, the macroscopic surface layer and/or the parts not melt-coated are protected from exposure by covering it when melt-coating the macroscopic surface.
Another embodiment of the present invention employs a collagen-coated, combined elastic implantable device configured as a sleeve-like extension around the implantable device, as described above. The collagen matrix sleeve may be implanted at the site of tissue repair and regeneration, or may be implanted near or in contact with the site. Such positioning enables the collagen matrix sleeve to be used to help retain the elastic matrix, facilitate tissue seal formation and help prevent leakage. In a particular embodiment, the presence of collagen in the elastomeric matrix 10 can enhance cellular ingrowth and proliferation and improve mechanical stability by enhancing the attachment of fibroblasts to the collagen. The presence of collagen can stimulate the cells to penetrate earlier and/or more completely into the interconnected pores of the elastomeric matrix 10.
Tissue culture
The cell types that the biosustainable reticulated elastomeric matrix of the present invention is capable of supporting include cells that secrete structural proteins and cells that produce proteins characteristic of organ function. The ability of the elastomeric matrix to allow coexistence of multiple cell types and to support protein secreting cells demonstrates that the elastomeric matrix can be used for organ growth and organ reconstruction in vitro or in vivo. In addition, the biodurable reticulated elastomeric matrix may also be used for large-scale culture of human cell lines for implantation into the body in a number of applications, including implantation of fibroblasts, chondrocytes, osteoblasts, osteoclasts, bone cells, synovial cells, bone marrow stromal cells, stem cells, fibrochondrocytes, endothelial cells, smooth muscle cells, adipocytes, cardiac muscle cells, keratinocytes, hepatocytes, leukocytes, macrophages, endocrine cells, genitourinary cells, lymphatic cells, pancreatic islet cells, muscle cells, intestinal cells, kidney cells, vascular cells, thyroid cells, parathyroid cells, adrenal-hypothalamic-pituitary axis cells, bile duct cells, ovarian or testicular cells, salivary secretory cells, kidney cells, epithelial cells, nerve cells, stem cells, cells, Progenitor cells, myoblasts and intestinal cells.
The method of generating new tissue can be performed by implanting cells seeded on an elastomeric matrix (either prior to or simultaneously with implantation or with implantation followed by seeding). In this case, the elastomeric matrix may be designed to be closed to protect the implanted cells from the immune system of the human body; it can also be designed to be open to facilitate the integration of new cells into the human body. Thus, in another embodiment, the cells can be integrated (i.e., cultured and propagated) onto the elastomeric matrix before, simultaneously with, or after the elastomeric matrix is implanted in vivo.
In another embodiment, for tissue repair or tissue regeneration, implantable devices made from a biodurable reticulated elastomeric matrix are seeded with a cell and cultured prior to insertion into a patient (optionally via a delivery device). The tissue or cell culture is necessarily carried out in a suitable medium with or without stimulating factors such as pressure or positioning. Cells include fibroblasts, chondrocytes, osteoblasts, osteoclasts, osteocytes, synovial cells, bone marrow stromal cells, stem cells, fibrochondrocytes, endothelial cells, and smooth muscle cells.
The surface of the bio-sustainable reticulated elastomeric matrix having different pore morphologies, sizes, shapes and orientations allows the culturing of different types of cells, thereby developing cellular tissue engineering implantable devices specifically targeted for orthopedic applications, particularly for applications in soft tissue attachment, repair, regeneration, peri-accretion and/or support of the spine, shoulder, knee, hand or joint, and the growth of prosthetic organs. In another embodiment, all surfaces of the bio-sustainable reticulated elastomeric matrix possessing different pore morphologies, sizes, shapes and orientations can be subjected to such culturing.
In another embodiment, the biodurable reticulated elastomeric matrix of the present invention may be used in a mammary prosthesis, pacemaker housing, LVAD bladder area or as a tissue bridging matrix.
Delivery of pharmaceutically active agents
In another embodiment, the film-forming polymer used to coat reticulated elastomeric matrix 10 may provide a vehicle for the delivery and/or controlled release of a pharmaceutically active agent (e.g., drug), as described in the claimed priority application. In another embodiment, a pharmaceutically active agent is mixed with, covalently bound to, and/or adsorbed in or on the coating of elastomeric matrix 10 to form a pharmaceutical composition. In another embodiment, the components, polymers and/or mixtures used to form the foam contain a pharmaceutically active agent. To form such a foam, the aforementioned components, polymers and/or mixtures are mixed with the pharmaceutically active agent prior to the manufacture of the foam; or after manufacture, the pharmaceutically active agent is loaded onto the foam.
In one embodiment, the coating polymer and the pharmaceutically active agent have a common solvent. This can result in a coating that is a solution. In another embodiment, the pharmaceutically active agent may be present as a solid dispersion in a solution of the coating polymer dissolved in a solvent.
The reticulated elastomeric matrix 10 containing the pharmaceutically active agent may be prepared as follows: one or more pharmaceutically active agents are mixed with the polymer used to make the foam, with the solvent or with the polymer-solvent mixture and foamed. Alternatively, in one embodiment, the pharmaceutically active agent may be applied to the foam using a pharmaceutically acceptable carrier. If melt coating is used, then, in another embodiment, the pharmaceutically active agent withstands the melt processing temperature without significant loss of potency.
Formulations containing pharmaceutically active agents can be prepared by: one or more pharmaceutically active agents are mixed with, covalently bound to, and/or adsorbed onto the coating of the reticulated elastomeric matrix 10, or are incorporated into a hydrophilic or hydrophobic coating. The pharmaceutically active agent may be present as a liquid, finely divided solid or in another suitable physical form. Typically, but optionally, the matrix may contain one or more conventional additives such as diluents, carriers, excipients, stabilizers and the like.
In another embodiment, the top coating may be used to delay the release of the pharmaceutically active agent. In another embodiment, the top coating may be used as a matrix for the delivery of another pharmaceutically active agent. Layered coatings comprising layers of fast and slow hydrolyzing polymers may be used to release the pharmaceutically active agent in stages or to control the release of different pharmaceutically active agents in different layers. The polymer blend may also be used to control the release rate of different pharmaceutically active agents or to provide a balance between coating characteristics (e.g., elasticity, toughness) and drug delivery (e.g., release characteristics) characteristics. Polymers with different solvent solubilities may be used to form different polymer coatings for delivery of different pharmaceutically active agents or to control the release of pharmaceutically active agents.
The amount of pharmaceutically active agent present depends on the particular pharmaceutically active agent used and the disease being treated. In a specific embodiment, the pharmaceutically active agent is present in an effective amount. In another embodiment, the pharmaceutically active agent is present in an amount from about 0.01% to about 60% by weight of the coating. In another embodiment, the pharmaceutically active agent is present in an amount from about 0.01% to about 40% by weight of the coating. In another embodiment, the pharmaceutically active agent is present in an amount from about 0.1% to about 20% by weight of the coating.
Many different pharmaceutically active agents and reticulated elastomeric matrices may be used in combination. Generally speaking, pharmaceutically active agents that may be administered by the pharmaceutical combination of the present invention include, but are not limited to, any therapeutically or pharmaceutically active agent (including, but not limited to, nucleic acids, proteins, lipids, and carbohydrates) that possesses the desired physiological characteristics for the implantation site or administration by the pharmaceutical combination of the present invention. Therapeutic agents include, but are not limited to, anti-infective agents, such as antibiotics and antivirals; chemotherapeutic agents, such as anticancer agents; an anti-rejection agent; analgesics and analgesic compositions; an anti-inflammatory agent; hormones, such as steroids; growth factors (including but not limited to cytokines, chemokines, and interleukins) and other natural or genetically engineered proteins, glycans, glycoproteins, and lipoproteins. These growth factors are described in detail in Vicki Rosen and The Cellular and Molecular Basis of bone Formation and repair, R.G.Landes Company, incorporated herein by reference in their entirety. Other therapeutic agents include thrombin inhibitors, antithrombin agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, surface glycoprotein receptor inhibitors, antiplatelet agents, antimitotic agents, microtubule inhibitors, antisecretory agents, actin inhibitors, remodeling inhibitors, antisense nucleic acids, antimetabolites, antiproliferative agents, anticancer chemotherapeutic agents, anti-inflammatory steroids, non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, Angiotensin Converting Enzyme (ACE) inhibitors, free radical scavengers, chelators, antioxidants, antipolyases, antiviral agents, Phototherpeutic agents and gene therapy agents.
In addition, various proteins (including short chain peptides), growth agents, chemotactic agents, growth factor receptors, or ceramic particles may be added to the foam during processing; after the foams are formed, they can be adsorbed onto the foam surface or packed into the foam. For example, in one embodiment, the pores of the foam can be partially or completely filled with biocompatible resorbable synthetic or biological polymers (e.g., collagen or elastin), biocompatible ceramic materials (hydroxyapatite), and mixtures thereof, and may optionally contain materials that promote tissue growth through the device. Such tissue growth materials include, but are not limited to, autograft, allograft or allograft bone, bone marrow and morphogenic proteins. Biopolymers can also be used as conducting or chemotactic materials, or as delivery vehicles for growth factors. Examples of the biopolymer include recombinant collagen, collagen of animal origin, elastin, and hyaluronic acid. A pharmaceutically active coating or surface treatment may also be present on the surface of the material, for example, bioactive peptide sequences (RGD's) can be attached to the surface to facilitate protein uptake and subsequent cell tissue attachment.
Bioactive molecules include, but are not limited to, proteins, collagens (including types IV and XVIII), fibrillar collagens (including types I, II, III, V, and XI), FACIT collagens (types IX, XII, XIV), other collagens (types VI, VII, and MDI), short chain collagens (types VIII, X), elastin, kinetin-1, fibrillin, fibronectin, fibrin, fibrinogen, proteoglycans, fibromodulins, fibulin, phosphatidylinositolglycan, vitronectin, laminin, nidogen, matrilin, perlecan, heparin, heparan sulfate, decorin, filaggrin, keratin, connexin (syndecan), transmembrane heparin sulfate proteoglycans (agrin), integrins, polymerins (agregregac), biglycan, bone sialoprotein, cartilage matrix protein, collagen, cat-301 proteoglycan, CD44, cholinesterase, HB-GAM, hyaluronic acid binding protein, mucin, osteopontin, plasminogen activator inhibitor, restricin, filaggrin, tenascin, thrombospondin, tissue-type plasminogen activator, urokinase-type plasminogen activator, Versican (Versican), wenweibull's factor (von Willebrand factor), dextran, arabinogalactan, polyglucose, polylactide-glycolide (polylactide-glycolide), alginate, pullulan, gelatin, and albumin.
Other biologically active molecules include, but are not limited to, cell adhesion molecules and cell matrix proteins (matricellular proteins), which in turn include immunoglobulins (Ig, including monoclonal and polyclonal antibodies), cadherin, integrins, selectins, and the H-CAM superfamily. Examples of such include, but are not limited to AMOG, CD2, CD4, CDS, C-CAM (CELL-CAM 105), CELL surface galactosyltransferase, connexin, desmocollin, desmoglein, axon fascin, F11, GPIb-IX complex, intercellular adhesion molecules, leukocyte common antigen protein tyrosine phosphate (LCA, CD45), LFA-1, LFA-3, Mannose Binding Protein (MBP), MTJC18, myelin-associated glycoprotein (MAG), neuronal adhesion molecules (NCAM), fascin, glial, neurochemokine, netrin, PECAM-1, PH-20, semaphorin, TAG-1, VCAM-1, SPARC/osteonectin, CCN1(CYR61), CCN2(CTGF, connective tissue growth factor), CCN3(NOV), CCN4(WISP-1), CCN5(WISP-2), CCN6(WISP-3), encapsulating (occluding) and blocking (claudin). Growth factors include, but are not limited to, BMP's (1-7), BMP-like proteins (GFD-5, -7, -8), Epidermal Growth Factor (EGF), Erythropoietin (EPO), Fiber Growth Factor (FGF), Growth Hormone (GH), ghRF, granulocyte stimulating factor (G-CSF), granulocyte-macrophage stimulating factor (GM-CSF), insulin-like growth factor (IGF-I, IGF-II), insulin-like growth factor binding protein (IGFBP), macrophage stimulating factor (M-CSF), multi-cell stimulating factor (II-3), platelet-derived growth factor (PDGF), tumor growth factors (TGF- α, TGF- β), tumor necrosis factor (TNF- α), vascular endothelial growth factors (VEGF's), Angiopoietins, placental growth factor (PIGF), interleukins, and receptor proteins or other molecules thought to bind to the aforementioned factors. Short chain peptides include, but are not limited to (named by the one-letter amino acid code) RGD, EILDV, RGDS, RGES, RFDS, GRDGS, GRGS, GRGDTP, and QPPRARI.
Other post-treatment of reticulated elastomeric matrices
In addition to reticulating and imparting internal pore characteristics as already discussed above, the elastomeric matrix 10 can be subjected to further processing steps. For example, the internal porosity of the elastomeric matrix 10 may be hydrophilically treated, as described above, either by post-treatment or by placing the elastomeric matrix in a hydrophilic environment, thereby rendering the microscopic surface more chemically reactive. In another embodiment, biologically useful compounds, or controlled release compositions containing them, may be attached to the surface of the inner pore for local delivery and release, and these embodiments are described in the claimed priority application.
In another embodiment, the product made from the elastomeric matrix 10 of the present invention can be annealed to stabilize the structure. Annealing at elevated temperatures can increase the crystallinity of the semi-crystalline polyurethane. Structural stability and/or additional crystallinity can provide enhanced storage stability for implantable devices made with elastomeric matrix 10. In another embodiment, the annealing is performed at a temperature in excess of about 50 ℃. In another embodiment, the annealing is performed at a temperature in excess of about 100 ℃. In another embodiment, the annealing is performed at a temperature in excess of about 125 ℃. In another embodiment, the annealing is performed for a time of at least about 2 hours. In another embodiment, the annealing is performed for a time period of about 4 hours to about 8 hours. In crosslinked polyurethanes, processing at elevated temperatures can also promote structural stability and long-term storage stability.
The elastomeric matrix 10 may also be formed into various shapes and sizes during the manufacturing or manufacturing process. The shape may be an operational configuration, such as any of the shapes and configurations described in the claimed priority application, or a bulk stocked shape. The stored articles may then be cut, trimmed, perforated or otherwise shaped for end use. The shaping and sizing can be done using, for example, a blade, punch, drill, or laser. In various embodiments, the temperature or processing temperature of the sized and shaped cutting tool may be greater than 100 ℃. In another embodiment, the temperature or processing temperature of the sized and shaped cutting tool may be greater than 130 ℃. In one embodiment, the final treatment step may include finishing the protrusions of the macroscopic surface, such as struts, etc., which may irritate the biological tissue. In another embodiment, the final treatment step may include thermal annealing. Annealing can be performed before or after final cutting and shaping.
Shaping and sizing can include custom shaping and sizing to match the implantable device to a particular treatment site of a patient, which can be determined by imaging or other techniques known in the art. In particular, one or a small number (e.g., less than about 6 in one embodiment and less than about 2 in another embodiment) of elastomeric matrices 10 may comprise an implantable device system to treat damaged tissue in need of repair and/or regeneration.
The size and shape of the device fabricated from the elastomeric matrix 10 may vary depending on the particular tissue repair and regeneration treatment site. In one embodiment, the device has a major dimension of about 0.5 mm to about 500 mm before being compressed and delivered. In another specific embodiment, the device has a major dimension of about 10 mm to about 500 mm before being compressed and delivered. In another specific embodiment, the device has a major dimension of about 50 mm to about 200 mm before being compressed and delivered. In another embodiment, the device has a major dimension of about 30 mm to about 100 mm before being compressed and delivered. The elastomeric matrix 10 exhibits a compression set when compressed and delivered through a delivery device such as a catheter, syringe or endoscope. In another embodiment, the compression set and its standard deviation are taken into account when designing the pre-compression dimensions of the device.
In one embodiment, an implantable device or device system is used to treat a patient that does not itself completely fill the target cavity or other site where the device system is present, but rather is determined by the volume at the entrance to the site. In a particular embodiment, the implantable device or device system does not completely fill the target cavity or other site where the device system is present, even if the pores of the elastomeric matrix are occupied by biological fluids or tissue. In another embodiment, the fully expanded volume of the implantable device or device system in situ is still at least 1% less than the volume of the site. In another embodiment, the fully expanded volume of the implantable device or device system in situ is still at least 15% less than the volume of the site. In another embodiment, the fully expanded volume of the implantable device or device system in situ is still at least 30% less than the volume of the site.
In another embodiment, the volume of said implantable device or device system after in situ full expansion is at least 1% to about 40% greater than the volume of said cavity. In another embodiment, the volume of the implantable device or device system after in situ full expansion is at least 5% to about 25% greater than the volume of the cavity. In another embodiment, the ratio of the volume of the implantable device to the volume occupied by the site of orthopedic application is from about 70% to about 90%. In another embodiment, the ratio of the volume of the implantable device to the volume occupied by the site of orthopedic application is from about 90% to about 100%. In another embodiment, the ratio of the volume of the implantable device to the volume occupied by the site of orthopedic application is from about 90% to less than about 100%. In another embodiment, the ratio of the volume of the implantable device to the volume occupied by the site of orthopedic application is from about 100% to about 140%. In another embodiment, the ratio of the volume of the implantable device to the volume occupied by the site of orthopedic application is from about 100% to about 200%. In another embodiment, the ratio of the volume of the implantable device to the volume occupied by the site of orthopedic application is from about 100% to about 300%.
The implantable device or device system can include one or more elastomeric matrices 10 occupying a central position at the treatment site. In one embodiment, the implantable device or device system may comprise one or more elastomeric matrices 10 positioned at the entrance of the treatment site. In another embodiment, an implantable device or device system comprises one or more elastomeric matrices 10 spanning or covering damaged tissue. In another embodiment, an implantable device or device system comprises one or more flexible, possibly sheet-like, elastomeric matrices 10. In another embodiment, such an elastomeric matrix 10 migrates to or near the cavity wall with the assistance of suitable fluid dynamics at the implantation site.
The bio-sustainable reticulated elastomeric matrix 10, or an implantable device system containing such a matrix, can be sterilized by any method known in the art, including gamma irradiation, autoclaving, ethylene oxide sterilization, infrared irradiation, and electron beam irradiation. In a particular embodiment, the biodurable elastomer used to make the elastomeric matrix 10 is resistant to such sterilization without losing useful physical and mechanical properties. The use of gamma irradiation can potentially provide additional crosslinking to enhance the performance of the device.
In one embodiment, the sterilized product may be packaged in a sterile package made of paper, polymer, or other suitable material. In another embodiment, within such a package, the resilient matrix 10 is compressed within a retaining member to facilitate loading into a delivery device, such as a catheter or endoscope, in a compressed configuration. In another embodiment, the elastomeric matrix 10 comprises an elastomer having a compression set that allows it to expand to a substantial proportion of its pre-compression volume, for example, to return to 50% of its pre-compression volume at 25 ℃. In another embodiment, the elastomeric matrix 10 is compressed into a bag and expansion can occur after typical commercial storage and distribution times (typically over 3 months and up to 1 or 5 years from manufacture to use).
Radiopacity
In a particular embodiment, the implantable device can be rendered radiopaque for in vivo imaging, for example, by adhering to, covalently bonding to, and/or integrating with the radiopaque material particles of the elastomeric matrix itself. Radiopaque materials include sulfates of titanium, tantalum, tungsten, barium, or other suitable materials known in the art.
Use of implantable devices
Reticulated elastomeric matrix 10 and implantable device systems incorporating the reticulated elastomeric matrix 10 may be used, as described in the claimed priority application. In one non-limiting example, one or more reticulated elastomeric matrices 10 are selected according to a given locus. Each stream is compressed and loaded into a delivery device, such as a catheter, endoscope, syringe, etc. The delivery device is woven through the vasculature or other vasculature of the subject patient host, and the reticulated elastomeric matrix 10 is then released from the delivery device and anchored (e.g., sutured) to the target repair or regeneration site. Once released at the site, the reticulated elastomeric matrix 10 elastically expands to approximately its original, relaxed size and shape, and certainly to the limits of its compression set and any desired curvature, coverage or other configuration of the anatomical structure of the site that the implantable device may assume. In another embodiment, the implantable device is inserted by an open surgical procedure.
In another embodiment, cellular entities (e.g., fibroblasts and tissue) are capable of invading and growing into the reticulated elastomeric matrix 10. Such ingrowth, where appropriate, can extend into the internal pores 20 and interstices of the inserted reticulated elastomeric matrix 10. Finally, the elastomeric matrix 10 may be substantially filled with proliferating, ingrowth cells to provide a substance capable of occupying the sites or voids within the elastomeric matrix 10. Types of ingrowth tissue may include, but are not limited to, fibrous tissue and endothelial tissue.
In another embodiment, the implantable device or device system allows cells to grow and proliferate throughout the site, site boundaries, or some exposed surface, thereby sealing the site. Over time, this induced vascular entity caused by tissue in-growth may cause the implantable device to integrate into the channel. Over time, tissue in-growth can form a very effective barrier to prevent migration of the implantable device. It also prevents re-communication of the channel. In another embodiment, the ingrowth tissue is scar tissue that is long lasting, non-injurious and/or mechanically stable. In another embodiment, the implanted reticulated elastomeric matrix is completely filled and/or coated with tissue, fibrous tissue, scar tissue, or the like, over a period of time, such as 2 weeks to 3 months to 1 year.
Other uses for the reticulated elastomeric matrix 10 include biological implants, particularly for implantation into the human body, for tissue proliferation, support, regeneration and/or repair; for therapeutic purposes; or for cosmetic, reconstructive, maxillofacial, cranial, urological, gastroesophageal, or other purposes. Implantable devices made from reticulated elastomeric matrix 10 may be used as tissue engineering scaffolds or other comparable substrates to support cell proliferation applications in vitro, for example, in orthopedic applications such as soft tissue attachment, regeneration, proliferation, or support or in the growth of major organ tissues. The reticulated elastomeric matrix 10 can be used for long-term implantation in many applications. It has also proven advantageous for such tissue engineering and other applications that there is no carcinogenicity, mutagenicity, teratogenicity, cytotoxicity or other adverse biological effects.
In another embodiment, the properties of the reticulated elastomeric matrix 10 are configured to match the target tissue to provide flexibility and possibilities for use in many applications. The properties of the elastomeric matrix can be engineered, such as by controlling the amount of cross-linking agent, the amount of crystallization, the chemical composition, the chemical type of solvent or solvent mixture (when a solvent is used during processing), the annealing conditions, the curing conditions, and the degree of reticulation. Unlike biodegradable polymers, when used as a scaffold, the reticulated elastomeric matrix 10 maintains its physical properties and performance in vivo for a significant period of time. Thus, it does not cause adverse tissue reactions that are observed with biodegradable implants that rupture and degrade. The high pore content and degree of reticulation of the reticulated elastomeric matrix 10 allows tissue ingrowth and cell proliferation to occur within the matrix. In one embodiment, the ingrowth tissue and/or proliferative cells occupy from about 51% to about 99% of the volume of the interconnected pore phase 14 of the initial implantable device, thereby providing the functionality of the restored or replaced original tissue, such as the ability to withstand stress.
In another embodiment, the features of the implantable device and its function, as described above, make it suitable for use as a tissue engineering scaffold to handle many orthopedic applications, including soft tissue attachment, regeneration, hyperplasia or support and ingrowth of major organ tissue and similar tissue, such scaffolds including but not limited to spinal, shoulder, knee, hand or joint encircling repair and regeneration devices, as described in the claimed priority application.
In one embodiment, the reticulated elastomeric matrix 10 may be suitably shaped to form a closed device to seal the annulus opening created by a discectomy procedure to reinforce and stabilize the disc annulus in the event of a disc herniation (also known as herniation or bulging or herniation). Such closure devices can be compressed and delivered through a cannula used in a discectomy procedure into the annular opening. Such devices may be secured at the opening by at least two mechanisms: first, the outward elasticity of the reticulated solid phase 12 can provide a mechanical means of resisting migration; second, the reticulated solid phase 12 may serve as a scaffold to support fibrocartilage ingrowth into the interconnected porous phase 14 of the elastomeric matrix. Additional reinforcement may be achieved by using anchors, sutures, or bio-glues and adhesives known in the art. The closure device may support fibrocartilage ingrowth into the elastomeric matrix of the implantable device.
In another embodiment, implantable devices made from a biodurable reticulated elastomeric matrix provide a method of treating so-called hard tissue disorders, such as maxillofacial or cranial tissue disorders. In another embodiment, implantable devices made from a biodurable reticulated elastomeric matrix provide a stable method of treating so-called soft tissue disorders, e.g., tendon hyperplasia, articular cartilage repair, meniscus repair and reconstruction, anterior cruciate ligament reconstruction, disc herniation; a scaffold for nucleus replacement and annulus repair is also provided.
In another embodiment, the reticulated elastomeric matrix 10 can be formed as a composite patch that can be anchored, for example, by being sutured into an appropriate site to provide support to the tendons as they heal, allowing for in situ proliferation and reinforcement of the tendons. In the case where the tendon tissue has deteriorated and the remaining tendon is not strong enough to support the necessary sutures to successfully anchor the tendon; or in the case of tendons and muscles that have contracted and cannot be sufficiently stretched for reattachment (contracted tendons), this is particularly useful for repair of the shoulder rotator cuff and glenoid labrum (bankart); it is also particularly useful for tendons, muscles or tissues that have been torn from an injury. The synthetic patch can act as a scaffold for tissue ingrowth, strengthening and providing support to the tendon during healing. This implantable device also allows the repair of otherwise inoperable tendons that cannot be reattached without some type of stent.
In another embodiment, the reticulated elastomeric matrix 10 can be formed into a biocompatible scaffold or substrate that, when implanted in an acellular manner, can support tissue repair and regeneration of articular cartilage and is potentially useful in the treatment of knee injuries such as meniscal repair, anterior cruciate ligament reconstruction (ACL). Alternatively, the implantable device may also provide a basis for cell therapy applications to support tissue repair and regeneration of articular cartilage, and have potential use in meniscus repair and ACL reconstruction. For example, the bio-durable implantable device can be used as a mold for autologous cells obtained from the patient, which can be cultured in an in vitro laboratory environment and then implanted into the patient at the articular cartilage defect. The ability of the implantable device to incorporate osteoinductive factors such as growth factors, e.g., autologous growth factors derived from platelets and leukocytes, enables its functionalization to modulate cellular function and actively induce tissue in-growth. The resulting implantable device will fill the cartilage defect, support autologous tissue repair and regeneration, and then integrate into the damaged knee.
In another embodiment, the reticulated elastomeric matrix 10 can be mechanically secured to the injured site. The reticulated elastomeric matrix can be located within, adjacent to, and/or overlying the target lesion site. The reticulated elastomeric matrix may act as a defect filler, replacement tissue, tissue reinforcement, and/or augmentation patch. In another embodiment, the reticulated elastomeric matrix is capable of spanning the defect and bridging the natural tissue interstices (e.g., maxillofacial or cranial) together.
In yet another embodiment, the implantable devices disclosed herein can be used as drug delivery vehicles. For example, the bio-durable solid phase 12 can be mixed with, covalently bound to, and/or adsorbed into a therapeutic agent. A wide variety of therapeutic agents can be delivered by the implantable device, such as those disclosed previously in this specification.