Patent Description:
This invention is directed to a sclerosing agent and bone graft material for use in a method for treatment of bone, including image-guided and/or minimally invasive treatment of bone lesions such as unicameral bone cysts.

Lesions in the bone, including cystic bone lesions or bone cysts, can cause pain and may predispose a person to fracture and may disrupt bone growth in children.

Simple or unicameral bone cysts (UBCs) are solitary or unilocular bone lesions of unclear etiology. They comprise approximately <NUM>% of primary bone lesions and are most commonly diagnosed in children <NUM> to <NUM> years of age. They have a single cavity and tend to arise at long bone metaphyses, most commonly within the humerus and femur. Other bone cysts are septated, and have multiple cavities, for example from two to twenty cavities. Aneurysmal bone cysts (ABCs) are expansile blood-filled bone lesions having numerous channels or cavities. They are less common than UBCs; however, they are more locally aggressive.

Existing treatment approaches for the management of bone cysts are highly variable and recurrence is not uncommon. Treatment options range from watchful waiting to mechanical curettage, in which a curved metal impactor is used to physically disrupt the bone cyst wall, to steroid injection, bone grafting, screw cannulation, metal splints, or a combination of these techniques. There is currently no standardized approach to treatment of bone cysts, and the variable techniques currently performed are associated with relatively high recurrence rates.

Treatment of bone lesions, especially in the pediatric population, often entails multiple and/or a variety of treatments with limited success. <NPL>), describes a procedure where <NUM>% ethanol solution (sclerosant) is injected into the cyst to chemically cauterize the cyst lining. A cannula connected to a syringe is used for the ethanol injection to avoid accidental damage to the adjacent healthy tissue. The ethanol is left in place for about thirty seconds and then aspirated out with the same syringe.

The invention as described in claim <NUM> provides a sclerosing agent and bone graft material for use in a method for treatment of a bone lesion in a patient, the method comprising: locating a treatment volume in the bone of the patient, wherein the treatment volume is a unicameral bone cyst; placing a venting device into the treatment volume, wherein the venting device comprises a needle; administering the sclerosing agent to the treatment volume; and after administering the sclerosing agent, administering the bone graft material to the treatment volume; wherein administering the sclerosing agent to the treatment volume includes administering a fluid comprising the sclerosing agent and is performed using a delivery device that comprises a needle, and wherein the sclerosing agent is aspirated through the venting device in a push-pull fashion, irrigating the treatment volume. In some embodiments, the patient is a pediatric patient.

In some embodiments, administering a sclerosing agent to the treatment volume includes using imaging to guide the administration of the sclerosing agent. In some embodiments, placing a delivery device into the treatment volume includes using imaging to guide the placement of the delivery device. In some embodiments, administering bone graft material to the treatment volume includes using imaging to guide the administration of the bone graft material.

In some embodiments, the delivery device comprises a needle. In other embodiments, the delivery device comprises two or more needles. Placing the delivery device into the treatment volume can include placing each of one of more needles into the treatment volume. The size of the needle and/or needles can be determined at least in part by the viscosity of the bone graft material. Less viscous bone graft material can be delivered with smaller (e.g. higher gauge) needles.

In some embodiments, the sclerosing agent comprises one or more of doxycycline, ethanol, sodium tetradecyl sulfate, bleomycin, group A streptococcus, Streptococcus pyogenes, and polidocanol.

The invention includes placing a venting device into the treatment volume. Administering a sclerosing agent to the treatment volume includes administering a fluid comprising the sclerosing agent to the treatment volume, and administering bone graft material to the treatment volume can cause a portion of the fluid comprising the sclerosing agent to exit the treatment volume through the venting device. The venting device comprises a first needle. The delivery device comprises a second needle. The second needle can be larger than the first needle, e.g., the gauge of the second needle can be lower than the gauge of the first needle. The treatment volume comprises a unicameral bone cyst. In another aspect of the disclosure, the treatment volume comprises a portion of a septated bone cyst. The portion of the septated bone cyst can be the entirety of the septated bone cyst. The septated bone cyst can be an aneurysmal bone cyst.

Embodiments of the invention can further include preparing the treatment volume, for example, before the step of administering the sclerosing agent, for example, by mechanical elimination (e.g. disruption) of tissue within the treatment volume. Preparing the treatment volume can include breaking one or more barriers within the treatment volume. Preparing the treatment volume can include reducing the number of cavities in the treatment volume. In some embodiments, a curette is used to prepare the treatment volume. In some embodiments, an inflatable balloon is used to prepare the treatment volume.

Disclosed but not part of the invention as claimed is a kit for treatment of a patient, comprising bone graft material, a tube or device for delivery of the bone graft material into a treatment volume of a bone of the patient; and a tube or device for venting a fluid comprising a sclerosing agent from the treatment volume. In some embodiments, the tube for delivery of the bone graft material is also suitable for delivery of the fluid comprising the sclerosing agent. The kit can further include a device for preparation of the treatment volume.

In some embodiments of the kit, the device for preparation of the treatment volume is a curette or an inflatable balloon. In some embodiments of the kit, the bone graft material is in the form of a powder, a putty, a paste, or granules. In some embodiments of the kit, the bone graft comprises a volume of 5cc, a volume of 10cc, a volume of 20cc, or a volume of 40cc. In some embodiments of the kit, the bone graft material comprises a volume greater than 45cc. In some embodiments of the kit, the bone graft material comprises a volume greater than 45cc and less than, for example, 55cc, 60cc, 90cc, 95cc or 100cc.

In some embodiments of the kit, the tube for venting is a first needle and the tube for delivery of the bone graft material is a second needle. In some embodiments, the second needle is larger than the first needle, e.g. the gauge of the second needle is lower than the gauge of the first needle. In some embodiments, the second needle has a gauge of <NUM> or higher (smaller needle) (i.e., the needle is equal in size to or smaller than a <NUM> gauge needle), and the first needle has a gauge of <NUM> or higher (smaller needle). In some embodiments, the second needle has a gauge of <NUM> or lower (larger needle) (i.e. the needle is equal in size to or larger than a <NUM> gauge needle), and the first needle has a gauge of <NUM> or higher (smaller needle). In some embodiments, the second needle has a gauge of <NUM> or higher (smaller needle) and the first needle has a gauge of <NUM> or higher (smaller needle).

The more generic description of the invention is provided for illustrative purposes only. Embodiments not falling under these claims are for reference purposes only. Any reference in the description to methods of treatment refer to the products of the present invention for use in a method for treatment of a bone lesion in a patient. This patent application describes systems and methods for chemical curettage of bone and administration of bone graft material, including for treatment of unicameral (UBC) and other bone cysts, not covered by the claims. The systems and methods can use imaging, for example, methods of interventional radiology, to guide the chemical curettage and/or application of graft material. The methods can be minimally invasive and suitable for performance in one or more outpatient procedures. The systems and methods can be minimally invasive and use imaging to guide the chemical curettage and/or application of graft material.

As used herein, "to treat" and "treatment" includes any use of the described methods, and unless otherwise specified, is not limited to treatment of a disease or condition. For the sake of clarity, "to treat" or "treatment" includes use of the methods of the invention for prophylactic or preventive purposes, or without diagnosis of a disease state or condition. As used herein, "treatment volume" refers to a space in a bone, for example, a cavity or pocket or a set of cavities or pockets, that is subjected to the methods described herein. The treatment volume is typically within the bone and can be filled in full or in part with non-bone material, for example, fluid. The treatment volume is a unicameral bone cyst.

This patent application describes the administration of a sclerosing agent into the treatment volume, e.g. by injection, followed by the administration of bone graft material into the treatment volume, e.g. by injection. Administration of the sclerosing agent is accomplished with a needle, and administration of the bone graft material can be accomplished with any device, but preferred devices are those that can effect delivery into the treatment volume without the need for a surgical incision, for example, devices employing a needle or needles as are known for medical use. Such a needle or needles are typically made of thin walled stainless steel and have a hollow center, a beveled end for ease of penetration of tissue, and a hub suitable for fixation to a syringe or other repository of material that is moved through the needle. The bone graft material can be delivered by a device that does not have a needle, for example, by any device that provides for placement of one end of a tube or tubular element into a patient's bone.

The needle or needles can be of a size that is suitable for subcutaneous injection or larger, for example, the needle or needles can be from about <NUM>-<NUM> gauge (smaller diameter) to about <NUM>-<NUM> gauge (larger diameter). Smaller diameter needles are preferred to minimize impact on and damage to the patient's tissues, but larger needles may be necessary to effect delivery of viscous bone graft material. Less viscous bone material can be delivered with a smaller diameter needle (higher gauge) than more viscous bone material. Currently available synthetic bone graft material can be delivered without complication to relatively large treatment volumes using an <NUM> to <NUM> gauge needle, and delivery to small treatment volumes may be feasible with a <NUM> to <NUM> gauge needle. A venting needle can be smaller than this, e.g. <NUM> to <NUM> gauge.

As used herein, the term "bone graft material" refers to any material conductive to osteogenesis or bone regeneration, including material that can be used to provide an osteoconductive scaffold and/or that supports the growth of osteoblasts and the formation of bone when prepared and administered to bone. Bone graft material can be autograft, allograft, or synthetic. In one preferred embodiment, the bone graft material is synthetic. Preferably, the bone graft material is injectable, for example, after preparation including mixing the bone graft material with a liquid.

Synthetic bone graft materials include, without limitation, hydroxyapatite, tricalcium phosphate, calcium sulfate, and calcium phosphate, and combinations thereof. For example, Collagraft (Zimmer and Collagen Corporation) is a mixture of porous beads composed of <NUM>% hydroxyapatite and <NUM>% tricalcium phosphate ceramic with fibrilar collagen. Other examples of bone graft material products, without limitation, are Norian SRS® (Synthes Inc. ), Norian Drillable® (Synthes Inc. ), BoneSource® (Stryker Inc. ), HydroSet® (Stryker Inc. ), Calcibon® (Biomet Inc. ), alpha-BSM® (ETEX Corp. ), and Callos® (Skeletal Kinetics LLC). Bone graft materials include products that are provided in the form of a power, granules, or putty, a paste, and which may be mixed with liquid to form a compound suitable for use. In one preferred embodiment, the bone graft material is a CaSO<NUM>-CaPO<NUM> type of synthetic bone graft material, for example, as provided in GeneX® (Biocomposites) or Pro-Dense® Injectable Regenerative Graft (Wright Medical Technology), for example, a synthetic composite material comprising two calcium phosphate compounds as described in "<NPL>).

As used herein, the term "chemical curettage" refers to any administration, e.g. application, exposure, or instillation, of a sclerosing agent to disrupt, destroy, or remove tissue, e.g. in a bone lesion or cyst, including without limitation by injection, irrigation, or the like of a liquid composition comprising the sclerosing agent. Chemical curettage is a form of sclerotherapy. Chemical curettage can be accomplished with any of a variety of chemical agents having sclerosing activity, including without limitation doxycycline, ethanol, sodium tetradecyl sulfate, bleomycin, group A Streptococcus (GAS) or Streptococcus pyogenes, polidocanol, and similar agents. In one preferred embodiment, the sclerosing agent is the antibiotic doxycycline. Doxycycline has been administered safely to ABCs. The safety and efficacy of doxycycline as a chemical sclerosant is also established in visceral cysts and soft tissue lymphatic malformations. Examples of preparations of sclerosing agents include, but are not limited to including, Acticlate, Adoxa CK, Adoxa Pak, Adoxa TT, Alodox, Avidoxy, Doryx, Docy-<NUM>, Mondoxyne NL, Monodox, Morgidox, Oracea, Oraxyl, Periostat Targadox, Vibramycin calcium, Vibramycin Hyclate, Vibramycin monohydrate, Vibra-Tab, Belnoxane, Picibanil (OK-<NUM>), Varithena, and Asclera.

In one embodiment, this patent application describes an outpatient option for treatment of bone lesions. In one embodiment, this patent application describes a minimally invasive, image-guided procedure (MIIP) or technique for treatment of bone.

As used herein, the term "minimally invasive" refers to a surgical technique that limits the damage to the body resulting from a treatment, including methods that limit the size and/or number of any incisions, and which thereby lessen the time required for wound healing or patient recovery, lessen the risk of infection, bleeding, or complication, and/or lessen the pain, discomfort, or impact (e.g. from scarring) on the patient. As used herein, minimally invasive techniques preferably have incisions of less than a few millimeters, most preferably <NUM> or less, and do not require stitches.

As used herein, the term "image-guided" refers to procedures where the surgeon uses preoperative or intraoperative images in order to directly or indirectly guide the placement of a surgical instrument within the patient. For example, a wire, catheter or needle can be placed with the guidance of fluoroscopy, ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). Contrast agents may be introduced to facilitate imaging. Image-guided procedures are commonly performed by interventional radiologists and techniques for image guidance are well-known in the field of interventional radiology.

In a preferred embodiment, the systems and methods are for minimally invasive, image-guided treatment of bone cysts, including but not limited to cystic lesions that occur in the long bones (e.g. the humerus, femur, tibia, clavicles, etc.) and the flat bones (e.g. the pelvis, etc.). In a further preferred embodiment, the systems and methods are for minimally invasive, image-guided treatment of UBCs. In another aspect of the disclosure, the systems and methods are for minimally invasive, image-guided treatment of septated cysts, including ABCs.

The systems and methods are particularly useful for treatment of pediatric conditions. The systems and methods can be used for symptomatic and asymptomatic lesions, including lesions that are currently managed conservatively with activity restriction alone.

For example, as shown in <FIG>, two <NUM> stab incisions (indicated in <FIG> by the two arrows) and two needles (shown in <FIG>) can be used to perform chemical curettage followed by application of bone graft material. The stab incisions heal relatively quickly without stiches and leave minimal scarring. In comparison, surgical curettage treatment of the same patient required an incision of <NUM>-<NUM>, splaying of the tissue down to the bone, and opening of the bone (so that the cyst could be seen and treated by the surgeon), mechanical curettage of the bone cyst with a surgical tool, followed by application of bone graft material with a spatula into the opening, and closure of the wound with stiches, resulting in a substantial scar (indicated in <FIG> by the brackets).

A septated bone cyst has two or more cavities that may be separated, in full or in part, by a wall of bone or fibrous tissue, as shown in <FIG>. Treatment of septated cysts may include mechanical elimination of such dividing structures. The walls that create compartments within the cysts can be broken with a surgical device or tool, thereby creating a more open compartment for treatment. For example, a curette or other surgical tool, for example a tool having a small scoop, hook or gouge, can be inserted into a treatment area and used to exert force on the dividing structures sufficient to break them.

In a minimally invasive alternative, an inflatable balloon can be inserted into the treatment area and expanded, thereby exerting force on the dividing structures and breaking them. For example, the KyphX Xpander Inflatable Bone Tamp can be used for such a purpose. A balloon is inserted into the cyst, shown in <FIG>, and expanded, as shown in <FIG>, thereby breaking the wall or walls within the cyst and creating a single cavity within the cyst, as shown in <FIG>.

Preparation of septated treatment volumes, e.g. to create fewer and/or large cavities, facilitates access to the entirety of the treatment volume and may improve the quality and/or extent of treatment. For example, such preparation may permit the sclerosing agent to reach more of the cyst wall than would otherwise be possible, and may permit introduction of bone graft material to more of the treatment volume than would otherwise be possible.

The lining of an active bone cyst is known to secrete fluids and enzymes, which may disrupt the underlying bone, for example, causing thinning that disrupts the cortex and/or making a lesion prone to fracture. Mechanical curettage of the cyst membrane lining, typically performed surgically, is known to reduce the risk of recurrence of a bone cyst and/or the need for secondary intervention. It is believed that disrupting the wall lining of an active bone cyst, for example, destroying this lining in full or in part, arrests further fluid secretion into the cyst cavity and thereby arrests cyst progression.

Chemical curettage of a bone cyst is a minimally invasive alternative to mechanical curettage of a cyst wall, for example, the wall of a UBC. Chemical curettage can also be used to treat a cyst volume, for example, the volume of an ABC, or another defined treatment volume, for example, a volume defined as suitable for a single treatment, but is not part of the invention as claimed. The system and methods of the invention can be used to treat bone defects resulting from various disease processes, including for example Gorham-Stout disease, but are not part of the invention as claimed.

Chemical curettage of bone is achieved by administration of a sclerosing agent to the treatment volume, for example, by injection into or irrigation of the treatment volume with fluid containing the sclerosing agent. The sclerosing agent is allowed to remain within the treatment volume for a time, and is then displaced, e.g. by administration of bone graft material, or otherwise removed, e.g. by aspiration. One or more such administrations of sclerosing agent can be made, for example, one, two, or thee administrations can be made. The sclerosing agent is allowed to remain in the treatment volume for a period of time, for example, for about <NUM> to about <NUM> minutes. In a preferred embodiment, the sclerosing agent is allowed to remain within the bone for eight to fifteen minutes, more preferably for about ten minutes. In a further preferred embodiment, the sclerosing agent is administered twice, in each instanced being allowed to remain within the cyst for eight to fifteen minutes, more preferably for about ten minutes.

Chemical curettage is preferably performed under general anesthesia.

Physical or chemical cauterization is believed to impede the underlying disease process of bone cysts. But until bone growth resumes, the bone cortex remains fragile and the treated lesions remain vulnerable to fracture. The introduction of bone graft material into the treatment volume provides increased strength to the compromised bone in the post-procedural period.

In the system and methods of the invention, a minimally invasive mechanism for administration of bone graft material is provided. This mechanism is suitable for administration of bone graft material to treat a UBC without a surgical incision. This mechanism can also be used to treat a cyst volume, for example, the volume of an ABC, or another defined treatment volume, for example, a volume defined as suitable for a single treatment. The system and methods of the invention can be used to treat bone defects resulting from various disease processes, including for example Gorham-Stout disease.

Administration of bone graft material is achieved by delivering the material into the treatment volume, for example, through an insertable and typically tubular delivery device. In a preferred embodiment, bone graft material is administered by injection with a needle. Preferably, bone graft material that is sufficient to fill the treatment volume is delivered. The bone graft material remains in the bone, providing stability and fostering growth of bone.

Administration of bone graft material is preferably performed under general anesthesia.

The bone graft material can be synthetic. Synthetic bone grafts typically promote faster, denser, and stronger bone regeneration than autologous bone grafts. For example, the bone graft material can be a calcium sulfate-calcium phosphate (CaSO4-CaPO4) material, such as PRO-DENSE (Wright Medical Technology Inc. , Arlington, TN). This synthetic bone graft material progresses through a triphasic resorption pattern, with initial resorption of CaSO4, followed by brushite, and finally beta-tricalcium phosphate.

The treatment volume must be localized and its volume, dimensions, or general size estimated. This can be approximated prior to a procedure or at the time of the procedure by imaging. A bone cyst or area for treatment can be localized, for example using fluoroscopy or sonographically, and marked on the skin. For example, the upper and lower margins of a UBC can be marked on the skin. In addition, ultrasound mapping of the area of concern can be performed to identify critical structures such as arteries or nerves. Such methods are known to interventional radiologists, but may not be known to orthopedic surgeons.

A delivery device may be placed into the treatment volume. Image-guided techniques can be used to ensure proper placement of the delivery device. Such methods are known in the field of interventional radiology, and include, for example, introduction of a contrast agent into the treatment volume for purposes of imaging. A small incision, e.g. about <NUM>, can be made at the cyst margin as marked on the skin, and the delivery device is then advanced into the cyst percutaneously. The delivery device is a needle.

Choice of needle gauge can be determined by the estimated size of the treatment volume, (e.g. the cyst size), viscosity of the bone graft material, and/or the expected amount of synthetic graft to be administered. For example, a <NUM>-gauge needle may be appropriate for many UBCs, but an <NUM>-gauge needle may be preferred for larger cysts to permit delivery of larger volumes of bone graft material. A larger gauge (i.e. smaller diameter) needle may minimize impacts to the patient and may be made possible by lowering the viscosity of the bone graft material or use of less viscous bone graft material.

A venting device should be used for administration of fluids to a closed-compartment target volume, such as a UBC. For example, a second small incision, e.g. about <NUM>, can be made, e.g. at the cyst margin as marked on the skin. The venting device is a needle, and is advanced into the cyst percutaneously. A venting needle is typically smaller than or the same size as a treatment needle, for example, a <NUM>-gauge or <NUM>-gauge venting needle can be placed for use with an <NUM>-gauge, <NUM>-gauge or <NUM> gauge treatment needle.

In the absence of a venting device, a closed-compartment target volume may become pressurized, and this may lead to egress of cyst contents, including sclerosants, into systemic drainage via medullary veins, likely decreasing the efficacy of the sclerotherapy. Venous egress of bone graft material due to inadequate venting of the target volume may increase the theoretical risk of devastating venous embolic complications.

The treatment volume can be determined at the time of the procedure via contrast injection into the treatment volume. For example, Omnipaque-<NUM> (GE Healthcare), a water-soluble iodinated contrast, can be diluted with sterile saline and injected via the treatment needle during fluoroscopic visualization, taking care to ensure fluid egress via the venting device. Failure to observe fluid egress via the venting device during injection of the treatment device should alert the physician that one or both of the devices may not be positioned adequately.

Chemical curettage of the treatment volume is achieved by injection of the sclerosing agent through the treatment device. The sclerosing agent is aspirated through the venting device in a push-pull fashion, irrigating the treatment volume. For example, doxycycline (<NUM>/mL), in a volume to match the cyst volume, can be injected through the treatment device, aspirated for one minute, and then allowed to dwell in the treatment volume for another nine minutes. The doxycycline appears yellow prior to initial injection, although is expected to progressively darken during the irrigation process. A second round of sclerosant irrigation can be performed using similar technique and fresh doxycycline solution, in which case the total duration of the sclerotherapy is <NUM> minutes.

After chemical curettage, bone graft material is delivered to the treatment volume. The volume of bone graft material prepared is based on an estimate of the treatment volume. For example, a volume of bone graft material that is about the same as, or greater than, the treatment volume is prepared. The bone graft material is administered by delivering it into the treatment volume, for example, by injection. The bone graft material is radiopaque and can be delivered during live fluoroscopy. Delivery of the radiopaque synthetic bone graft material should be stopped when either the entire lesion appears opacified with the graft material, e.g. as indicated by exit of the material through the venting device.

After the bone graft material is delivered, the treatment device and venting device can be removed. At the termination of the procedure, the incisions can be covered with sterile dressings. Stitches are typically not necessary and the sterile dressings can be safely removed about <NUM> to <NUM> hours later.

While the procedure just described is a minimally invasive procedure, preferably image guided, chemical curettage followed by the introduction of bone graft material could also be performed in an "open" manner, i.e., after making an incision and splaying the tissue down to the bone, and optionally opening the bone. In one such open embodiment, the sclerosing agent can be administered with any of a variety of applicators suitable for irrigation of an opening, e.g. with a syringe. In another open embodiment, the bone graft material can be administered according to current practice, e.g., with a spatula or by injection via large bore needle. In a preferred open embodiment, the bone is not opened, and the sclerosing agent and bone graft material are delivered with one or more needles and/or another tubular delivery device. This avoids unnecessary disruption of the bone structure and may provide for more complete administration of the bone graft material to all portions of the treatment volume.

Radiographs can be used to assess the treatment region after chemical curettage and administration of bone graft material. In some embodiments, the bone graft material can be initially hyperdense relative to normal adjacent bone, and can become less dense as it is slowly resorbed. The radiographic evolution of graft material decreasing density should not be confused with cyst recurrence. A recurrence may have cortical bone adjacent to the area of bone graft resorption that is thinned and scalloped.

Factors evaluated on radiographs can include lesion size, amount of new bone formation within the cyst, amount of residual cyst lucency, presence of cortical thickening, and presence of a sclerotic margin. The Modified Neer Classification of Radiographic Healing, shown in Table <NUM>, can be used to classify the degree of healing of a bone cyst.

The systems and methods described herein provide a high radiographic healing rate and a return to normal activity that is at least comparable to existing surgical techniques. The methods can be less invasive than the existing surgical alternatives, and can thereby lessen the time required for wound healing and patient recovery; lessen the risk of infection, bleeding, and complications; and lessen the pain, discomfort, and general impact on the patient, with better cosmetic outcomes. In addition, the time required to complete a procedure as described herein is generally less than the time required to perform an alternative surgical treatment.

Retrospective evaluation of twelve pediatric patients, ages <NUM>-<NUM> years, undergoing treatment for a UBC, at a single institution. All UBCs were treated in a single, minimally invasive, image guided procedure using percutaneous needle access into the UBC followed by chemical curettage (a form of sclerotherapy) and injection of regenerative synthetic graft. Patients were followed clinically, and with serial radiographs, to evaluate for healing and complications. Mean time to return to full activity was <NUM> months post procedure, with a mean clinical follow-up time of <NUM> months.

Fifteen patients were initially enrolled in this IRB approved study from August <NUM> through May <NUM>. The diagnosis of UBC was made via radiographs and/or magnetic resonance imaging (MRI).

Combination sclerotherapy and graft injection with CaSO<NUM>-CaPO<NUM> was performed in a single setting as an outpatient procedure with an average procedure time of <NUM> minutes (range <NUM>-<NUM> minutes). Mean volume of doxycycline instilled during cyst sclerotherapy was <NUM> (<NUM>/ml and a range <NUM>-<NUM>). Mean volume of CaSO<NUM>-CaPO<NUM> synthetic graft material administered was <NUM> (range <NUM>-<NUM>).

Patients were followed clinically for a minimum of three months post procedure, with radiographs performed at follow-up visits. One patient was excluded as they had imaging consistent with a fractured UBC that had subsequently rehealed into multiple cysts, and <NUM> other patients were excluded secondary to follow up of less than <NUM> months.

Assessment of treatment response was evaluated using the Modified Neer Classification of Radiographic Healing, as shown above in Table <NUM>. All radiographs were evaluated by four attending pediatric radiologists. Treatment success in this series was defined as post treatment radiographs exhibiting findings of Modified Neer classes <NUM> or <NUM>.

Procedure Technique. All procedures were performed under general anesthesia. For each procedure, the cyst was localized under fluoroscopy, and the upper and lower margins of the cyst were marked on the skin. Ultrasound mapping of the area of concern was performed to identify critical structures such as arteries or nerves. However, the cyst itself could often be visualized sonographically due to associated cortical thinning.

A <NUM> incision was made at each cyst margin as marked on the skin, and an <NUM>-gauge or <NUM>-gauge "treatment" needle was advanced into the cyst percutaneously. Choice of needle gauge was determined by cyst size and the expected amount of synthetic graft to be administered, with <NUM>-gauge needles used in larger cysts. A second <NUM> incision was made along the remaining marked margin of the lesion, and a <NUM>-gauge or <NUM>-gauge "venting" needle was placed. For example, as shown in <FIG>, an <NUM>-gauge "treatment" needle and a smaller <NUM> gauge "venting" needle were positioned within the left proximal femur UBC for a patient who exhibited pain and limp.

Next, Omnipaque-<NUM> (GE Healthcare), a water-soluble iodinated contrast, was diluted with sterile saline in a <NUM>:<NUM> ratio and was injected via the treatment needle during fluoroscopic visualization, taking care to ensure fluid egress via the venting needle. Contrast injection was performed to confirm a cystic nature of the UBC, to ensure adequate diffusion of the injected contrast throughout the cystic cavity, as well as to assess the presence of unexpected significant vascular outflow. Occasionally, an incomplete septation within the cyst was encountered, likely secondary healing change related to a prior pathologic fracture or prior treatment.

Doxycycline (<NUM>/mL), in a volume to match the cyst volume, was injected through the treatment needle and aspirated through the venting needle in a push-pull fashion, irrigating the cyst for one minute. The doxycycline was allowed to dwell for another nine minutes. A second round of sclerosant irrigation was then performed using similar technique and fresh doxycycline solution; thus, the total duration of doxycycline sclerotherapy was <NUM> minutes.

Utilizing the cyst volume determined during initial contrast injection, a similar volume of synthetic bone graft material was prepared and injected through the treatment needle during live fluoroscopy. Injection of the radiopaque synthetic bone graft material was stopped when either the entire lesion appears opacified with the graft material or the material was seen to exit the venting needle. As shown for example in <FIG>, this resulted in dense packing of synthetic graft within the cyst after sclerotherapy.

Both needles were removed, and each incision was sterilely dressed. Post procedure activity instructions and limitations varied depending on the patient's cyst size and location; any limitations remained in place until evidence of healing was present on follow-up radiographs. For example, as shown in <FIG>, at a <NUM> month follow up, there was cortical thickening and progressive sclerosis (i.e. stiffening or hardening of the bone) of the left femur UBC.

The study population consisted of nine (<NUM>%) male patients and three (<NUM>%) female patients, with an average age of <NUM> years at the time of treatment (range <NUM>-<NUM>, SD <NUM>) (Table <NUM>). Seven lesions (<NUM>%) were located in the humerus, two (<NUM>%) in the tibia, and one in the ilium, the femur, and the navicular bone. Radiographs demonstrated open physes, consistent with skeletal immaturity, in <NUM> of <NUM> patients at the time of treatment. Patients either had an MRI, radiographs, or both during their initial clinical evaluation.

Six patients presented with a history of pathologic fracture. For example, as shown in <FIG>, one patient presented with left humerus UBC and prior healed pathologic fracture. <FIG> is a frontal radiograph that shows a left humerus expansile lucent lesion with cortical thinning, consistent with UBC. <FIG> shows increased cortical thickening and dense packing of the synthetic graft, consistent with healing, three months post treatment with doxycycline sclerotherapy and synthetic grafting.

Three patients presented with history of recurrent UBC after prior mechanical curettage and grafting. For example, as shown in <FIG>, one patient presented with right humerus UBC and history of recurrence, including a prior healed pathologic fracture, post prior surgical curettage and grafting. <FIG> is a frontal radiograph that shows a right humeral UBC with an associated fracture which subsequently underwent surgical curettage and grafting. <FIG> is a follow-up radiograph from <NUM> year later that shows recurrence. The patient subsequently underwent sclerotherapy and grafting. <FIG> shows increased sclerosis (stiffening or hardening) and cortical thickening <NUM> months post doxycycline sclerotherapy and synthetic grafting. <FIG> shows complete graft resorption without evidence of cyst recurrence at <NUM> months post treatment.

A summary of data for the patients and their treatment is provided in Table <NUM> below.

The most recent follow-up radiographs showed healing of the UBC (Modified Neer class <NUM>) in <NUM> patients (<NUM>%) and healing with a small defect (Modified Neer class <NUM>) in one patient (<NUM>%). No perioperative complications were observed. In summary, <NUM> of <NUM> (<NUM>%) patients showed healed cysts at their most recent follow-up and there was one case of recurrence noted at <NUM> months. Patients were pain-free and returned to normal physical activity on average within <NUM> months, and all patients remained asymptomatic at the most recent follow-up. There were no adverse events related to the procedures.

A patient with Gorham-Stout disease (syndrome), also known as vanishing bone disease, was treated with the minimally invasive, image-guided methods described herein. Gorham-Stout disease is a rare condition of unknown etiology, characterized by destruction of osseous matrix and proliferation of vascular structures, resulting in diffuse destruction and absorption of bone.

In this particular case, there was diffuse involvement of the entire skeleton resulting in marked morbidity and fracture merely from moving. The decision to treat the whole right femur was made as no appropriate surgical alternative exists and the patient had exhausted medical alternatives. Using techniques similar to those described here for treatment of UBCs and ABCS, seven accesses were performed along the entirety of the right femur, each resulting in placement of a needle, and using a combination of curettes and balloons, the multiple cysts walls were disrupted, the wall linings were sclerosed, and the femur was grafted in its entirety.

<FIG> shows the proximal portion of the patient's femur before (<FIG>) and after (<FIG>) preparation of the treatment volume, chemical curettage and injection of bone graft material, all performed in a minimally invasive manner with image guidance. <FIG> shows the placement of three needles and administration of bone graft material performed as part of this procedure. Bone graft was administered from each needle as the other needles acted as a venting needle and the need for more than one needle was due to the presence of multiple cystic cavities. <FIG> shows the distal portion of the patient's femur before (<FIG>) and after (<FIG>) preparation of the treatment volume, chemical curettage and injection of bone graft material, all performed in a minimally invasive manner with image guidance. <FIG> shows the placement of two needles and administration of bone graft material as part of this procedure. <FIG> shows mechanical preparation of the treatment using a curette, which was done prior to introduction of the sclerosant, as part of this treatment procedure.

Prior to this treatment, a similar procedure was performed on the left humerus of the same patient. Nine months after the procedure, the left humerus showed increased bone cortical thickening and sclerosis (stiffening or hardening) and no fracture.

Two patients having ABCs were treated with the methods described here.

One patient presenting with an ABC in the right clavicle, as shown in <FIG>, was treated as follows: Image-guided preparation of the treatment volume was completed using a balloon, as shown in <FIG>; image-guided chemical curettage was performed by percutaneous administration of doxycycline with a needle; and bone graft material was delivered via a delivery needle with placement of a venting needle, as shown in <FIG>, filling the treatment volume shown in <FIG>, as demonstrated in <FIG>.

One patient presenting with an ABC in the right humerus was treated in a similar manner.

Disclosed but not part of the invention as claimed is a kit for performing the methods described herein.

In some embodiments, the kit includes bone graft material. The bone graft material may be in any form, including a powder, granules, or putty, a paste form, that is or can be made suitable for injection into a treatment volume of a bone of the patient. In some embodiments, the kit includes a tube or tubular device suitable for venting the treatment volume of a bone of a patient, and a tube or tubular device suitable for delivery of the bone graft material into the treatment volume. The device suitable for delivery of the bone graft material can be suitable for delivery of a fluid comprising a sclerosing agent into the treatment volume.

In some embodiments, the bone graft material must be mixed with liquid to become suitable for injection into bone. In some embodiments, the device suitable for venting the fluid is a needle and the device suitable for delivery of the bone graft material is a needle. In some embodiments, the needle for deliver is larger than the needle for venting, to accommodate the viscosity of the bone graft material. In some embodiments, the needle for delivery is as small as the venting needle. In some embodiments, the needle for delivery has a gauge of <NUM> or higher (smaller), e.g. <NUM> gauge, <NUM> gauge, or <NUM> gauge. Smaller needles can be used for delivery of less viscous bone graft material.

In some embodiments, the kit further includes a device for preparation of the treatment volume. The device for preparation of the treatment volume can have one or more expandable components, such as one or more balloons. The device for preparation of the treatment volume can be a surgical tool, e.g. a curette.

The phrase "as used herein" encompasses all of the specification, the abstract, the drawings (figures), and the claims.

As used herein, the use of the singular includes the plural and vice versa unless expressly stated to be otherwise, or as obvious from the context that such is not intended. That is, "a," "an" and "the" refer to one or more of whatever the word modifies. For example, "a sample" may refer to one sample, two samples, etc. Likewise, "the sample" may refer to one, two or more samples. By the same token, words such as, without limitation, "samples" would refer to one sample as well as to a plurality of samples unless it is expressly stated or obvious from the context that such is not intended.

As used herein, unless specifically defined otherwise, any words of approximation such as without limitation, "about," "essentially," "substantially," and the like mean that the element so modified need not be exactly what is described but can vary from the description. The extent to which the description may vary will depend on how great a change can be instituted and have one of ordinary skill in the art recognize the modified version as still having the properties, characteristics and capabilities of the unmodified word or phrase. With the preceding discussion in mind, a numerical value herein that is modified by a word of approximation may vary from the stated value by ±<NUM>% in some embodiments, by ±<NUM>% in some embodiments, by ±<NUM>% in some embodiments, or in some embodiments, may be within the <NUM>% confidence interval. As used herein, all numbers which represent physical values or measurements are subject to the standard error in the measurement of the value.

As used herein, any ranges presented are inclusive of the end-points. In addition, throughout this disclosure, various aspects of this invention may be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. As an example, a description of a range such as from <NUM> to <NUM> should be considered to have specifically disclosed subranges such as from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM> etc., as well as individual numbers within that range, for example, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>. Unless expressly indicated, or from the context clearly limited to integers, a description of a range such as from <NUM> to <NUM> should be considered to have specifically disclosed subranges <NUM> to <NUM>, etc., and individual values such as <NUM>, etc. that is non-integer individual values and ranges beginning with, ending with or both beginning with and ending with non-integer value(s).

As used herein, the word "about" may be used to characterize a particular value. When values are expressed as approximations by use of the antecedent "about," it will be understood that the particular value forms another embodiment. As a non-limiting example, if "from about <NUM> to about <NUM>" is disclosed, another embodiment is "from <NUM> to <NUM>," even if not expressly disclosed. Likewise, if one embodiment disclosed is a temperature of "about <NUM>%," then another embodiment is "<NUM>%," even if not expressly disclosed. Similarly, numbers or ranges presented as a specific value or specific range also encompass another embodiment in which the number or the end of the range is preceded by "about. " As a non-limiting example, if "an abundance of <NUM>%" is expressly disclosed, then another embodiment is "an abundance of about <NUM>%," even if not expressly disclosed. In a similar manner, if "from <NUM> to <NUM>" is disclosed, another embodiment is "from about <NUM> to about <NUM>," even if not expressly disclosed.

As used herein, the use of "preferred," "preferably," or "more preferred," and the like to describe an embodiment refers to preferences as they existed at the time of filing of the patent application.

Claim 1:
A sclerosing agent and bone graft material for use in a method for treatment of a bone lesion in a patient, the method comprising:
locating a treatment volume in the bone of the patient, wherein the treatment volume is a unicameral bone cyst;
placing a venting device into the treatment volume, wherein the venting device comprises a needle;
administering the sclerosing agent to the treatment volume; and
after administering the sclerosing agent, administering the bone graft material to the treatment volume;
wherein administering the sclerosing agent to the treatment volume includes administering a fluid comprising the sclerosing agent and is performed using a delivery device that comprises a needle, and wherein the sclerosing agent is aspirated through the venting device in a push-pull fashion, irrigating the treatment volume.