Patent Application
20120130489
Embodiments of the present inventions relate to post-surgical implants and delivery devices and systems for delivering such implants to a post-surgical cavity, such as a post-lumpectomy cavity.
According to embodiments thereof, the present inventions are drawn to post-surgical implants and methods of forming the same from one or more polymerizing biomaterials that are introduced within a post-surgical cavity in a patient, and controllably solidified to form the implant in situ within the cavity.
According to an embodiment thereof, the present invention is a soft tissue implant formed in situ.
According to another embodiment, the present invention is a method of forming an implant within a post-surgical cavity. The method may include steps of providing a balloon within the cavity; introducing a gelling initiator into the balloon; introducing, into the balloon, a polymer susceptible to solidifying when in contact with the gelling initiator; enabling the introduced polymer to solidify through contact with the introduced gelling initiator to form the implant, and rupturing the balloon and extracting the ruptured balloon from the cavity such that the formed implant remains within and directly contacts an interior surface of the cavity.
According to further embodiments, the polymer and the gelling initiator may be introduced into the balloon separately from one another. The polymer introducing step may be carried out with the polymer including alginate. The gelling initiator providing step may be carried out with the gelling initiator including divalent cations of bivalent metals. The gelling initiator providing step may be carried out with the gelling initiator including a cross-linking agent. The polymer may be introduced into the balloon prior to introducing the gelling initiator into the balloon. Alternatively, the gelling initiator may be introduced into the balloon prior to introducing the polymer into the balloon. The polymer introducing step may be carried out with the polymer including alginate dispersed in an aqueous solution at a concentration of about 0.1% to about 80% by weight. The method may further include a step of expanding the balloon within the cavity. The polymer introducing step may include introducing a volume of about 0.01 cc to about 600 cc of the polymer into the balloon. The gelling initiator introducing step may be carried out by introducing a volume of about 0.01 cc to about 900 cc of the gelling initiator into the balloon. The gelling initiator introducing step may be carried out by introducing the gelling initiator along with a biologically active substance into the balloon. The polymer introducing step may be carried out by introducing the polymer along with a biologically active substance into the balloon. The gelling introducing step may be carried out with the gelling initiator having a predetermined porosity. The gelling initiator introducing step may be carried out with the gelling initiator being configured with divalent cations of bivalent metals coupled with a biologically active substance. The gelling initiator introducing step may be carried out with the gelling initiator having a porosity that is different from a porosity of the polymer. The method may further include a step of foaming the gelling initiator such that the foamed gelling initiator has, exhibits or defines a predetermined porosity. The method may also include a step of introducing gas bubbles into the gelling initiator such that the foamed gelling initiator has, exhibits or defines a predetermined porosity.
The balloon providing step may be carried out with the balloon being configured to isolate the introduced polymer and gelling initiator from bodily fluids within the cavity. The balloon providing step may be carried out with the balloon being configured with locally thinner portions. The balloon providing step may be carried out with the balloon being configured to selectively rupture within the cavity. The balloon rupturing and extracting step may be carried out by pulling the balloon in a proximal direction while the balloon is disposed within the cavity. The balloon extracting step may include causing the ruptured balloon to slide over the formed implant, bringing the formed implant and the cavity into contact. The balloon providing step may be carried out with an interior surface of the balloon further including or defining a porous layer or portion. The method may also include a step or steps of determining relative amounts and concentrations of gelling initiator and polymer to form an implant having desired characteristics in controlled manner.
According to yet another embodiment thereof, the present invention is a delivery system. The delivery system may include a first source of polymer; a second source, separate from the first source, of a gelling initiator that may be configured to gel the polymer, and a catheter configured to deliver the polymer and the gelling initiator to a cavity within the patient such that the delivered polymer and gelling initiator may be initially isolated from the cavity and only selectively exposed to the cavity after the polymer has at least partially gelled.
The catheter may include a balloon configured to isolate the delivered polymer and gelling initiator from the cavity. The balloon may include or otherwise define a porous interior surface, section or portion configured to contain at least a portion of the gelling initiator. The porous interior surface or portion may be configured to release the contained gelling initiator at least when the introduced polymer applies pressure there against.
The polymer may include, for example, alginate. The gelling initiator may include divalent cations. The gelling initiator may include a cross-linking agent. The catheter may be configured to deliver the polymer and the gelling initiator separately to the cavity and to isolate them from the cavity (i.e., from the tissue sidewalk of the cavity) until the polymer has at least partially gelled. The balloon may include locally weaker portions. The delivery system may further include a marker configured to be delivered within the balloon within the cavity.
Many medical procedures require the surgical formation and maintenance of a cavity within a patient's body. For example, the treatment of certain tumors may require a multi-faceted approach that includes a combination of surgery, radiation therapy and chemotherapy. In such an approach, after an initial surgical procedure has been performed to remove as much of a tumor as possible, radiation and chemotherapy are performed to kill remaining cancerous cells that could not be removed surgically.
More than 1,250,000 reconstructive procedures are performed on the breast each year. Surgically formed cavities, particularly post-lumpectomy cavities, often cause local deformation of the tissue surrounding the lumpectomy site, leading to poor cosmetic results. Women afflicted with breast cancer, congenital defects or damage resulting from trauma typically have very few alternatives to breast reconstruction. Breast reconstruction is frequently performed at the time, or shortly after, mastectomy or lumpectomy for cancer treatments. Reconstructive procedures frequently involve moving vascularized skin flaps with underlying connective and adipose tissue from one region of the body, e.g., the buttocks or the abdominal region, to the breast region, resulting in additional trauma to the patient and longer healing times. Often, surgeons use synthetic breast implants and tissue expanders for reconstruction, which typically require additional procedures and which may cause further complications especially in the patients who went through local radiation therapy such as partial breast irradiation brachytherapy.
Embodiments of the present inventions provide methods, systems and devices for the formulation and formation of biodegradable implants within a surgical resection cavity formed from solid tissue, such as a lumpectomy cavity formed in a breast following breast cancer surgery or other procedure. Such implants may initially be formulated and formed within a containment structure such as a balloon that has been inserted within the cavity in a minimally invasive manner. The balloon may then be expanded and a self-polymerizing biomaterial or combination of biocompatible materials may be selectively introduced therein in a controlled fashion to completely or at least partially fill the interior volume of the balloon. One or more of the biocompatible materials may already be present within the balloon. When the implant has at least partially polymerized (e.g., solidified), the balloon may then be withdrawn from the cavity, leaving the at least partially solidified implant in place, leaving only a small wound for closure.
The formulation and formation of the present implants may be carried out under a variety of guiding visualization modalities, such as ultrasound, for example. Indeed, a small diameter trocar, delivery catheter, and biocompatible biopolymer that is capable of controllable solidification may be selectively introduced into the post-surgical cavity under ultrasonic guidance. Ultrasound and/or other visualization modalities may be used to aid in the planning of immediate or subsequent treatment of the postsurgical cavity.
According to embodiments of the present inventions, the implant 208 has no existence outside of the balloon 206 within the post-surgical cavity. Only the constituent materials thereof exist separately prior to their respective introduction into the balloon 206. Therefore, the implant 208 is not inserted or delivered within the cavity, but is formulated (and its resultant characteristics determined) and formed (including caused to assume its shape) within a containment structure that is itself inserted within the post-surgical cavity. In this manner, the containment structure acts as a bio-reactor into which the constituent components of the to-be-formed implant are introduced to formulate and form the implant in situ. The implant, therefore, is both formulated (its composition, structure and characteristics determined) and formed of its constituent materials within the balloon 206, which is itself within the post-surgical cavity.
The implant 208 may include a gel or a pre-polymer composition (such as, for example, alginate) which, after introduction into the balloon 206, may be treated with a catalyst or cross-linker (e.g., divalent cations of bivalent metals) to initiate and cause polymerization or gelation. The material for the implant 208 may also include a material such as gelatin that is a liquid melt at a first temperature and that is capable of solidification to a non-fluent state by exposure to a comparatively lower physiological temperature within the cavity and to an environment such as body fluids.
The materials used to form the implant 208 in situ may include a first reagent such as a polymer (such as, for example, alginate or gelatin) and a second reagent such as an initiator, catalyst or cross-linker. According to embodiments of the present invention, the polymer may be such that it is susceptible to gelling (becoming a gel) when subjected to certain environmental conditions. For example, the polymer may include a solution containing an effective amount of a bio-compatible and bio-degradable natural polymer, such as alginate. As is known, alginate, extracted from seaweed, is a linear copolymer that may include homopolymeric blocks of (1-4)-linked β-D-mannuronate (M) and its C-5 epimer α-L-guluronate (G) residues, respectively, covalently linked together in different sequences or blocks. The monomers may appear in homopolymeric blocks of consecutive G-residues (G-blocks), consecutive M-residues (M-blocks), alternating M and G-residues (MG-blocks) or randomly organized blocks. The alginate may be dispersed in a solvent (such as an aqueous solution, for example). The amount of alginate dispersed in the aqueous solution may be freely chosen, but for the constraint that the alginate solution should have a sufficiently low coefficient of viscosity so as to be efficiently delivered to the balloon 206 within the cavity. Higher concentrations of alginate within a solution will yield firmer gels. For example, a concentration of alginate in the aqueous solution may be selected within the range of about 0.1% to about 30% by weight. For example, a concentration of alginate in the aqueous solution may be selected within the range of about 0.1% to about 80% (for example) by weight. Concentrations outside of these ranges may also be used. The implant material may include a salt of alginic acid, such as, for example, the sodium salt of alginic acid NaC6H7O6.
As is known, an alginate gel may be characterized as being a part solid and part solution. After gelling, water molecules are physically entrapped by the matrix formed by the alginate material. Alginate gel develops in the presence of a divalent ionic solution that may include, for example, cations such as Ca2+, Br2+ or Sr2+. Here, a calcium salt with good, or limited solubility, or complexed Ca2+ ions may be mixed with an alginate solution into which the calcium ions are released. The gelling initiator or cross-linker may be or include CaCl2 and the polymer may be or include a sodium alginate solution (such as, for example, the material sold under the trade name of PRONOVA™ and manufactured by NovaMatrix).
The amounts of the polymer and the cross-linking agent may be freely selected such that the resulting implant occupies substantially all of the volume of the inflated balloon 206 and, consequently, substantially all of the volume of the cavity once the balloon 206 is extracted therefrom. Therefore, the size of the cavity may dictate the relative amounts of the polymer such as alginate and of the cross-ling agent. Stated differently, the relative amounts of the constituent reagents of the implant to be formed in situ may be a function of at least the size of the expanded balloon and/or a function of the volume of the post-surgical cavity. The implant 208 may be formed, for example, of about 0.05 cc to about 400 cc of polymer or polymer solution, such as the alginate solution described above. For example, the implant 208 may be formed of about 0.2 cc to about 4 cc of alginate-containing solution. Only as much cross-linking agent as is necessary to cause at least partial gelation of the alginate or other polymer need be used. For example, the alginate-containing solution may be gelled or cross-linked when bathed in about 0.02 on to about 600 cc of gelling initiating cross-linker. For example, an amount selected from about 0.1 cc to about 8 cc of cross-linker, such NaCl2, for example, may be effective to gel the alginate-containing solution. However, it is to be understood that the above ranges are only illustrative and that other ranges are possible, as those of skill in this art may appreciate.
According to embodiments of the present inventions, a delivery system may be provided for introducing an initially fluent material through an opening and into an inflated balloon 206 and then activating the material by exposure to a catalyst or cross-linking agent. As those of skill in this art may appreciate, many different configurations of such a delivery system are possible and fall within the scope of the present inventions. The catalyst (e.g., a cross-linking agent) may be combined with a bio-active material such as a therapeutic agent and/or other polymer solution. The cross-linking agent may have itself been treated, agitated or foamed to exhibit a (even temporary) predetermined porosity that may be characterized by a predetermined pore density and/or predetermined pore architecture. Alternatively, the containment structure (e.g., balloon) within which the cross-linking agent is contained may have a predetermined porosity or may include a layer having such predetermined porosity.
According to embodiments of the present inventions, the balloon 316 may be formed of or include, for example, silicone, polyurethane and/or any other suitable bio-compatible material. The balloon, as is known, may be formed (for example) by dipping a preform into a volume of silicone dispersion, coating the external surface(s) of the preform with a layer of silicone, curing the silicone and removing the silicone from the preform. The balloon 316 may, in this manner, have a smooth inner surface. Embodiments of the present inventions may use such a smooth-sided balloon 316. According to such embodiments, the gelling initiator or cross-linker may be introduced within the balloon 316, followed by the alginate solution or other polymer gel such as gelatin. Alternatively, the gelling initiator or cross-linking agent may already be present within the balloon prior to its insertion into the post-surgical cavity 304. The thereafter introduced alginate solution, other polymer gel or gelatin may displace some of the volume of cross-linker already present within the interior of the balloon 316. Such displaced volume of cross-linker may be evacuated through, for example, a port 318, 320 within the proximal portion 314 of the catheter 308. Now bathed in the remaining volume of cross-linker, the alginate solution, other polymer, gel or gelatin begins to solidify through a gradual cross-linking or other solidification process. Alternatively, the cross-linker and the alginate solution, gel or gelatin may be introduced in the opposite order or may be introduced into the interior of the balloon 316 at the same time, taking care that a rapidly solidifying polymer does not clog the delivery lumen(s) of the catheter 308.
While a balloon 316 having a smooth or relatively smooth interior surface may be used, other embodiments of the present inventions envisage a porous layer, structure or section disposed, formed on or coupled to the interior surface of the balloon 316. Such a porous layer or discrete section or portion may be of the same or a different material than the mate of the balloon 316. For example, both the balloon 316 and the porous layer may be formed of the same material, such as silicone or polyurethane. In that case, a cross-section of the balloon may reveal a porosity gradient from the exterior surface (that surface of the balloon 316 in contact with the cavity sidewalls) to the interior surface of the balloon. Alternatively, the balloon 316 and the porous layer may be formed of different materials. For example, the balloon 316 may be formed of or include silicone, while the porous layer formed on or disposed on the interior surface thereof may be formed of or include polyurethane, or vice-versa. The thickness of the porous layer may be freely chosen according to, for example, the dimensions of the balloon, the concentration of the gelling initiator or cross-linking agent to be contained therein, the amount of polymer to be cross-linked, and the pore morphology of the porous layer. For example, the thickness of the porous layer may be less than a millimeter up to several centimeters and may occupy a volume of up to, for example, one quarter or one half of the interior volume of the expanded containment structure or balloon.
According to an embodiment of the present inventions, such a porous layer may be loaded with a predetermined volume of cross-linker and/or other biologically active substance. The presence of the porous layer (or other layer configured to hold a volume of cross-linking agent) is advantageous, as it can hold, its porous architecture, a volume of cross-linker and optionally a quantity of some other biologically active and beneficial substance such as, for example, an antimicrobial agent, an analgesic agent, a chemotherapy agent, an anti-angiogenesis agent or a steroidal agent, to name but a few of the possibilities.
According to this embodiment of the present inventions, the balloon 316 may be inserted, in its un-inflated state, into the cavity 304. Thereafter, the balloon 316 may be inflated (with air or CO2, for example) or otherwise expanded and a volume of cross-linker and optionally some biologically active substance, thereby bathing the interior of the balloon in the resulting solution. The CO2 inflation or expansion of the balloon may be omitted. Some of that introduced solution will be absorbed within the spongy matrix of the porous layer on the interior surface of the balloon 316. Excess solution may then be evacuated or left in place, to be displaced by the polymer (such as the previously described alginate solution, gel or gelatin) thereafter introduced to the interior of the balloon 316. This polymer introduced into the interior of the balloon 316 may then exert pressure against the cross-linking agent-containing porous layer, thereby releasing the cross-linking agent, which then comes into contact with the introduced polymer (e.g., alginate solution). As the cross-linking agent is released from the porous layer, the alginate (and/or other polymer) solution becomes more and more cross-linked and gradually solidifies. Depending upon the selected concentration of alginate in the introduced solution and the concentration of cross-linking (or other gelling initiator) agent within the porous layer and the time period during which the two are left in contact with one another, the introduced polymer will solidify more or less rapidly and to a greater or lesser degree. This rate is freely selectable by judiciously selecting the amounts of, ratios and concentrations of the constituent components of the implant to be formed. The solidified (e.g., cross-linked) alginate solution then forms the implant that is to be left in place after the balloon is breached or otherwise opened and extracted from the cavity 304.
Once the alginate solution, polymer or gel 410 and the cross-linking agent-containing solution 408 have mixed (or at least have come into contact with one another) and polymerized in situ within the balloon to form a solidified biomaterial (or at least partially solidified material), the containment structure (for example, the balloon 406) may then be opened, breached or otherwise ruptured. The rupturing may be carried out with a sharp object such as a needle, tapered instrument or some other rupturing instrument. Alternatively, the rupturing may be carried out by some selectively actuable structure(s) on the trocar or the catheter, as suggested at 420 in
Indeed, as shown in
According to further embodiments, a bio-compatible marker may be introduced along with, for example, the cross-linking agent-containing solution or along with a polymer or a gel. The marker is preferably radio-opaque and echogenic, that is, visible under X-ray and/or ultrasound, for example. The marker may be made from a non-magnetic material, so as to be MRI-compatible. For example, the radio-opaque element may be formed of a bio-compatible metal such as, for example, stainless steel, or titanium, or Nitinol®, a nickel-titanium alloy. The formulated implant will then solidify around the marker, which marker should remain in place even after the cross-linked alginate implant has been resorbed by the body. The presence of such a marker will facilitate the localization of the surgery and subsequent implant formation.
The polymer (such as the alginate-containing solution) and the cross-linking agent-containing solution or cross-linking agent-containing solution mixed or otherwise coupled with a biologically active substance may be provided and packaged separately in pre-measured quantities, with the physician deciding the quantities of each to introduce into the balloon before or during the implant-forming procedure. This and the other embodiments shown and described herein may be provided as an assembled system or provided as a kit, in sterile packaging. The delivery system may be configured for one-time use or portions thereof may be re-usable. Those of skill in this art may recognize other alternative embodiments and all such alternative embodiments are deemed to fall within the scope of the present invention.
Indeed, the disclosed embodiments of the present inventions are not limited to those shown and described herein but may include any number of other variations. Modification of the above-described methods and devices for carrying out the described embodiments are possible and all such modification are deemed to fall within the scope of the present inventions.
The present application claims priority to copending and commonly assigned U.S. provisional application Ser. No. 61/346,326 filed on May 19, 2010, which application is incorporated herewith by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61346326 | May 2010 | US |
