Tissue spacer

Abstract

To provide improved methods of radiation therapy, including reducing the dose of radiation therapy to tissue proximate to the site of radiation therapy.SOLUTION: A method of spacing a first tissue site in a subject from a second tissue site in the subject, the method comprising: (a) placing a viscoelastic medium in spaced relation between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises non-animal stabilized hyaluronic acid ("NASHA") and a gadolinium complex.SELECTED DRAWING: Figure 9

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 62 / 843,267, filed May 3, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Radiation therapy is generally considered a palliative treatment option for severe or rare cases of melanoma. However, recently, there has been an increasing demand for new systems and methods of melanoma management. Brachytherapy techniques, including balloon or strut multicatheter brachytherapy, involve applicators placed into the surgical cavity by the breast surgeon at the time of or immediately after wide local excision.

[0003] Current treatments have numerous drawbacks known in the art, including difficulty in imaging across all imaging modalities across all cavity locations, difficulty in application, and migration of the balloon, structure, or spacer after their placement. Summary of the Invention

[0004] The formulations and methods described herein include improved methods of radiation therapy. More specifically, the formulations and methods described herein include reducing the radiation therapy dose to tissues adjacent to the site of radiation therapy.

[0005] Aspects of the disclosure described herein include a method of spacing a first tissue site of a subject from a second tissue site of a subject, the method comprising disposing a viscoelastic medium in the space between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises non-animal stabilized hyaluronic acid ("NASHA") and a gadolinium complex. In some embodiments, the method further comprises monitoring or imaging the space between the first tissue site and the second tissue site. In some embodiments, the space between the first tissue site and the second tissue site ranges from about 0.1 cm to about 10 cm. In some embodiments, the gadolinium complex is present in a range from about 1 mg / ml to about 10 mg / ml. In some embodiments, the viscoelastic medium comprises a volume of about 1 ml to about 50 ml. In some embodiments, the viscoelastic medium is dispensed through a 10-25 gauge needle. In some embodiments, the viscoelastic medium comprises NASHA at a concentration ranging from about 5 mg / ml to about 100 mg / ml. In some embodiments, the viscoelastic medium comprises gel particles ranging in size from about 0.2 mm to about 5 mm. In some embodiments, the viscoelastic medium is placed subcutaneously or subepidermally. In some embodiments, the first tissue site and the second tissue site are selected from the group consisting of breast, head and neck, cervix, vagina, base of spine, skin, pancreas, liver, or lung of a subject. In some embodiments, the imaging comprises real-time imaging. In some embodiments, the viscoelastic medium is configured to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium. In some embodiments, the imaging comprises MRI, CT, ultrasound, or a combination thereof. In some embodiments, the viscoelastic medium is bioabsorbable.

[0006] Another aspect of the disclosure described herein includes a method of spacing a first tissue site of a subject from a second tissue site of a subject, the method comprising disposing a viscoelastic medium between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises one or more visualization additives. In some embodiments, the method further comprises monitoring or imaging the distance between the first tissue site and the second tissue site. In some embodiments, the distance between the first tissue site and the second tissue site is within a range of about 0.1 cm to about 10 cm. In some embodiments, the visualization additive is present in an amount sufficient to produce contrast when imaged by an imaging modality. In some embodiments, the viscoelastic medium comprises a volume of about 1 ml to about 50 ml. In some embodiments, the viscoelastic medium is dispensed through a 10-25 gauge needle. In some embodiments, the viscoelastic medium comprises hyaluronic acid, polyethylene glycol, or dextranomer at a concentration ranging from about 5 mg / ml to about 100 mg / ml. In some embodiments, the viscoelastic medium comprises gel particles ranging in size from about 0.08 mm to about 5 mm. In some embodiments, the viscoelastic medium is placed subcutaneously or subepidermally. In some embodiments, the tissue site and the second tissue site are selected from the group consisting of breast, head and neck, cervix, vagina, base of spine, skin, pancreas, liver, or lung of a subject. In some embodiments, the imaging comprises real-time imaging. In some embodiments, the imaging is performed within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium. In some embodiments, the imaging comprises MRI, CT, ultrasound, or a combination thereof. In some embodiments, the imaging modality comprises MRI, CT, ultrasound, or a combination thereof. In some embodiments, the viscoelastic medium is substantially immobile prior to and during the imaging. In some embodiments, the visualization additive comprises one or more nanoparticles. In some embodiments, the visualization additive comprises a precious metal. In some embodiments, the precious metal comprises iron or gold.In some embodiments, the viscoelastic medium is bioabsorbable. In some embodiments, the visualization additive comprises iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or a combination thereof.

[0007] Another aspect of the disclosure described herein is a method of preventing or reducing damage to tissue adjacent to a radiation therapy site in a subject undergoing radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the radiation therapy site, wherein the bioabsorbable viscoelastic medium comprises a visualization additive. In some embodiments, the injection displaces the tissue a distance ranging from about 0.1 cm to about 10 cm. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise hyaluronic acid or a derivative thereof. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml. In some embodiments, the injection is administered through a 10-25 gauge needle. In some embodiments, the concentration of hyaluronic acid ranges from about 5 mg / ml to about 100 mg / ml. In some embodiments, the size of the gel particles ranges from about 0.2 mm to about 5 mm. In some embodiments, the injection is subcutaneous or subepidermal. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the visualization additive comprises one or more nanoparticles. In some embodiments, the nanoparticles comprise a precious metal. In some embodiments, the radiation therapy dose in contact with tissue adjacent to the site of radiation therapy is reduced by about 10% to about 80%. In some embodiments, the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. The method of any one of embodiments 35-48, further comprising administering hyaluronidase at the site of radiation therapy. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. In some embodiments, the administration of hyaluronidase occurs about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, the method further comprises imaging the site of radiation therapy. In some embodiments, the imaging comprises serial imaging. In some embodiments, the imaging comprises MRI, CT scan, ultrasound, or a combination thereof.

[0008] Another aspect of the disclosure described herein includes a method for reducing a radiation therapy dose to tissue adjacent to a radiation therapy site in a subject receiving radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the radiation therapy site. In some embodiments, the injection displaces the tissue a distance ranging from about 0.1 cm to about 10 cm. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise hyaluronic acid or a derivative thereof. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml. In some embodiments, the injection is administered through a 10-25 gauge needle. In some embodiments, the concentration of hyaluronic acid ranges from about 5 mg / ml to about 100 mg / ml. In some embodiments, the size of the gel particles ranges from about 0.2 mm to about 5 mm. In some embodiments, the injection is subcutaneous or subepidermal. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the viscoelastic medium further comprises one or more nanoparticles. In some embodiments, the nanoparticles comprise a precious metal. In some embodiments, the radiation therapy dose is reduced by about 10% to about 80%. In some embodiments, the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. In some embodiments, the administration of hyaluronidase occurs about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium.

[0009] Another aspect of the disclosure described herein includes a method for temporarily superspacing tissue adjacent to a site of radiation therapy, comprising injecting a formulation comprising crosslinked hyaluronic acid or a derivative thereof and a large amount of degradable nanoparticles encapsulating hyaluronidase. In some embodiments, the amount of degradable nanoparticles encapsulating hyaluronidase is directly proportional to the desired distance of superspacing relative to the desired duration of superspacing. In some embodiments, the method further comprises injecting a bioabsorbable viscoelastic medium into a blood vessel, wherein the blood vessel is directly connected to the tumor. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise hyaluronic acid or a derivative thereof. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml. In some embodiments, the injection is performed through a 10-25 gauge needle. In some embodiments, the concentration of hyaluronic acid ranges from about 5 mg / ml to about 100 mg / ml. In some embodiments, the size of the gel particles ranges from about 0.2 mm to about 5 mm. In some embodiments, blood flow to the tumor is avoided or reduced. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the method includes administering hyaluronidase at the site of radiation therapy. In some embodiments, the administration of hyaluronidase occurs about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, the method further includes excising remaining tumor cells from the subject.

[0010] Another aspect of the disclosure described herein includes a composition comprising a viscoelastic medium and a visualization additive. In some embodiments, the visualization additive is present in an amount sufficient to produce contrast when imaged by an imaging modality. In some embodiments, the viscoelastic medium comprises a volume of about 1 ml to about 50 ml. In some embodiments, the viscoelastic medium is configured to be deployed through a 10-25 gauge needle. In some embodiments, the viscoelastic medium comprises hyaluronic acid, polyethylene glycol, or dextranomer at a concentration ranging from about 5 mg / ml to about 100 mg / ml. In some embodiments, the viscoelastic medium comprises gel particles ranging in size from about 0.08 mm to about 5 mm. In some embodiments, the visualization additive configures the viscoelastic medium to be imaged, wherein the imaging comprises real-time imaging. In some embodiments, the visualization additive configures the viscoelastic medium to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of deployment of the viscoelastic medium. In some embodiments, the visualization additive configures the viscoelastic medium to be imaged, where the imaging comprises MRI, CT, ultrasound, or a combination thereof. In some embodiments, the imaging modality comprises MRI, CT, ultrasound, or a combination thereof. In some embodiments, the viscoelastic medium is configured to be substantially immobile upon displacement. In some embodiments, the visualization additive comprises one or more nanoparticles. In some embodiments, the visualization additive comprises a precious metal. In some embodiments, the precious metal comprises iron or gold. In some embodiments, the viscoelastic medium is bioabsorbable. In some embodiments, the visualization additive comprises iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or a combination thereof.

[0011] Further provided herein is the use of a viscoelastic medium for the manufacture of a drug. In some embodiments, greater than 70% (v / v) of the particles are within a given size range under physiological conditions, including in humans. Provided herein are particles of a viscoelastic medium, which are injectable gel particles having a size range of 1 to 5 mm when exposed to a physiological salt solution. Subcutaneous administration of an implant containing gel particles made of a viscoelastic medium, which are significantly larger than previously used implants made of a viscoelastic medium, is useful for avoiding migration and / or displacement of the implant or portions thereof from the desired site of radiation protection. Furthermore, the limited displacement of the implant combined with the significant particle size can facilitate easy removal of the implant, if necessary. In one embodiment herein, the particle size is within the range of 1 to 2.5 mm. In some embodiments, the size is within the range of 2.5 to 5 mm. In embodiments herein, the viscoelastic medium is selected from the group consisting of polysaccharides and derivatives thereof. In some embodiments, the viscoelastic medium is selected from stable glycosaminoglycans and derivatives thereof. In some embodiments, the viscoelastic medium is selected from the group consisting of stabilized hyaluronic acid, stabilized chondroitin sulfate, stabilized heparin, and derivatives thereof. In some embodiments herein, the viscoelastic medium is selected from the group consisting of cross-linked hyaluronic acid and derivatives thereof. In some embodiments, the concentration of the viscoelastic medium in the gel particles is in the range of 5-100 mg / ml when exposed to physiological salt solution. In some embodiments, the particles herein are injectable through a 20-gauge or larger needle by applying a pressure of 15-50 N.

[0012] Further provided herein is a method for producing gel particles of an injectable viscoelastic medium, the method comprising the steps of: (i) producing a gel having a desired concentration of the viscoelastic medium; and (ii) mechanically disrupting the gel into gel particles having a size in the range of 1 to 5 mm when exposed to a physiological salt solution.

[0013] Also provided herein is a radiation protective implant comprising particles of a viscoelastic medium, the majority of which, when exposed to physiological salt solution, are injectable gel particles having a size in the range of 1-5 mm. In one embodiment of the implant, the size is in the range of 1-2.5 mm. In another embodiment of the implant, the size is in the range of 2.5-5 mm.

[0014] Further provided herein is a method for radioprotection of adjacent organs in a mammal, including a human, comprising subepidermal administration of an implant comprising injectable gel particles of a viscoelastic medium at a site in the mammal where soft tissue radioprotection is desired, wherein the primary volume of the particles has a size in the range of 1-5 mm when exposed to physiological salt solution. In some embodiments, the administration is selected from the group consisting of subcutaneous administration, submuscular administration, and epiperiosteal administration. In some embodiments, the size is in the range of 1-2.5 mm. In some embodiments, the site of radioprotection is selected from facial tissues and other tissues covered by exposed skin. In some embodiments, the size is in the range of 2.5-5 mm. In some embodiments, the administration is selected from the group consisting of a single administration and a multi-layer administration.

[0015] Further provided herein are injectable gel particles according to embodiments herein for use as a medicament. Further provided herein are injectable radioprotective implants comprising injectable gel particles according to embodiments herein for use as a medicament.

[0016] Also provided herein are methods of using injectable gel particles of a viscoelastic medium according to embodiments herein. In some embodiments, the particles have an average size in the range of 1-5 mm when exposed to physiological salt solution for the manufacture of a medicament for therapeutic radioprotection in a mammal, including a human, wherein the medicament is suitable for subepidermal administration according to embodiments herein at a site in the mammal where therapeutic radioprotection is desired.

[0017] Further provided herein are particles of a viscoelastic medium, which are injectable gel particles having a size in the range of 1 to 5 mm when exposed to physiological salt solution. The particles are useful in radioprotective implants comprising particles of a viscoelastic medium, a majority of the particles being injectable gel particles having a particular size or range of sizes in the range of 1 to 5 mm when exposed to physiological salt solution. The implants, in turn, are useful in methods of radioprotection in mammals, including humans, comprising subcutaneous administration of an implant comprising injectable gel particles of a viscoelastic medium at a site in the mammal where radioprotection is desired, wherein a majority of the particles have a size in the range of 1 to 5 mm when exposed to physiological salt solution.

[0018] Another aspect provided herein is a method of preventing or reducing damage to tissue adjacent to a radiation therapy site in a subject undergoing radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the radiation therapy site. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise hyaluronic acid or a derivative thereof.

[0019] In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 10 cm. In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 0.2 cm, about 0.1 cm to about 0.5 cm, about 0.1 cm to about 1 cm, about 0.1 cm to about 2 cm, about 0.1 cm to about 3 cm, about 0.1 cm to about 4 cm, about 0.1 cm to about 5 cm, about 0.1 cm to about 6 cm, about 0.1 cm to about 7 cm, about 0.1 cm to about 8 cm, about 0.1 cm to about 10 cm, about 0.2 cm to about 0.5 cm, about 0.2 cm to about 1 cm, about 0.2 cm to about 2 cm m, about 0.2cm to about 3cm, about 0.2cm to about 4cm, about 0.2cm to about 5cm, about 0.2cm to about 6cm, about 0.2cm to about 7cm, about 0.2cm to about 8cm, about 0.2cm to about 10cm, about 0.5cm to about 1 cm, approximately 0.5cm to approximately 2cm, approximately 0.5cm to approximately 3cm, approximately 0.5cm to approximately 4cm, approximately 0.5cm to approximately 5cm, approximately 0.5cm to approximately 6cm, approximately 0.5cm to approximately 7cm, approximately 0.5cm to approximately 8cm, approximately 0.5cm to approximately 1 0cm, approximately 1cm to approximately 2cm, approximately 1cm to approximately 3cm, approximately 1cm to approximately 4cm, approximately 1cm to approximately 5cm, approximately 1cm to approximately 6cm, approximately 1cm to approximately 7cm, approximately 1cm to approximately 8cm, approximately 1cm to approximately 10cm, approximately 2cm to approximately 3cm, approximately 2cm to 4cm, 2cm to 5cm, 2cm to 6cm, 2cm to 7cm, 2cm to 8cm, 2cm to 10cm, 3cm to 4cm, 3cm to 5cm, 3cm to 6cm, 3cm to 6cm In some embodiments, the injection displaces tissue by a distance of about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 3 cm to about 8 cm, about 3 cm to about 10 cm, about 4 cm to about 5 cm, about 4 cm to about 6 cm, about 4 cm to about 7 cm, about 4 cm to about 8 cm, about 4 cm to about 10 cm, about 5 cm to about 6 cm, about 5 cm to about 7 cm, about 5 cm to about 8 cm, about 5 cm to about 10 cm, about 6 cm to about 7 cm, about 6 cm to about 8 cm, about 6 cm to about 10 cm, about 7 cm to about 8 cm, about 7 cm to about 10 cm, or about 8 cm to about 10 cm.In some embodiments, the injection displaces the tissue a distance of at least about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, or about 8 cm. In some embodiments, the injection displaces the tissue a distance of at most about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, or about 10 cm. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml.In some embodiments, the injection may be about 1 ml to about 2 ml, about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 15 ml, about 1 ml to about 20 ml, about 1 ml to about 25 ml, about 1 ml to about 30 ml, about 1 ml to about 35 ml, about 1 ml to about 40 ml, about 1 ml to about 45 ml, about 1 ml to about 50 ml, about 2 ml to about 5 ml, about 2 ml to about 10 ml, about 2 ml to about 15 ml, about 2 ml to about 20 ml, about 2 ml to about 25 ml, about 2 ml to about 3 0ml, about 2ml to about 35ml, about 2ml to about 40ml, about 2ml to about 45ml, about 2ml to about 50ml, about 5ml to about 10ml, about 5ml to about 15ml, about 5ml to about 20ml, about 5ml to about 25ml, about 5ml to about 30ml, approximately 5ml to approximately 35ml, approximately 5ml to approximately 40ml, approximately 5ml to approximately 45ml, approximately 5ml to approximately 50ml, approximately 10ml to approximately 15ml, approximately 10ml to approximately 20ml, approximately 10ml to approximately 25ml, approximately 10ml to approximately 30ml, approximately 10ml to about 35ml, about 10ml to about 40ml, about 10ml to about 45ml, about 10ml to about 50ml, about 15ml to about 20ml, about 15ml to about 25ml, about 15ml to about 30ml, about 15ml to about 35ml, about 15 ml~about 40ml, about 15ml~about 45ml, about 15ml~about 50ml, about 20ml~about 25ml, about 20ml~about 30ml, about 20ml~about 35ml, about 20ml~about 40ml, about 20ml~about 45ml, about 20ml In some embodiments, the injection comprises a volume of about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, about 50 ml, about 25 ml to about 30 ml, about 25 ml to about 35 ml, about 25 ml to about 40 ml, about 25 ml to about 45 ml, about 25 ml to about 50 ml, about 30 ml to about 35 ml, about 30 ml to about 40 ml, about 30 ml to about 45 ml, about 30 ml to about 50 ml, about 35 ml to about 40 ml, about 35 ml to about 45 ml, about 35 ml to about 50 ml, about 40 ml to about 45 ml, about 40 ml to about 50 ml, or about 45 ml to about 50 ml. In some embodiments, the injection comprises a volume of at least about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, or about 45 ml.In some embodiments, the injection comprises a volume of up to about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.

[0020] In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 11, about 10 to about 12, about 10 to about 13, about 10 to about 14, about 10 to about 15, about 10 to about 16, about 10 to about 18, about 10 to about 20, about 10 to about 22, about 10 to about 24, about 10 to about 26, about 11 to about 12, about 11 to about 13, about 11 to about 14, about 11 to about 15, about 11 to about 16, about 11 to about 18, about 11 to about 20, about 11 to about 22, about 11 to about 24, about 11 to about 26, about 12 to about 13, about 12 to about 14, about 12 to about 15, about 12 to about 16, about 12 to about 18, about 12 to about 20, about 12 to about 22, about 12 to about 24, about 12 to about 26, about 13 to about 14, about 13 to about 15, about 13 to about 16, about 1 3 to about 18, about 13 to about 20, about 13 to about 22, about 13 to about 24, about 13 to about 26, about 14 to about 15, about 14 to about 16, about 14 to about 18, about 14 to about 20, about 14 to about 22, about 14 to about 24, about 14 to about 26, about 15 to about 16, about 15 to about 18, about 15 to about 20, about 15 to about 22, about 15 to about 24, about 15 to about 26 In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, about 26, about 16 to about 18, about 16 to about 20, about 16 to about 22, about 16 to about 24, about 16 to about 26, about 18 to about 20, about 18 to about 22, about 18 to about 24, about 18 to about 26, about 20 to about 22, about 20 to about 24, about 20 to about 26, about 22 to about 24, about 22 to about 26, or about 24 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26. In some embodiments, the injection is performed with a needle having a gauge of at least about 10, about 11, about 12, 13, about 14, about 15, about 16, about 18, about 20, about 22, or about 24. In some embodiments, the injection is performed with a needle having a gauge of at most about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26.

[0021] In some embodiments, the concentration of hyaluronic acid in the spacer material ranges from about 1 mg / ml to about 100 mg / ml. In some embodiments, the concentration of hyaluronic acid in the spacer material ranges from about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, about 5 mg / ml to about 5 mg / ml. Approximately 15mg / ml, approximately 5mg / ml~approximately 20mg / ml, approximately 5mg / ml~approximately 25mg / ml, approximately 5mg / ml~30mg / ml, approximately 5mg / ml~approximately 40mg / ml, approximately 5mg / ml~approximately 50mg / ml, approximately 5mg / ml~approximately 60mg / ml, approx. Approximately 80mg / ml, approximately 5mg / ml to approximately 100mg / ml, approximately 10mg / ml to approximately 15mg / ml, approximately 10mg / ml to approximately 20mg / ml, approximately 10mg / ml to approximately 25mg / ml, approximately 10mg / ml to approximately 30mg / ml, approximately 10mg / ml to approximately 40mg / ml, approximately 10mg / ml to about 50mg / ml, about 10mg / ml to about 60mg / ml, about 10mg / ml to about 80mg / ml, about 10mg / ml to about 100mg / ml, about 15mg / ml to about 20mg / ml, about 15mg / ml to about 25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20mg / ml to about 25mg / ml , about 20 mg / ml to about 30 mg / ml, about 20 mg / ml to about 40 mg / ml, about 20 mg / ml to about 50 mg / ml, about 20 mg / ml to about 60 mg / ml, about 20 mg / ml to about 80 mg / ml, about 20 mg / ml to about 100 mg / ml, about 25 mg / ml ~30mg / ml, 25mg / ml~40mg / ml, 25mg / ml~50mg / ml, 25mg / ml~60mg / ml, 25mg / ml~80mg / ml, 25mg / ml~100mg / ml, 30mg / ml~40mg / ml,The range is from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 60 mg / ml, from about 30 mg / ml to about 80 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 40 mg / ml to about 50 mg / ml, from about 40 mg / ml to about 60 mg / ml, from about 40 mg / ml to about 80 mg / ml, from about 40 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 60 mg / ml, from about 50 mg / ml to about 80 mg / ml, from about 50 mg / ml to about 100 mg / ml, from about 60 mg / ml to about 80 mg / ml, from about 60 mg / ml to about 100 mg / ml, or from about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of hyaluronic acid in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of hyaluronic acid in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of hyaluronic acid in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0022] In some embodiments, the particle size is about 0.1 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.5 mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.2mm to about 10mm, about 0.5mm to about 1m m, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 10 mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm, Approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm, approximately 2mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the size of the particles is at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, In some embodiments, the size of the particles is at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0023] In some embodiments, the injection is subcutaneous or subepidermal. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the viscoelastic medium further comprises nanoparticles. In some embodiments, the nanoparticles comprise a precious metal. In some embodiments, the dose of radiation therapy in contact with tissue adjacent to the site of radiation therapy is reduced by about 10% to about 80%. In some embodiments, the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy.

[0024] In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 95%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 30%, about 5% ~ about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 95%, about 10% to about 15%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 95%, about 15% to about 20%, about 15% to about 30%, about 15% to about 40 %, about 15% to about 50%, about 15% to about 60%, about 15% to about 70%, about 15% to about 80%, about 15% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 8 In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 95%, about 70% to about 80%, about 70% to about 95%, or about 80% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by at least about 1%, about 5%, about 10%, 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by up to about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 95%.

[0025] In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 0.5 hours, from about 0.1 hours to about 1 hour, from about 0.1 hours to about 2 hours, from about 0.1 hours to about 4 hours, from about 0.1 hours to about 6 hours, from about 0.1 hours to about 8 hours, from about 0.1 hours to about 10 hours, from about 0.1 hours to about 14 hours, from about 0.1 hours to about 18 hours, from about 0.1 hours to about 24 hours, from about 0.1 hours to about 95 hours, from about 0.5 hours to about 1 hour, or from about 0.5 hours to about 2 hours after injection of the bioabsorbable viscoelastic medium. about 0.5 hours to about 4 hours, about 0.5 hours to about 6 hours, about 0.5 hours to about 8 hours, about 0.5 hours to about 10 hours, about 0.5 hours to about 14 hours, about 0.5 hours to about 18 hours, about 0.5 hours to about 24 hours, about 0.5 hours to about 95 hours, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hour to about 95 hours, about 2 hours About 4 hours, about 2 to about 6 hours, about 2 to about 8 hours, about 2 to about 10 hours, about 2 to about 14 hours, about 2 to about 18 hours, about 2 to about 24 hours, about 2 to about 95 hours, about 4 to about 6 hours, about 4 to about 8 hours, about 4 to about 10 hours, about 4 to about 14 hours, about 4 to about 18 hours, about 4 to about 24 hours, about 4 to about 95 hours, about 6 to about 8 hours, about 6 to about 10 hours, about 6 to about 14 hours, about 6 to about 18 hours, about 6 hours In some embodiments, administration of hyaluronidase occurs about 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, about 95 hours, about 8 hours, about 10 hours, about 14 hours, about 10 hours, about 18 hours, about 10 hours, about 24 hours, about 10 hours, about 95 hours, about 14 hours, about 18 hours, about 14 hours, about 24 hours, about 14 hours, about 95 hours, about 18 hours, about 24 hours, about 18 hours, about 95 hours, or about 24 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium.In some embodiments, administration of the hyaluronidase occurs at least 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about, or about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of the hyaluronidase occurs at most about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, or about 95 hours after injection of the bioabsorbable viscoelastic medium.

[0026] Another aspect provided herein is a method of reducing a radiation therapy dose to tissue adjacent to a radiation therapy site in a subject receiving radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the radiation therapy site. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise hyaluronic acid or a derivative thereof.

[0027] In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 10 cm. In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 0.2 cm, about 0.1 cm to about 0.5 cm, about 0.1 cm to about 1 cm, about 0.1 cm to about 2 cm, about 0.1 cm to about 3 cm, about 0.1 cm to about 4 cm, about 0.1 cm to about 5 cm, about 0.1 cm to about 6 cm, about 0.1 cm to about 7 cm, about 0.1 cm to about 8 cm, about 0.1 cm to about 10 cm, about 0.2 cm to about 0.5 cm, about 0.2 cm to about 1 cm, about 0.2 cm to about 2 cm m, about 0.2cm to about 3cm, about 0.2cm to about 4cm, about 0.2cm to about 5cm, about 0.2cm to about 6cm, about 0.2cm to about 7cm, about 0.2cm to about 8cm, about 0.2cm to about 10cm, about 0.5cm to about 1 cm, approximately 0.5cm to approximately 2cm, approximately 0.5cm to approximately 3cm, approximately 0.5cm to approximately 4cm, approximately 0.5cm to approximately 5cm, approximately 0.5cm to approximately 6cm, approximately 0.5cm to approximately 7cm, approximately 0.5cm to approximately 8cm, approximately 0.5cm to approximately 1 0cm, approximately 1cm to approximately 2cm, approximately 1cm to approximately 3cm, approximately 1cm to approximately 4cm, approximately 1cm to approximately 5cm, approximately 1cm to approximately 6cm, approximately 1cm to approximately 7cm, approximately 1cm to approximately 8cm, approximately 1cm to approximately 10cm, approximately 2cm to approximately 3cm, approximately 2cm to 4cm, 2cm to 5cm, 2cm to 6cm, 2cm to 7cm, 2cm to 8cm, 2cm to 10cm, 3cm to 4cm, 3cm to 5cm, 3cm to 6cm, 3cm to 6cm In some embodiments, the injection displaces tissue by a distance of about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 3 cm to about 8 cm, about 3 cm to about 10 cm, about 4 cm to about 5 cm, about 4 cm to about 6 cm, about 4 cm to about 7 cm, about 4 cm to about 8 cm, about 4 cm to about 10 cm, about 5 cm to about 6 cm, about 5 cm to about 7 cm, about 5 cm to about 8 cm, about 5 cm to about 10 cm, about 6 cm to about 7 cm, about 6 cm to about 8 cm, about 6 cm to about 10 cm, about 7 cm to about 8 cm, about 7 cm to 10 cm, or about 8 cm to about 10 cm.In some embodiments, the injection displaces the tissue a distance of at least about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, or about 8 cm. In some embodiments, the injection displaces the tissue a distance of at most about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, or about 10 cm. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml.In some embodiments, the injection may be about 1 ml to about 2 ml, about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 15 ml, about 1 ml to about 20 ml, about 1 ml to about 25 ml, about 1 ml to about 30 ml, about 1 ml to about 35 ml, about 1 ml to about 40 ml, about 1 ml to about 45 ml, about 1 ml to about 50 ml, about 2 ml to about 5 ml, about 2 ml to about 10 ml, about 2 ml to about 15 ml, about 2 ml to about 20 ml, about 2 ml to about 25 ml, about 2 ml to about 3 0ml, about 2ml to about 35ml, about 2ml to about 40ml, about 2ml to about 45ml, about 2ml to about 50ml, about 5ml to about 10ml, about 5ml to about 15ml, about 5ml to about 20ml, about 5ml to about 25ml, about 5ml to about 30ml, approximately 5ml to approximately 35ml, approximately 5ml to approximately 40ml, approximately 5ml to approximately 45ml, approximately 5ml to approximately 50ml, approximately 10ml to approximately 15ml, approximately 10ml to approximately 20ml, approximately 10ml to approximately 25ml, approximately 10ml to approximately 30ml, approximately 10ml to about 35ml, about 10ml to about 40ml, about 10ml to about 45ml, about 10ml to about 50ml, about 15ml to about 20ml, about 15ml to about 25ml, about 15ml to about 30ml, about 15ml to about 35ml, about 15 ml~about 40ml, about 15ml~about 45ml, about 15ml~about 50ml, about 20ml~about 25ml, about 20ml~about 30ml, about 20ml~about 35ml, about 20ml~about 40ml, about 20ml~about 45ml, about 20ml In some embodiments, the injection comprises a volume of about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, about 50 ml, about 25 ml to about 30 ml, about 25 ml to about 35 ml, about 25 ml to about 40 ml, about 25 ml to about 45 ml, about 25 ml to about 50 ml, about 30 ml to about 35 ml, about 30 ml to about 40 ml, about 30 ml to about 45 ml, about 30 ml to about 50 ml, about 35 ml to about 40 ml, about 35 ml to about 45 ml, about 35 ml to about 50 ml, about 40 ml to about 45 ml, about 40 ml to about 50 ml, or about 45 ml to about 50 ml. In some embodiments, the injection comprises a volume of at least about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, or about 45 ml.In some embodiments, the injection comprises a volume of up to about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.

[0028] In some embodiments, the concentration of hyaluronic acid in the spacer material ranges from about 1 mg / ml to about 100 mg / ml. In some embodiments, the concentration of hyaluronic acid in the spacer material ranges from about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, about 5 mg / ml to about 5 mg / ml. Approximately 15mg / ml, approximately 5mg / ml~approximately 20mg / ml, approximately 5mg / ml~approximately 25mg / ml, approximately 5mg / ml~30mg / ml, approximately 5mg / ml~approximately 40mg / ml, approximately 5mg / ml~approximately 50mg / ml, approximately 5mg / ml~approximately 60mg / ml, approx. Approximately 80mg / ml, approximately 5mg / ml to approximately 100mg / ml, approximately 10mg / ml to approximately 15mg / ml, approximately 10mg / ml to approximately 20mg / ml, approximately 10mg / ml to approximately 25mg / ml, approximately 10mg / ml to approximately 30mg / ml, approximately 10mg / ml to approximately 40mg / ml, approximately 10mg / ml to about 50mg / ml, about 10mg / ml to about 60mg / ml, about 10mg / ml to about 80mg / ml, about 10mg / ml to about 100mg / ml, about 15mg / ml to about 20mg / ml, about 15mg / ml to about 25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20mg / ml to about 25mg / ml , about 20 mg / ml to about 30 mg / ml, about 20 mg / ml to about 40 mg / ml, about 20 mg / ml to about 50 mg / ml, about 20 mg / ml to about 60 mg / ml, about 20 mg / ml to about 80 mg / ml, about 20 mg / ml to about 100 mg / ml, about 25 mg / ml ~30mg / ml, 25mg / ml~40mg / ml, 25mg / ml~50mg / ml, 25mg / ml~60mg / ml, 25mg / ml~80mg / ml, 25mg / ml~100mg / ml, 30mg / ml~40mg / ml,The range is from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 60 mg / ml, from about 30 mg / ml to about 80 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 40 mg / ml to about 50 mg / ml, from about 40 mg / ml to about 60 mg / ml, from about 40 mg / ml to about 80 mg / ml, from about 40 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 60 mg / ml, from about 50 mg / ml to about 80 mg / ml, from about 50 mg / ml to about 100 mg / ml, from about 60 mg / ml to about 80 mg / ml, from about 60 mg / ml to about 100 mg / ml, or from about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of hyaluronic acid in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of hyaluronic acid in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of hyaluronic acid in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0029] In some embodiments, the particle size is about 0.1 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.5 mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.5mm to about 10mm, about 0.5mm to about 1m m, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 10 mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm, Approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm, approximately 2mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the size of the particles is at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, In some embodiments, the size of the particles is at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0030] In some embodiments, the injection is subcutaneous or subepidermal. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the viscoelastic medium further comprises nanoparticles. In some embodiments, the nanoparticles comprise a precious metal. In some embodiments, the radiation therapy dose is reduced by about 10% to about 80%. In some embodiments, the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy.

[0031] In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 95%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 30%, about 5% ~ about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 95%, about 10% to about 15%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 95%, about 15% to about 20%, about 15% to about 30%, about 15% to about 40 %, about 15% to about 50%, about 15% to about 60%, about 15% to about 70%, about 15% to about 80%, about 15% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 8 In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 95%, about 70% to about 80%, about 70% to about 95%, or about 80% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by at least about 1%, about 5%, about 10%, 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by up to about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 95%.

[0032] In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 0.5 hours, from about 0.1 hours to about 1 hour, from about 0.1 hours to about 2 hours, from about 0.1 hours to about 4 hours, from about 0.1 hours to about 6 hours, from about 0.1 hours to about 8 hours, from about 0.1 hours to about 10 hours, from about 0.1 hours to about 14 hours, from about 0.1 hours to about 18 hours, from about 0.1 hours to about 24 hours, from about 0.1 hours to about 95 hours, from about 0.5 hours to about 1 hour, or from about 0.5 hours to about 2 hours after injection of the bioabsorbable viscoelastic medium. about 0.5 hours to about 4 hours, about 0.5 hours to about 6 hours, about 0.5 hours to about 8 hours, about 0.5 hours to about 10 hours, about 0.5 hours to about 14 hours, about 0.5 hours to about 18 hours, about 0.5 hours to about 24 hours, about 0.5 hours to about 95 hours, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hour to about 95 hours, about 2 hours About 4 hours, about 2 to about 6 hours, about 2 to about 8 hours, about 2 to about 10 hours, about 2 to about 14 hours, about 2 to about 18 hours, about 2 to about 24 hours, about 2 to about 95 hours, about 4 to about 6 hours, about 4 to about 8 hours, about 4 to about 10 hours, about 4 to about 14 hours, about 4 to about 18 hours, about 4 to about 24 hours, about 4 to about 95 hours, about 6 to about 8 hours, about 6 to about 10 hours, about 6 to about 14 hours, about 6 to about 18 hours, about 6 hours In some embodiments, administration of hyaluronidase occurs about 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, about 95 hours, about 8 hours, about 10 hours, about 14 hours, about 10 hours, about 18 hours, about 10 hours, about 24 hours, about 10 hours, about 95 hours, about 14 hours, about 18 hours, about 14 hours, about 24 hours, about 14 hours, about 95 hours, about 18 hours, about 24 hours, about 18 hours, about 95 hours, or about 24 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium.In some embodiments, administration of the hyaluronidase occurs at least 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about, or about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of the hyaluronidase occurs at most about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, or about 95 hours after injection of the bioabsorbable viscoelastic medium.

[0033] Another aspect provided herein is a method for temporarily super-spacing tissue adjacent to a site of radiation therapy, the method comprising injecting a formulation comprising cross-linked hyaluronic acid or a derivative thereof and a large amount of degradable nanoparticles encapsulating hyaluronidase. In some embodiments, the amount of degradable nanoparticles encapsulating hyaluronidase is directly proportional to the desired distance of super-spacing relative to the desired duration of super-spacing.

[0034] Another aspect provided herein is a method of treating cancer in an afflicted subject, the method comprising injecting a bioabsorbable viscoelastic medium into a blood vessel, wherein the blood vessel is directly connected to a tumor. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise hyaluronic acid or a derivative thereof.

[0035] In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml. In some embodiments, the injection comprises a volume of about 1 ml to about 2 ml, about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 15 ml, about 1 ml to about 20 ml, about 1 ml to about 25 ml, about 1 ml to about 30 ml, about 1 ml to about 35 ml, about 1 ml to about 40 ml, about 1 ml to about 45 ml, about 1 ml to about 50 ml, about 2 ml to about 5 ml, about 2 ml to about 10 ml, about 2 ml to about 15 ml, about 2 ml to about 20 ml, about 2 ml to about 25 ml, about 2 ml to about 30 ml, about 2 ml to about 35 ml. ml, about 2ml to about 40ml, about 2ml to about 45ml, about 2ml to about 50ml, about 5ml to about 10ml, about 5ml to about 15ml, about 5ml to about 20ml, about 5m l ~ about 25ml, about 5ml - about 30ml, about 5ml - about 35ml, about 5ml - about 40ml, about 5ml - about 45ml, about 5ml - about 50ml, about 10ml - about 15 ml, about 10ml to about 20ml, about 10ml to about 25ml, about 10ml to about 30ml, about 10ml to about 35ml, about 10ml to about 40ml, about 10ml to about 45 ml, about 10ml to about 50ml, about 15ml to about 20ml, about 15ml to about 25ml, about 15ml to about 30ml, about 15ml to about 35ml, about 15ml to about 40 ml, about 15 ml to about 45 ml, about 15 ml to about 50 ml, about 20 ml to about 25 ml, about 20 ml to about 30 ml, about 20 ml to about 35 ml, about 20 ml to about 40 ml, about 20 ml to about 45 ml, about 20 ml to about 50 ml, about 25 ml to about 30 ml, about 25 ml to about 35 ml, about 25 ml to about 40 ml, about 25 ml to about 45 ml, about 25 ml to about 50 ml, about 30 ml to about 35 ml, about 30 ml to about 40 ml, about 30 ml to about 45 ml, about 30 ml to about 50 ml, about 35 ml to about 40 ml, about 35 ml to about 45 ml, about 35 ml to about 50 ml, about 40 ml to about 45 ml, about 40 ml to about 50 ml, or about 45 ml to about 50 ml. In some embodiments, the injection comprises a volume of about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.In some embodiments, the injection comprises a volume of at least about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, or about 45 ml, hi some embodiments, the injection comprises a volume of at most about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.

[0036] In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 11, about 10 to about 12, about 10 to about 13, about 10 to about 14, about 10 to about 15, about 10 to about 16, about 10 to about 18, about 10 to about 20, about 10 to about 22, about 10 to about 24, about 10 to about 26, about 11 to about 12, about 11 to about 13, about 11 to about 14, about 11 to about 15, about 11 to about 16, about 11 to about 18, about 11 to about 20, about 11 to about 22, about 11 to about 24, about 11 to about 26, about 12 to about 13, about 12 to about 14, about 12 to about 15, about 12 to about 16, about 12 to about 18, about 12 to about 20, about 12 to about 22, about 12 to about 24, about 12 to about 26, about 13 to about 14, about 13 to about 15, about 13 to about 16, about 1 3 to about 18, about 13 to about 20, about 13 to about 22, about 13 to about 24, about 13 to about 26, about 14 to about 15, about 14 to about 16, about 14 to about 18, about 14 to about 20, about 14 to about 22, about 14 to about 24, about 14 to about 26, about 15 to about 16, about 15 to about 18, about 15 to about 20, about 15 to about 22, about 15 to about 24, about 15 to about 26 In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, about 26, about 16 to about 18, about 16 to about 20, about 16 to about 22, about 16 to about 24, about 16 to about 26, about 18 to about 20, about 18 to about 22, about 18 to about 24, about 18 to about 26, about 20 to about 22, about 20 to about 24, about 20 to about 26, about 22 to about 24, about 22 to about 26, or about 24 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26. In some embodiments, the injection is performed with a needle having a gauge of at least about 10, about 11, about 12, 13, about 14, about 15, about 16, about 18, about 20, about 22, or about 24. In some embodiments, the injection is performed with a needle having a gauge of at most about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26.

[0037] In some embodiments, the concentration of hyaluronic acid in the spacer material ranges from about 1 mg / ml to about 100 mg / ml. In some embodiments, the concentration of hyaluronic acid in the spacer material ranges from about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, about 5 mg / ml to about 5 mg / ml. Approximately 15mg / ml, approximately 5mg / ml~approximately 20mg / ml, approximately 5mg / ml~approximately 25mg / ml, approximately 5mg / ml~30mg / ml, approximately 5mg / ml~approximately 40mg / ml, approximately 5mg / ml~approximately 50mg / ml, approximately 5mg / ml~approximately 60mg / ml, approx. Approximately 80mg / ml, approximately 5mg / ml to approximately 100mg / ml, approximately 10mg / ml to approximately 15mg / ml, approximately 10mg / ml to approximately 20mg / ml, approximately 10mg / ml to approximately 25mg / ml, approximately 10mg / ml to approximately 30mg / ml, approximately 10mg / ml to approximately 40mg / ml, approximately 10mg / ml to about 50mg / ml, about 10mg / ml to about 60mg / ml, about 10mg / ml to about 80mg / ml, about 10mg / ml to about 100mg / ml, about 15mg / ml to about 20mg / ml, about 15mg / ml to about 25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20mg / ml to about 25mg / ml , about 20 mg / ml to about 30 mg / ml, about 20 mg / ml to about 40 mg / ml, about 20 mg / ml to about 50 mg / ml, about 20 mg / ml to about 60 mg / ml, about 20 mg / ml to about 80 mg / ml, about 20 mg / ml to about 100 mg / ml, about 25 mg / ml ~30mg / ml, 25mg / ml~40mg / ml, 25mg / ml~50mg / ml, 25mg / ml~60mg / ml, 25mg / ml~80mg / ml, 25mg / ml~100mg / ml, 30mg / ml~40mg / ml,The range is from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 60 mg / ml, from about 30 mg / ml to about 80 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 40 mg / ml to about 50 mg / ml, from about 40 mg / ml to about 60 mg / ml, from about 40 mg / ml to about 80 mg / ml, from about 40 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 60 mg / ml, from about 50 mg / ml to about 80 mg / ml, from about 50 mg / ml to about 100 mg / ml, from about 60 mg / ml to about 80 mg / ml, from about 60 mg / ml to about 100 mg / ml, or from about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of hyaluronic acid in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of hyaluronic acid in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of hyaluronic acid in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0038] In some embodiments, the particle size is about 0.1 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.5 mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.5mm to about 10mm, about 0.5mm to about 1m m, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 10 mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm, Approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm, approximately 2mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the size of the particles is at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, In some embodiments, the size of the particles is at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0039] In some embodiments, blood flow to the tumor is avoided or reduced. In some embodiments, movement of viscoelastic media is avoided or reduced. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy.

[0040] In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 0.5 hours, from about 0.1 hours to about 1 hour, from about 0.1 hours to about 2 hours, from about 0.1 hours to about 4 hours, from about 0.1 hours to about 6 hours, from about 0.1 hours to about 8 hours, from about 0.1 hours to about 10 hours, from about 0.1 hours to about 14 hours, from about 0.1 hours to about 18 hours, from about 0.1 hours to about 24 hours, from about 0.1 hours to about 95 hours, from about 0.5 hours to about 1 hour, or from about 0.5 hours to about 2 hours after injection of the bioabsorbable viscoelastic medium. about 0.5 hours to about 4 hours, about 0.5 hours to about 6 hours, about 0.5 hours to about 8 hours, about 0.5 hours to about 10 hours, about 0.5 hours to about 14 hours, about 0.5 hours to about 18 hours, about 0.5 hours to about 24 hours, about 0.5 hours to about 95 hours, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hour to about 95 hours, about 2 hours About 4 hours, about 2 to about 6 hours, about 2 to about 8 hours, about 2 to about 10 hours, about 2 to about 14 hours, about 2 to about 18 hours, about 2 to about 24 hours, about 2 to about 95 hours, about 4 to about 6 hours, about 4 to about 8 hours, about 4 to about 10 hours, about 4 to about 14 hours, about 4 to about 18 hours, about 4 to about 24 hours, about 4 to about 95 hours, about 6 to about 8 hours, about 6 to about 10 hours, about 6 to about 14 hours, about 6 to about 18 hours, about 6 hours In some embodiments, administration of hyaluronidase occurs about 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, about 95 hours, about 8 hours, about 10 hours, about 14 hours, about 10 hours, about 18 hours, about 10 hours, about 24 hours, about 10 hours, about 95 hours, about 14 hours, about 18 hours, about 14 hours, about 24 hours, about 14 hours, about 95 hours, about 18 hours, about 24 hours, about 18 hours, about 95 hours, or about 24 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium.In some embodiments, administration of the hyaluronidase occurs at least 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about, or about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of the hyaluronidase occurs at most about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, or about 95 hours after injection of the bioabsorbable viscoelastic medium.

[0041] In some embodiments, the method further comprises the step of excising remaining tumor cells from the subject.

[0042] Another aspect provided herein is a formulation comprising cross-linked hyaluronic acid and a radiopaque compound selected from the group consisting of iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, and ioversol. In some embodiments, the formulation is used as a standard marker.

[0043] Another aspect provided herein is a method of preventing or reducing damage to tissue adjacent to a radiation therapy site in a subject undergoing radiation therapy comprising injecting a bioabsorbable viscoelastic medium at the radiation therapy site. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise polyethylene glycol or a derivative thereof.

[0044] In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 10 cm. In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 0.2 cm, about 0.1 cm to about 0.5 cm, about 0.1 cm to about 1 cm, about 0.1 cm to about 2 cm, about 0.1 cm to about 3 cm, about 0.1 cm to about 4 cm, about 0.1 cm to about 5 cm, about 0.1 cm to about 6 cm, about 0.1 cm to about 7 cm, about 0.1 cm to about 8 cm, about 0.1 cm to about 10 cm, about 0.2 cm to about 0.5 cm, about 0.2 cm to about 1 cm, about 0.2 cm to about 2 cm m, about 0.2cm to about 3cm, about 0.2cm to about 4cm, about 0.2cm to about 5cm, about 0.2cm to about 6cm, about 0.2cm to about 7cm, about 0.2cm to about 8cm, about 0.2cm to about 10cm, about 0.5cm to about 1 cm, approximately 0.5cm to approximately 2cm, approximately 0.5cm to approximately 3cm, approximately 0.5cm to approximately 4cm, approximately 0.5cm to approximately 5cm, approximately 0.5cm to approximately 6cm, approximately 0.5cm to approximately 7cm, approximately 0.5cm to approximately 8cm, approximately 0.5cm to approximately 1 0cm, approximately 1cm to approximately 2cm, approximately 1cm to approximately 3cm, approximately 1cm to approximately 4cm, approximately 1cm to approximately 5cm, approximately 1cm to approximately 6cm, approximately 1cm to approximately 7cm, approximately 1cm to approximately 8cm, approximately 1cm to approximately 10cm, approximately 2cm to approximately 3cm, approximately 2cm to 4cm, 2cm to 5cm, 2cm to 6cm, 2cm to 7cm, 2cm to 8cm, 2cm to 10cm, 3cm to 4cm, 3cm to 5cm, 3cm to 6cm, 3cm to 6cm In some embodiments, the injection displaces tissue by a distance of about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 3 cm to about 8 cm, about 3 cm to about 10 cm, about 4 cm to about 5 cm, about 4 cm to about 6 cm, about 4 cm to about 7 cm, about 4 cm to about 8 cm, about 4 cm to about 10 cm, about 5 cm to about 6 cm, about 5 cm to about 7 cm, about 5 cm to about 8 cm, about 5 cm to about 10 cm, about 6 cm to about 7 cm, about 6 cm to about 8 cm, about 6 cm to about 10 cm, about 7 cm to about 8 cm, about 7 cm to about 10 cm, or about 8 cm to about 10 cm.In some embodiments, the injection displaces the tissue a distance of at least about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, or about 8 cm. In some embodiments, the injection displaces the tissue a distance of at most about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, or about 10 cm. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml.In some embodiments, the injection is about 1 ml to about 2 ml, about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 15 ml, about 1 ml to about 20 ml, about 1 ml to about 25 ml, about 1 ml to about 30 ml, about 1 ml to about 35 ml, about 1 ml to about 40 ml, about 1 ml to about 45 ml, about 1 ml to about 50 ml, about 2 ml to about 5 ml, about 2 ml to about 10 ml, about 2 ml to about 15 ml, about 2 ml to about 20 ml, about 2 ml to about 25 ml, about 2 ml to about 30 ml, about 2 ml to about 35 ml ml, about 2ml to about 40ml, about 2ml to about 45ml, about 2ml to about 50ml, about 5ml to about 10ml, about 5ml to about 15ml, about 5ml to about 20ml, about 5m l ~ about 25ml, about 5ml - about 30ml, about 5ml - about 35ml, about 5ml - about 40ml, about 5ml - about 45ml, about 5ml - about 50ml, about 10ml - about 15 ml, about 10ml to about 20ml, about 10ml to about 25ml, about 10ml to about 30ml, about 10ml to about 35ml, about 10ml to about 40ml, about 10ml to about 45 ml, about 10ml to about 50ml, about 15ml to about 20ml, about 15ml to about 25ml, about 15ml to about 30ml, about 15ml to about 35ml, about 15ml to about 40 ml, about 15 ml to about 45 ml, about 15 ml to about 50 ml, about 20 ml to about 25 ml, about 20 ml to about 30 ml, about 20 ml to about 35 ml, about 20 ml to about 40 ml, about 20 ml to about 45 ml, about 20 ml to about 50 ml, about 25 ml to about 30 ml, about 25 ml to about 35 ml, about 25 ml to about 40 ml, about 25 ml to about 45 ml, about 25 ml to about 50 ml, about 30 ml to about 35 ml, about 30 ml to about 40 ml, about 30 ml to about 45 ml, about 30 ml to about 50 ml, about 35 ml to about 40 ml, about 35 ml to about 45 ml, about 35 ml to about 50 ml, about 40 ml to about 45 ml, about 40 ml to about 50 ml, or about 45 ml to about 50 ml. In some embodiments, the injection comprises a volume of about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml. In some embodiments, the injection comprises a volume of at least about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, or about 45 ml.In some embodiments, the injection comprises a volume of up to about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.

[0045] In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 11, about 10 to about 12, about 10 to about 13, about 10 to about 14, about 10 to about 15, about 10 to about 16, about 10 to about 18, about 10 to about 20, about 10 to about 22, about 10 to about 24, about 10 to about 26, about 11 to about 12, about 11 to about 13, about 11 to about 14, about 11 to about 15, about 11 to about 16, about 11 to about 18, about 11 to about 20, about 11 to about 22, about 11 to about 24, about 11 to about 26, about 12 to about 13, about 12 to about 14, about 12 to about 15, about 12 to about 16, about 12 to about 18, about 12 to about 20, about 12 to about 22, about 12 to about 24, about 12 to about 26, about 13 to about 14, about 13 to about 15, about 13 to about 16, about 1 3 to about 18, about 13 to about 20, about 13 to about 22, about 13 to about 24, about 13 to about 26, about 14 to about 15, about 14 to about 16, about 14 to about 18, about 14 to about 20, about 14 to about 22, about 14 to about 24, about 14 to about 26, about 15 to about 16, about 15 to about 18, about 15 to about 20, about 15 to about 22, about 15 to about 24, about 15 to about 26 In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, about 26, about 16 to about 18, about 16 to about 20, about 16 to about 22, about 16 to about 24, about 16 to about 26, about 18 to about 20, about 18 to about 22, about 18 to about 24, about 18 to about 26, about 20 to about 22, about 20 to about 24, about 20 to about 26, about 22 to about 24, about 22 to about 26, or about 24 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26. In some embodiments, the injection is performed with a needle having a gauge of at least about 10, about 11, about 12, 13, about 14, about 15, about 16, about 18, about 20, about 22, or about 24. In some embodiments, the injection is performed with a needle having a gauge of at most about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26.

[0046] In some embodiments, the concentration of polyethylene glycol in the spacer material ranges from about 1 mg / ml to about 100 mg / ml, in some embodiments, the concentration of polyethylene glycol in the spacer material ranges from about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, Approximately 5 mg / ml to approximately 15 mg / ml, approximately 5 mg / ml to approximately 20 mg / ml, approximately 5 mg / ml to approximately 25 mg / ml, approximately 5 mg / ml to 30 mg / ml, approximately 5 mg / ml to approximately 40 mg / ml, approximately 5 mg / ml to approximately 50 mg / ml, approximately 5 mg / ml to approximately 60 mg / m l, about 5 mg / ml to about 80 mg / ml, about 5 mg / ml to about 100 mg / ml, about 10 mg / ml to about 15 mg / ml, about 10 mg / ml to about 20 mg / ml, about 10 mg / ml to about 25 mg / ml, about 10 mg / ml to about 30 mg / ml, about 10 mg / ml ~40mg / ml, 10mg / ml~50mg / ml, 10mg / ml~60mg / ml, 10mg / ml~80mg / ml, 10mg / ml~100mg / ml, 15mg / ml~20mg / ml, 15mg / ml~25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20 mg / ml~about 25mg / ml, about 20mg / ml~about 30mg / ml, about 20mg / ml~about 40mg / ml, about 20mg / ml~about 50mg / ml, about 20mg / ml~about 60mg / ml, about 20mg / ml~about 80mg / ml, about 20mg / ml~about 1 00mg / ml, about 25mg / ml to about 30mg / ml, about 25mg / ml to about 40mg / ml, about 25mg / ml to about 50mg / ml, about 25mg / ml to about 60mg / ml, about 25mg / ml to about 80mg / ml, about 25mg / ml to about 100mg / ml,The range is from about 30 mg / ml to about 40 mg / ml, from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 60 mg / ml, from about 30 mg / ml to about 80 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 40 mg / ml to about 50 mg / ml, from about 40 mg / ml to about 60 mg / ml, from about 40 mg / ml to about 80 mg / ml, from about 40 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 60 mg / ml, from about 50 mg / ml to about 80 mg / ml, from about 50 mg / ml to about 100 mg / ml, from about 60 mg / ml to about 80 mg / ml, from about 60 mg / ml to about 100 mg / ml, or from about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of polyethylene glycol in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0047] In some embodiments, the particle size is about 0.1 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.5 mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.5mm to about 10mm, about 0.5mm to about 1m m, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 10 mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm, Approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm, approximately 2mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the size of the particles is at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, In some embodiments, the size of the particles is at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0048] In some embodiments, the injection is subcutaneous or subepidermal. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the viscoelastic medium further comprises nanoparticles. In some embodiments, the nanoparticles comprise a precious metal. In some embodiments, the dose of radiation therapy in contact with tissue adjacent to the site of radiation therapy is reduced by about 10% to about 80%. In some embodiments, the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy.

[0049] In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 95%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 30%, about 5% ~ about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 95%, about 10% to about 15%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 95%, about 15% to about 20%, about 15% to about 30%, about 15% to about 40 %, about 15% to about 50%, about 15% to about 60%, about 15% to about 70%, about 15% to about 80%, about 15% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 8 In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 95%, about 70% to about 80%, about 70% to about 95%, or about 80% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by at least about 1%, about 5%, about 10%, 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by up to about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 95%.

[0050] In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 0.5 hours, from about 0.1 hours to about 1 hour, from about 0.1 hours to about 2 hours, from about 0.1 hours to about 4 hours, from about 0.1 hours to about 6 hours, from about 0.1 hours to about 8 hours, from about 0.1 hours to about 10 hours, from about 0.1 hours to about 14 hours, from about 0.1 hours to about 18 hours, from about 0.1 hours to about 24 hours, from about 0.1 hours to about 95 hours, from about 0.5 hours to about 1 hour, or from about 0.5 hours to about 2 hours after injection of the bioabsorbable viscoelastic medium. about 0.5 hours to about 4 hours, about 0.5 hours to about 6 hours, about 0.5 hours to about 8 hours, about 0.5 hours to about 10 hours, about 0.5 hours to about 14 hours, about 0.5 hours to about 18 hours, about 0.5 hours to about 24 hours, about 0.5 hours to about 95 hours, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hour to about 95 hours, about 2 hours About 4 hours, about 2 to about 6 hours, about 2 to about 8 hours, about 2 to about 10 hours, about 2 to about 14 hours, about 2 to about 18 hours, about 2 to about 24 hours, about 2 to about 95 hours, about 4 to about 6 hours, about 4 to about 8 hours, about 4 to about 10 hours, about 4 to about 14 hours, about 4 to about 18 hours, about 4 to about 24 hours, about 4 to about 95 hours, about 6 to about 8 hours, about 6 to about 10 hours, about 6 to about 14 hours, about 6 to about 18 hours, about 6 hours In some embodiments, administration of hyaluronidase occurs about 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, about 95 hours, about 8 hours, about 10 hours, about 14 hours, about 10 hours, about 18 hours, about 10 hours, about 24 hours, about 10 hours, about 95 hours, about 14 hours, about 18 hours, about 14 hours, about 24 hours, about 14 hours, about 95 hours, about 18 hours, about 24 hours, about 18 hours, about 95 hours, or about 24 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium.In some embodiments, administration of the hyaluronidase occurs at least 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about, or about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of the hyaluronidase occurs at most about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, or about 95 hours after injection of the bioabsorbable viscoelastic medium.

[0051] Another aspect provided herein is a method of reducing a radiation therapy dose to tissue adjacent to a radiation therapy site in a subject receiving radiation therapy, the method comprising the step of injecting a bioabsorbable viscoelastic medium at the radiation therapy site. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise polyethylene glycol or a derivative thereof.

[0052] In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 10 cm. In some embodiments, the injection displaces the tissue a distance of about 0.1 cm to about 0.2 cm, about 0.1 cm to about 0.5 cm, about 0.1 cm to about 1 cm, about 0.1 cm to about 2 cm, about 0.1 cm to about 3 cm, about 0.1 cm to about 4 cm, about 0.1 cm to about 5 cm, about 0.1 cm to about 6 cm, about 0.1 cm to about 7 cm, about 0.1 cm to about 8 cm, about 0.1 cm to about 10 cm, about 0.2 cm to about 0.5 cm, about 0.2 cm to about 1 cm, about 0.2 cm to about 2 cm m, about 0.2cm to about 3cm, about 0.2cm to about 4cm, about 0.2cm to about 5cm, about 0.2cm to about 6cm, about 0.2cm to about 7cm, about 0.2cm to about 8cm, about 0.2cm to about 10cm, about 0.5cm to about 1 cm, approximately 0.5cm to approximately 2cm, approximately 0.5cm to approximately 3cm, approximately 0.5cm to approximately 4cm, approximately 0.5cm to approximately 5cm, approximately 0.5cm to approximately 6cm, approximately 0.5cm to approximately 7cm, approximately 0.5cm to approximately 8cm, approximately 0.5cm to approximately 1 0cm, approximately 1cm to approximately 2cm, approximately 1cm to approximately 3cm, approximately 1cm to approximately 4cm, approximately 1cm to approximately 5cm, approximately 1cm to approximately 6cm, approximately 1cm to approximately 7cm, approximately 1cm to approximately 8cm, approximately 1cm to approximately 10cm, approximately 2cm to approximately 3cm, approximately 2cm to 4cm, 2cm to 5cm, 2cm to 6cm, 2cm to 7cm, 2cm to 8cm, 2cm to 10cm, 3cm to 4cm, 3cm to 5cm, 3cm to 6cm, 3cm to 6cm In some embodiments, the injection displaces tissue by a distance of about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 3 cm to about 8 cm, about 3 cm to about 10 cm, about 4 cm to about 5 cm, about 4 cm to about 6 cm, about 4 cm to about 7 cm, about 4 cm to about 8 cm, about 4 cm to about 10 cm, about 5 cm to about 6 cm, about 5 cm to about 7 cm, about 5 cm to about 8 cm, about 5 cm to about 10 cm, about 6 cm to about 7 cm, about 6 cm to about 8 cm, about 6 cm to about 10 cm, about 7 cm to about 8 cm, about 7 cm to about 10 cm, or about 8 cm to about 10 cm.In some embodiments, the injection displaces the tissue a distance of at least about 0.1 cm, about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, or about 8 cm. In some embodiments, the injection displaces the tissue a distance of at most about 0.2 cm, about 0.5 cm, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, or about 10 cm. In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml.In some embodiments, the injection may be about 1 ml to about 2 ml, about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 15 ml, about 1 ml to about 20 ml, about 1 ml to about 25 ml, about 1 ml to about 30 ml, about 1 ml to about 35 ml, about 1 ml to about 40 ml, about 1 ml to about 45 ml, about 1 ml to about 50 ml, about 2 ml to about 5 ml, about 2 ml to about 10 ml, about 2 ml to about 15 ml, about 2 ml to about 20 ml, about 2 ml to about 25 ml, about 2 ml to about 3 0ml, about 2ml to about 35ml, about 2ml to about 40ml, about 2ml to about 45ml, about 2ml to about 50ml, about 5ml to about 10ml, about 5ml to about 15ml, about 5ml to about 20ml, about 5ml to about 25ml, about 5ml to about 30ml, approximately 5ml to approximately 35ml, approximately 5ml to approximately 40ml, approximately 5ml to approximately 45ml, approximately 5ml to approximately 50ml, approximately 10ml to approximately 15ml, approximately 10ml to approximately 20ml, approximately 10ml to approximately 25ml, approximately 10ml to approximately 30ml, approximately 10ml to about 35ml, about 10ml to about 40ml, about 10ml to about 45ml, about 10ml to about 50ml, about 15ml to about 20ml, about 15ml to about 25ml, about 15ml to about 30ml, about 15ml to about 35ml, about 15 ml~about 40ml, about 15ml~about 45ml, about 15ml~about 50ml, about 20ml~about 25ml, about 20ml~about 30ml, about 20ml~about 35ml, about 20ml~about 40ml, about 20ml~about 45ml, about 20ml In some embodiments, the injection comprises a volume of about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, about 50 ml, about 25 ml to about 30 ml, about 25 ml to about 35 ml, about 25 ml to about 40 ml, about 25 ml to about 45 ml, about 25 ml to about 50 ml, about 30 ml to about 35 ml, about 30 ml to about 40 ml, about 30 ml to about 45 ml, about 30 ml to about 50 ml, about 35 ml to about 40 ml, about 35 ml to about 45 ml, about 35 ml to about 50 ml, about 40 ml to about 45 ml, about 40 ml to about 50 ml, or about 45 ml to about 50 ml. In some embodiments, the injection comprises a volume of at least about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, or about 45 ml.In some embodiments, the injection comprises a volume of up to about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.

[0053] In some embodiments, the concentration of polyethylene glycol in the spacer material ranges from about 1 mg / ml to about 100 mg / ml, in some embodiments, the concentration of polyethylene glycol in the spacer material ranges from about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, Approximately 5 mg / ml to approximately 15 mg / ml, approximately 5 mg / ml to approximately 20 mg / ml, approximately 5 mg / ml to approximately 25 mg / ml, approximately 5 mg / ml to 30 mg / ml, approximately 5 mg / ml to approximately 40 mg / ml, approximately 5 mg / ml to approximately 50 mg / ml, approximately 5 mg / ml to approximately 60 mg / m l, about 5 mg / ml to about 80 mg / ml, about 5 mg / ml to about 100 mg / ml, about 10 mg / ml to about 15 mg / ml, about 10 mg / ml to about 20 mg / ml, about 10 mg / ml to about 25 mg / ml, about 10 mg / ml to about 30 mg / ml, about 10 mg / ml ~40mg / ml, 10mg / ml~50mg / ml, 10mg / ml~60mg / ml, 10mg / ml~80mg / ml, 10mg / ml~100mg / ml, 15mg / ml~20mg / ml, 15mg / ml~25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20 mg / ml~about 25mg / ml, about 20mg / ml~about 30mg / ml, about 20mg / ml~about 40mg / ml, about 20mg / ml~about 50mg / ml, about 20mg / ml~about 60mg / ml, about 20mg / ml~about 80mg / ml, about 20mg / ml~about 1 00mg / ml, about 25mg / ml to about 30mg / ml, about 25mg / ml to about 40mg / ml, about 25mg / ml to about 50mg / ml, about 25mg / ml to about 60mg / ml, about 25mg / ml to about 80mg / ml, about 25mg / ml to about 100mg / ml,The range is from about 30 mg / ml to about 40 mg / ml, from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 60 mg / ml, from about 30 mg / ml to about 80 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 40 mg / ml to about 50 mg / ml, from about 40 mg / ml to about 60 mg / ml, from about 40 mg / ml to about 80 mg / ml, from about 40 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 60 mg / ml, from about 50 mg / ml to about 80 mg / ml, from about 50 mg / ml to about 100 mg / ml, from about 60 mg / ml to about 80 mg / ml, from about 60 mg / ml to about 100 mg / ml, or from about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of polyethylene glycol in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0054] In some embodiments, the particle size is about 0.1 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.5 mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.5mm to about 10mm, about 0.5mm to about 1m m, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 10 mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm, Approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm, approximately 2mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the size of the particles is at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, In some embodiments, the size of the particles is at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0055] In some embodiments, the injection is subcutaneous or subepidermal. In some embodiments, migration of the viscoelastic medium is avoided or reduced. In some embodiments, the viscoelastic medium further comprises nanoparticles. In some embodiments, the nanoparticles comprise a precious metal. In some embodiments, the radiation therapy dose is reduced by about 10% to about 80%. In some embodiments, the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy.

[0056] In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 95%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 30%, about 5% ~ about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 95%, about 10% to about 15%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 95%, about 15% to about 20%, about 15% to about 30%, about 15% to about 40 %, about 15% to about 50%, about 15% to about 60%, about 15% to about 70%, about 15% to about 80%, about 15% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 8 In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 95%, about 70% to about 80%, about 70% to about 95%, or about 80% to about 95%. In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by at least about 1%, about 5%, about 10%, 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.In some embodiments, the volume of the viscoelastic medium at the site of radiation therapy is reduced by up to about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 95%.

[0057] In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 0.5 hours, from about 0.1 hours to about 1 hour, from about 0.1 hours to about 2 hours, from about 0.1 hours to about 4 hours, from about 0.1 hours to about 6 hours, from about 0.1 hours to about 8 hours, from about 0.1 hours to about 10 hours, from about 0.1 hours to about 14 hours, from about 0.1 hours to about 18 hours, from about 0.1 hours to about 24 hours, from about 0.1 hours to about 95 hours, from about 0.5 hours to about 1 hour, or from about 0.5 hours to about 2 hours after injection of the bioabsorbable viscoelastic medium. about 0.5 hours to about 4 hours, about 0.5 hours to about 6 hours, about 0.5 hours to about 8 hours, about 0.5 hours to about 10 hours, about 0.5 hours to about 14 hours, about 0.5 hours to about 18 hours, about 0.5 hours to about 24 hours, about 0.5 hours to about 95 hours, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hour to about 95 hours, about 2 hours About 4 hours, about 2 to about 6 hours, about 2 to about 8 hours, about 2 to about 10 hours, about 2 to about 14 hours, about 2 to about 18 hours, about 2 to about 24 hours, about 2 to about 95 hours, about 4 to about 6 hours, about 4 to about 8 hours, about 4 to about 10 hours, about 4 to about 14 hours, about 4 to about 18 hours, about 4 to about 24 hours, about 4 to about 95 hours, about 6 to about 8 hours, about 6 to about 10 hours, about 6 to about 14 hours, about 6 to about 18 hours, about 6 hours In some embodiments, administration of hyaluronidase occurs about 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, about 95 hours, about 8 hours, about 10 hours, about 14 hours, about 10 hours, about 18 hours, about 10 hours, about 24 hours, about 10 hours, about 95 hours, about 14 hours, about 18 hours, about 14 hours, about 24 hours, about 14 hours, about 95 hours, about 18 hours, about 24 hours, about 18 hours, about 95 hours, or about 24 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium.In some embodiments, administration of the hyaluronidase occurs at least 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about, or about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of the hyaluronidase occurs at most about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, or about 95 hours after injection of the bioabsorbable viscoelastic medium.

[0058] Another aspect provided herein is a method of temporarily superspacing tissue adjacent to a site of radiation therapy, the method comprising injecting a formulation comprising cross-linked polyethylene glycol or a derivative thereof and a large amount of degradable nanoparticles encapsulating hyaluronidase. In some embodiments, the amount of degradable nanoparticles encapsulating hyaluronidase is directly proportional to the desired distance of superspacing relative to the desired duration of superspacing.

[0059] Another aspect provided herein is a method of treating cancer in an afflicted subject, the method comprising injecting a bioabsorbable viscoelastic medium into a blood vessel, wherein the blood vessel is directly connected to a tumor. In some embodiments, the viscoelastic medium comprises gel particles. In some embodiments, the gel particles comprise polyethylene glycol or a derivative thereof.

[0060] In some embodiments, the injection comprises a volume of about 1 ml to about 50 ml. In some embodiments, the injection comprises a volume of about 1 ml to about 2 ml, about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 15 ml, about 1 ml to about 20 ml, about 1 ml to about 25 ml, about 1 ml to about 30 ml, about 1 ml to about 35 ml, about 1 ml to about 40 ml, about 1 ml to about 45 ml, about 1 ml to about 50 ml, about 2 ml to about 5 ml, about 2 ml to about 10 ml, about 2 ml to about 15 ml, about 2 ml to about 20 ml, about 2 ml to about 25 ml, about 2 ml to about 30 ml, about 2 ml to about 35 ml. ml, about 2ml to about 40ml, about 2ml to about 45ml, about 2ml to about 50ml, about 5ml to about 10ml, about 5ml to about 15ml, about 5ml to about 20ml, about 5m l ~ about 25ml, about 5ml - about 30ml, about 5ml - about 35ml, about 5ml - about 40ml, about 5ml - about 45ml, about 5ml - about 50ml, about 10ml - about 15 ml, about 10ml to about 20ml, about 10ml to about 25ml, about 10ml to about 30ml, about 10ml to about 35ml, about 10ml to about 40ml, about 10ml to about 45 ml, about 10ml to about 50ml, about 15ml to about 20ml, about 15ml to about 25ml, about 15ml to about 30ml, about 15ml to about 35ml, about 15ml to about 40 ml, about 15 ml to about 45 ml, about 15 ml to about 50 ml, about 20 ml to about 25 ml, about 20 ml to about 30 ml, about 20 ml to about 35 ml, about 20 ml to about 40 ml, about 20 ml to about 45 ml, about 20 ml to about 50 ml, about 25 ml to about 30 ml, about 25 ml to about 35 ml, about 25 ml to about 40 ml, about 25 ml to about 45 ml, about 25 ml to about 50 ml, about 30 ml to about 35 ml, about 30 ml to about 40 ml, about 30 ml to about 45 ml, about 30 ml to about 50 ml, about 35 ml to about 40 ml, about 35 ml to about 45 ml, about 35 ml to about 50 ml, about 40 ml to about 45 ml, about 40 ml to about 50 ml, or about 45 ml to about 50 ml. In some embodiments, the injection comprises a volume of about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.In some embodiments, the injection comprises a volume of at least about 1 ml, about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, or about 45 ml, hi some embodiments, the injection comprises a volume of at most about 2 ml, about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 35 ml, about 40 ml, about 45 ml, or about 50 ml.

[0061] In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10 to about 11, about 10 to about 12, about 10 to about 13, about 10 to about 14, about 10 to about 15, about 10 to about 16, about 10 to about 18, about 10 to about 20, about 10 to about 22, about 10 to about 24, about 10 to about 26, about 11 to about 12, about 11 to about 13, about 11 to about 14, about 11 to about 15, about 11 to about 16, about 11 to about 18, about 11 to about 20, about 11 to about 22, about 11 to about 24, about 11 to about 26, about 12 to about 13, about 12 to about 14, about 12 to about 15, about 12 to about 16, about 12 to about 18, about 12 to about 20, about 12 to about 22, about 12 to about 24, about 12 to about 26, about 13 to about 14, about 13 to about 15, about 13 to about 16, about 1 3 to about 18, about 13 to about 20, about 13 to about 22, about 13 to about 24, about 13 to about 26, about 14 to about 15, about 14 to about 16, about 14 to about 18, about 14 to about 20, about 14 to about 22, about 14 to about 24, about 14 to about 26, about 15 to about 16, about 15 to about 18, about 15 to about 20, about 15 to about 22, about 15 to about 24, about 15 to about 26 In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, about 26, about 16 to about 18, about 16 to about 20, about 16 to about 22, about 16 to about 24, about 16 to about 26, about 18 to about 20, about 18 to about 22, about 18 to about 24, about 18 to about 26, about 20 to about 22, about 20 to about 24, about 20 to about 26, about 22 to about 24, about 22 to about 26, or about 24 to about 26. In some embodiments, the injection is performed with a needle having a gauge of about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26. In some embodiments, the injection is performed with a needle having a gauge of at least about 10, about 11, about 12, 13, about 14, about 15, about 16, about 18, about 20, about 22, or about 24. In some embodiments, the injection is performed with a needle having a gauge of at most about 11, about 12, about 13, about 14, about 15, about 16, about 18, about 20, about 22, about 24, or about 26.

[0062] In some embodiments, the concentration of polyethylene glycol in the spacer material ranges from about 1 mg / ml to about 100 mg / ml, in some embodiments, the concentration of polyethylene glycol in the spacer material ranges from about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, Approximately 5 mg / ml to approximately 15 mg / ml, approximately 5 mg / ml to approximately 20 mg / ml, approximately 5 mg / ml to approximately 25 mg / ml, approximately 5 mg / ml to 30 mg / ml, approximately 5 mg / ml to approximately 40 mg / ml, approximately 5 mg / ml to approximately 50 mg / ml, approximately 5 mg / ml to approximately 60 mg / m l, about 5 mg / ml to about 80 mg / ml, about 5 mg / ml to about 100 mg / ml, about 10 mg / ml to about 15 mg / ml, about 10 mg / ml to about 20 mg / ml, about 10 mg / ml to about 25 mg / ml, about 10 mg / ml to about 30 mg / ml, about 10 mg / ml ~40mg / ml, 10mg / ml~50mg / ml, 10mg / ml~60mg / ml, 10mg / ml~80mg / ml, 10mg / ml~100mg / ml, 15mg / ml~20mg / ml, 15mg / ml~25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20 mg / ml~about 25mg / ml, about 20mg / ml~about 30mg / ml, about 20mg / ml~about 40mg / ml, about 20mg / ml~about 50mg / ml, about 20mg / ml~about 60mg / ml, about 20mg / ml~about 80mg / ml, about 20mg / ml~about 1 00mg / ml, about 25mg / ml to about 30mg / ml, about 25mg / ml to about 40mg / ml, about 25mg / ml to about 50mg / ml, about 25mg / ml to about 60mg / ml, about 25mg / ml to about 80mg / ml, about 25mg / ml to about 100mg / ml,The range is from about 30 mg / ml to about 40 mg / ml, from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 60 mg / ml, from about 30 mg / ml to about 80 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 40 mg / ml to about 50 mg / ml, from about 40 mg / ml to about 60 mg / ml, from about 40 mg / ml to about 80 mg / ml, from about 40 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 60 mg / ml, from about 50 mg / ml to about 80 mg / ml, from about 50 mg / ml to about 100 mg / ml, from about 60 mg / ml to about 80 mg / ml, from about 60 mg / ml to about 100 mg / ml, or from about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of polyethylene glycol in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0063] In some embodiments, the particle size is about 0.1 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.5 mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.5mm to about 10mm, about 0.5mm to about 1m m, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 10 mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm, Approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm, approximately 2mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the size of the particles is at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, hi some embodiments, the particles are at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0064] In some embodiments, blood flow to the tumor is avoided or reduced. In some embodiments, movement of viscoelastic media is avoided or reduced. In some embodiments, the method comprises administering hyaluronidase at the site of radiation therapy.

[0065] In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of hyaluronidase occurs from about 0.1 hours to about 0.5 hours, from about 0.1 hours to about 1 hour, from about 0.1 hours to about 2 hours, from about 0.1 hours to about 4 hours, from about 0.1 hours to about 6 hours, from about 0.1 hours to about 8 hours, from about 0.1 hours to about 10 hours, from about 0.1 hours to about 14 hours, from about 0.1 hours to about 18 hours, from about 0.1 hours to about 24 hours, from about 0.1 hours to about 95 hours, from about 0.5 hours to about 1 hour, or from about 0.5 hours to about 2 hours after injection of the bioabsorbable viscoelastic medium. about 0.5 hours to about 4 hours, about 0.5 hours to about 6 hours, about 0.5 hours to about 8 hours, about 0.5 hours to about 10 hours, about 0.5 hours to about 14 hours, about 0.5 hours to about 18 hours, about 0.5 hours to about 24 hours, about 0.5 hours to about 95 hours, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hour to about 95 hours, about 2 hours About 4 hours, about 2 to about 6 hours, about 2 to about 8 hours, about 2 to about 10 hours, about 2 to about 14 hours, about 2 to about 18 hours, about 2 to about 24 hours, about 2 to about 95 hours, about 4 to about 6 hours, about 4 to about 8 hours, about 4 to about 10 hours, about 4 to about 14 hours, about 4 to about 18 hours, about 4 to about 24 hours, about 4 to about 95 hours, about 6 to about 8 hours, about 6 to about 10 hours, about 6 to about 14 hours, about 6 to about 18 hours, about 6 hours In some embodiments, administration of hyaluronidase occurs about 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, about 95 hours, about 8 hours, about 10 hours, about 14 hours, about 10 hours, about 18 hours, about 10 hours, about 24 hours, about 10 hours, about 95 hours, about 14 hours, about 18 hours, about 14 hours, about 24 hours, about 14 hours, about 95 hours, about 18 hours, about 24 hours, about 18 hours, about 95 hours, or about 24 hours to about 95 hours after injection of the bioabsorbable viscoelastic medium.In some embodiments, administration of the hyaluronidase occurs at least 0.1 hours, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about, or about 24 hours after injection of the bioabsorbable viscoelastic medium. In some embodiments, administration of the hyaluronidase occurs at most about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 14 hours, about 18 hours, about 24 hours, or about 95 hours after injection of the bioabsorbable viscoelastic medium.

[0066] In some embodiments, the method further comprises the step of excising remaining tumor cells from the subject.

[0067] Another aspect provided herein is a formulation comprising cross-linked polyethylene glycol and a radiopaque compound selected from the group consisting of iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, and ioversol. In some embodiments, the formulation is used as a standard marker.

[0068] This patent application contains at least one drawing executed in color. Copies of this patent or patent application with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0069] The novel features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0070] [Figure 1A] 1 is an exemplary image of an injection area of ​​a mastectomy specimen, according to embodiments herein. [Figure 1B]10 is an exemplary image showing the injection of a spacer into a mastectomy specimen using ultrasound guidance, according to embodiments herein. [Figure 2A] 1 is an exemplary ultrasound image of glandular and adipose tissue within a mastectomy specimen, according to embodiments herein. [Figure 2B] 1 is an exemplary ultrasound image of a spacer, glandular tissue, and adipose tissue within a mastectomy specimen, according to embodiments herein. [Figure 3A] 1 is an exemplary computed tomography (CT) scan of a hyaluronic acid (HA) spacer in a mastectomy specimen, according to embodiments herein. [Figure 3B] 1 is an exemplary ultrasound image of an HA spacer in a mastectomy specimen, according to embodiments herein. [Figure 3C] 1 is an exemplary CT scan of a polyethylene glycol (PEG) spacer in a mastectomy specimen, according to embodiments herein. [Figure 3D] 1 is an exemplary CT scan of a PGA spacer in a mastectomy specimen, according to embodiments herein. [Figure 4A] 1 is an exemplary image showing a simulated permanent breast seed implant (PBSI) brachytherapy plan of a hyaluronic acid (HA) spacer in a mastectomy specimen, according to embodiments herein. [Figure 4B] 1 is an exemplary ultrasound image of an HA spacer in a mastectomy specimen, according to embodiments herein. [Figure 5A] 1 is an exemplary image of a computed tomography scan before hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5B] 1 is an exemplary image of a computed tomography scan after a hydrogel spacer injection between the head of the pancreas and the duodenum, according to embodiments herein. [Figure 5C] 10 is an exemplary image of a whole histological specimen following a hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5D] 10 is an exemplary image of a computed tomography scan prior to an open hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5E] 10 is an exemplary image of a computed tomography scan following an open abdominal hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5F] 10 is an exemplary image of a whole histological specimen following an open abdominal hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5G] 1 is an exemplary image of a computed tomography scan prior to endoscopic hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5H] 1 is an exemplary image of a computed tomography scan following endoscopic hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 5I] 10 is an exemplary image of a whole histological specimen following endoscopic hydrogel spacer injection between the pancreas head and duodenum, according to embodiments herein. [Figure 6A] 1 is an exemplary first image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining, according to embodiments herein. [Figure 6B] 10 is an exemplary second image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining, according to embodiments herein. [Figure 6C] 1 is an exemplary first high magnification image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining, according to embodiments herein. [Figure 6D] 10 is an exemplary third image of a formalin-fixed paraffin-embedded section after hematoxylin-eosin staining, according to embodiments herein. [Figure 6E] 10 is an exemplary second high magnification image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining, according to embodiments herein. [Figure 7A] FIG. 1 is a diagram of an exemplary first stereotactic radiotherapy plan prior to placement of a hydrogel spacer, according to embodiments herein. [Figure 7B] FIG. 10 is a diagram of an exemplary first stereotactic radiotherapy plan after placement of a hydrogel spacer, according to embodiments herein. [Figure 7C] FIG. 10 is a diagram of an exemplary second stereotactic radiotherapy plan prior to placement of a hydrogel spacer, according to embodiments herein. [Figure 7D] FIG. 10 is a diagram of an exemplary second stereotactic radiotherapy plan after placement of a hydrogel spacer, according to embodiments herein. [Figure 8A] 1 is an exemplary baseline image of a computed tomography scan of the duodenum and stereotactic radiotherapy planning, according to embodiments herein. [Figure 8B] 1 is an exemplary image of a computed tomography scan and stereotactic radiotherapy plan of the duodenum with 2 mm spacing, according to embodiments herein. [Figure 8C] 1 is an exemplary image of a computed tomography scan and stereotactic radiotherapy plan of the duodenum with 3 mm intervals, according to embodiments herein. [Figure 8D] 1 is an exemplary image of a computed tomography scan and stereotactic radiotherapy plan of the duodenum at 5 mm intervals according to embodiments herein. [Figure 8E] 1 is an exemplary image of a computed tomography scan and stereotactic radiotherapy plan of the duodenum with an 8 mm interval, according to embodiments herein. [Figure 8F] 1 is an exemplary image of a computed tomography scan and stereotactic radiotherapy plan of the duodenum with 15 mm intervals, according to embodiments herein. [Figure 9] 1 shows an MRI scan of bladder markings, a CT scan of liver markings, an MRI scan of liver markings, and an MRI of neck markings, according to embodiments herein. [Figure 10A] 1 shows an MRI scan of a submandibular tumor before treatment, according to embodiments herein. [Figure 10B] 1 shows an MRI scan of a submandibular tumor with a distance measurement of approximately 1 cm, according to embodiments herein. [Figure 10C] 1 shows an MRI six months after tumor removal, according to embodiments herein. [Figure 11A] 10 shows an image of an applicator needle being inserted from the left side of the cervix, according to embodiments herein. [Figure 11B] 1 shows an image of the location of a single 20 Gy dose of radiation, according to embodiments herein. [Figure 12] 1 shows an MRI image of a paravertebral dosing procedure according to embodiments herein. [Figure 13A] 1 shows a diagram illustrating a reconstructed rectum and prostate before brachytherapy irradiation, according to embodiments herein. [Figure 13B] 1 shows a diagram illustrating a reconstructed rectum and prostate after an initial brachytherapy irradiation, according to embodiments herein. [Figure 14A] FIG. 1 shows a diagram illustrating radiation levels before brachytherapy irradiation where the rectum and prostate are separated by more than 25 mm, according to embodiments herein. [Figure 14B] 1 shows a diagram illustrating radiation levels after brachytherapy irradiation where the rectum and prostate are separated by more than 25 mm, according to embodiments herein. [Figure 14C] 1 shows an MRI scan of the prostate and rectum 4 hours after injection, according to embodiments herein. [Figure 15A] 1 shows an X-ray computed tomography image before radiation therapy, according to embodiments herein. [Figure 15B] 1 shows an X-ray computed tomography image before external beam therapy treatment planning, according to embodiments herein. [Figure 16A]10A-10C show ultrasound and power Doppler images showing a planned path for needle insertion, according to embodiments herein. [Figure 16B] 10A-10C show ultrasound and power Doppler images showing brachytherapy dose distribution and inserted brachytherapy needles, according to embodiments herein. [Figure 16C] 10 shows an ultrasound image after the skin has been raised by 7 mm, according to embodiments herein. [Figure 17A] 1 shows X-ray computed tomography and brachytherapy dose distributions according to embodiments herein. [Figure 17B] 10 shows an X-ray computed tomography scan and images of a second lesion according to embodiments herein. [Figure 17C] 1 shows an X-ray computed tomography scan of tumors without recurrence one year after treatment according to embodiments herein. [Figure 18A] Figure 1 shows the initial visualization additive release from the viscoelastic medium. [Figure 18B] Analysis of the visualization additive after release from the viscoelastic medium at 7 and 24 hours is shown. DETAILED DESCRIPTION OF THE INVENTION

[0071] Provided herein are methods for reducing the toxicity of advanced cancer ablation treatments to adjacent organs. The methods provide space between single or multiple tumor sites and adjacent healthy organs while maintaining or increasing the patient's quality of life. Such separation of toxicity can be achieved by inserting spacers around one or more tumor sites, which can be performed simultaneously with standard marker placement.

[0072] Subcutaneous spacer material The subcutaneous spacer material herein is configured to form a cavity adjacent to a treated organ to prevent radiation or toxic damage to the organ adjacent or adjacent to the treated organ. The subcutaneous spacer material herein may include a viscoelastic medium containing hyaluronic acid particles. The particle size and concentration of hyaluronic acid within the spacer material can be adjusted to provide a hardness, density, or both that allows for consistent and uniform injection and cavity formation.

[0073] In some embodiments, the implant comprises particles of one or more viscoelastic media dispersed in buffered saline, a suitable saline solution, or both. In some embodiments, the implant further comprises other additives, such as local anesthetics, anti-inflammatory drugs, antibiotics, and supportive agents (e.g., bone growth factors or cells). In some embodiments, a viscoelastic media may also be included, which may be formed from the same material as the particles or a different material from the particles. In some embodiments, the viscoelastic media is not present as particles.

[0074] Viscoelastic media according to embodiments herein can include gels, dispersions, solutions, suspensions, slurries, and mixtures thereof. In some embodiments, the media exist as a gel or a dispersion of gel-like particles. The viscoelastic media provided herein may be more resistant to biodegradation in vivo than native hyaluronic acid. The long-term existence of a stable viscoelastic material is advantageous to patients because it allows for longer periods between treatments. The viscoelastic media herein are biocompatible, sterilized, and may exist as particles.

[0075] Advantageously, the viscoelastic medium herein is stable within physiological conditions, but may be transient under these conditions. In some embodiments, about 70 to about 90% of the viscoelastic medium remains in vivo for at least two weeks. In some embodiments, at least 70% of the viscoelastic medium remains in vivo for between about two weeks and two years. In some embodiments, at least 90% of the viscoelastic medium remains in vivo for between about two weeks and two years. The viscoelastic medium may naturally degrade after five years or more in vivo.

[0076] Viscoelastic media include, but are not limited to, polysaccharides and their derivatives. Suitable viscoelastic media include stable starch and its derivatives. Suitable viscoelastic media can also be selected from stable glycosaminoglycans and their derivatives, such as stable hyaluronic acid, stable chondroitin sulfate, stable heparin, and their derivatives. One example of a viscoelastic medium is stable non-animal hyaluronic acid ("NASHA"). NASHA is produced from non-animal sources (bacteria). The retention time of the viscoelastic medium depends on the particle size of the viscoelastic medium.

[0077] In some embodiments, the size of the particles of the viscoelastic medium is specifically tailored. This particle size can be achieved by producing a gel made from the viscoelastic medium at a desired concentration and subjecting the gel to physical disruption. Physical disruption may include chopping, grinding, filtering, or any combination thereof. The resulting gel particles can be dispersed in a saline solution to produce a gel dispersion or slurry having particles of the desired size. Particle size can be determined by any suitable method, such as laser diffraction, microscopy, or filtration. In some embodiments, the specific shape of the gel particles is not critical. The size of a spherical particle can be equivalent to its diameter. This size can be measured as an average size, median size, maximum size, or minimum size.

[0078] In some embodiments, the particles have a size in the range of 1-2.5 mm, such as 1.5-2 mm, in the presence of saline solution. In some embodiments, the particles have a size in the range of 2.5-5 mm, such as 3-4 mm, in the presence of saline solution. At least 50% (v / v) of the particles may have a size of at least about 1 mm. At least 50% (v / v) of the particles may have a size of about 1-5 mm in the presence of saline solution. In some embodiments, more than 70% (v / v) of the particles are within a given size limit under physiological conditions. In some embodiments, more than 90% (v / v) of the particles are within a given size limit under physiological conditions. Administration of an implant using a method according to an embodiment herein prevents or reduces migration and / or dislodgement of the implant. The implant comprises or consists of larger particles ranging from 1-5 mm under physiological conditions. Larger particles exhibit less in vitro migration and are more easily removed. In some embodiments, the viscoelastic medium is present as particles less than 0.1 mm in size.

[0079] In some embodiments, the particle size is about 0.05 to 0.1 mm, or about 0.05 to 0.06 mm, about 0.05 to 0.07 mm, about 0.05 to 0.08 mm, about 0.05 to 0.09 mm, about 0.05 to 0.1 mm, about 0.06 to 0.07 mm, about 0.06 to 0.08 mm, about 0.06 to 0.09 mm, about 0.06 to 0.1 mm, about 0.07 to 0.08 mm, about 0.07 to 0.09 mm, about 0.07 to 0.1 mm, about 0.08 to 0.09 mm, about 0.08 to 0.1 mm, or about 0.09 to 0.1 mm. In some embodiments, the particles have a size of about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, or about 0.1 mm. In some embodiments, the particles have a size of at least about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, or about 0.09 mm. In some embodiments, the particles have a size of at most about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, or about 0.1 mm.

[0080] In some embodiments, the particle size is about 0.1 mm to about 10 mm, or about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, or about 0.2 mm to about 1 mm. .5mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.2mm to about 10mm, about 0.5mm to about 1mm, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5mm to about 6mm, about 0.5mm to about 8mm, about 0.5mm to about 1 0mm, about 1mm to about 1.5mm, about 1mm to about 2mm, about 1mm to about 3mm, about 1mm to about 4mm, about 1mm to about 5mm, about 1mm to about 6mm, about 1mm to about 8mm, about 1mm to about 10mm, about 1.5mm to about 2mm , about 1.5mm to about 3mm, about 1.5mm to about 4mm, about 1.5mm to about 5mm, about 1.5mm to about 6mm, about 1.5mm to about 8mm, about 1.5mm to about 10mm, about 2mm to about 3mm, about 2mm to about 4mm, about 2mm to about about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particle size is about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the particles have a size of at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, hi some embodiments, the particles have a size of at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0081] Suitable viscoelastic media also include stable dextran and its derivatives, such as dextranomers (Dx). Dx is a large molecule composed of many cross-linked dextran polymers. The dextran molecular structure contains glucose units linked by small, lightly branched, linear α-1,6-glycosidic bonds. This structure forms a gel when water is added. For most medical purposes, dextran polymers with molecular weights of 70 kDa and 40 kDa are used. During Dx synthesis, these polymers are linked together by the addition of a cross-linking agent. This manufacturing process allows the dextran polymers to be linked together and cross-linked into small beads known as microspheres. The degree of cross-linking affects the properties of Dx, as well as the size of the individual microspheres. Dx microspheres can be produced in a variety of sizes, with those used in Q-Med's products ranging from 80 to 250 μm.

[0082] In some embodiments, the molecular weight of Dx is between about 40 kDa and about 70 kDa. In some embodiments, the molecular weight of Dx is about 70 kDa. In some embodiments, the molecular weight of Dx is at least about 40 kDa.

[0083] In some embodiments, the viscoelastic medium is cross-linked hyaluronic acid, or a derivative thereof.

[0084] One suitable cross-linked hyaluronic acid can be obtained by cross-linking hyaluronic acid. The viscoelastic medium can also be a combination of two or more suitable viscoelastic mediums listed herein or otherwise known in the art. The viscoelastic medium can be of non-animal origin.

[0085] In some embodiments, the viscoelastic medium comprises a hydrogel. In some embodiments, the hydrogel is formed from natural, synthetic, or biosynthetic polymers. In some embodiments, the natural polymer comprises a glycosaminoglycan, a polysaccharide, a protein, or any combination thereof. In some embodiments, the glycosaminoglycan is dermatan sulfate, hyaluronic acid, chondroitin sulfate, chitin, heparin, keratan sulfate, keratosulfate, or any combination thereof. In some embodiments, the hydrogel comprises an acidic carboxy polymer, an acrylic acid-based polymer, polyacrylamide, a starch graft copolymer, an acrylic acid polymer, or any combination thereof. In some embodiments, the hydrogel comprises allylpentaerythritol, polyacrylic acid, an ester-crosslinked polyglycan, or any combination thereof.

[0086] In some embodiments, the viscoelastic medium is hydrophilic.

[0087] In some embodiments, the viscoelastic medium comprises a combination of disclosed compounds. In one example, the viscoelastic medium comprises hyaluronic acid and Dx. In another example, the viscoelastic medium comprises NASHA / Dx gel. In some embodiments, the NASHA / Dx gel has a sufficiently low viscosity that it can be injected via a syringe using only finger pressure. In some embodiments, the NASHA / Dx gel has a sufficiently high viscosity to avoid leakage from the injection site. In some embodiments, the NASHA / Dx gel has a long degradation time that allows for the natural formation of connective tissue at the implant site and stabilizes it. In some embodiments, the viscoelastic medium further comprises carbon-coated zirconium beads, calcium hydroxylapatite, or both.

[0088] The size of gel particles may depend on the ionic strength of the buffer, solution, carrier, or any combination thereof contained in and / or surrounding the gel particles. Therefore, a given particle size can be assumed under physiological conditions, particularly isotonic conditions. In some embodiments, the gel particles contain and are dispersed in a saline solution. In some embodiments, the gel particles are temporarily sized differently by exposing them to a solution of a different osmotic pressure. The particle size is within a given range under physiological conditions when implanted subcutaneously in the body or when exposed to a physiological or isotonic saline solution (a solution with the same osmotic pressure as the relevant body fluid, such as isotonic with serum).

[0089] In some embodiments, the particle size is specifically tailored. This can be achieved by producing a gel made from a viscoelastic medium at a desired concentration and subjecting the gel to physical disruption. Physical disruption may include chopping, grinding, filtering, or any combination thereof. The resulting gel particles can be dispersed in a saline solution to produce a gel dispersion or slurry having particles of the desired size. Particle size can be determined by any suitable method, such as laser diffraction, microscopy, or filtration. In some embodiments, the specific shape of the gel particles is not critical. The size of a spherical particle can be equivalent to its diameter. This size can be measured as an average size, median size, maximum size, or minimum size.

[0090] In some embodiments, the particles have a size in the range of 1-2.5 mm, such as 1.5-2 mm, in the presence of saline solution. In some embodiments, the particles have a size in the range of 2.5-5 mm, such as 3-4 mm, in the presence of saline solution. At least 50% (v / v) of the particles may have a size of at least about 1 mm. At least 50% (v / v) of the particles may have a size of about 1-5 mm in the presence of saline solution. In some embodiments, more than 70% (v / v) of the particles are within a given size limit under physiological conditions. In some embodiments, more than 90% (v / v) of the particles are within a given size limit under physiological conditions. Administration of an implant using a method according to an embodiment herein prevents or reduces migration and / or dislodgement of the implant. The implant comprises or consists of larger particles of 1-5 mm under physiological conditions. Larger particles exhibit less in vitro migration and are more easily removed. In some embodiments, the viscoelastic medium is absent as particles less than 0.1 mm in size. In some embodiments, Dx is comprised of microspheres. In some embodiments, the microspheres have a diameter of about 80 μm to about 250 μm. In some embodiments, the microspheres have a diameter of at least about 80 μm. In some embodiments, the microspheres have a diameter of at most 250 μm. In some embodiments, Dx is comprised of microspheres. The microspheres have a diameter of about 80 μm to about 250 μm. In some embodiments, the microspheres have a diameter of at least about 80 μm. In some embodiments, the microspheres have a diameter of at most 250 μm.

[0091] In some embodiments, the particles have specifically tailored density, hardness, or both. The density of the gel particles can be adjusted by adjusting the concentration of the viscoelastic medium, the amount and type of crosslinker, or both. Harder particles can be achieved by increasing the concentration of the viscoelastic medium in the gel. Harder particles may be less viscoelastic than softer particles and exhibit a longer in vivo half-life. The particles herein must retain sufficient viscoelastic properties to allow safe injection. In some embodiments, the implant comprises both soft and hard gel particles. The soft and hard gel particles may be made from the same or different viscoelastic mediums. The resulting gel particle mixture combines the desired softness / hardness properties for use in radiative protection and long-term in vivo durability.

[0092] Method for forming spacer material The subcutaneous spacer material herein is configured to form a cavity adjacent to a treated organ to prevent radiation or toxic damage to the organ adjacent or adjacent to the treated organ. The subcutaneous spacer material herein may include a viscoelastic medium containing hyaluronic acid particles. The particle size and concentration of hyaluronic acid within the spacer material can be adjusted to provide a hardness, density, or both that allows for consistent and uniform injection and cavity formation.

[0093] Provided herein are methods of forming spacer materials, the methods comprising forming an aqueous solution containing a water-soluble cross-linkable polysaccharide, initiating cross-linking of the polysaccharide in the presence of a multifunctional cross-linking agent, sterically hindering the cross-linking reaction to terminate before gelation occurs to produce an activated polysaccharide, and reintroducing sterically unhindered conditions to the activated polysaccharide to continue the cross-linking reaction until a viscoelastic gel is formed. In some embodiments, the step of initiating the cross-linking reaction in the presence of a multifunctional cross-linking agent can be carried out at a pH value that varies depending primarily on whether ether or ester reactions are to be promoted.

[0094] The crosslinker may be any conventional crosslinker known to be useful in connection with biocompatible polysaccharides. However, crosslinkers include aldehydes, epoxides, polyaziridyl compounds, glycidyl ethers, divinyl sulfones, or any combination thereof. Glycidyl ethers represent a group that may conveniently be 1,4-butanediol diglycidyl ether. In some embodiments, the spacer material comprises a hydrogel containing glycosaminoglycans extracted from natural sources that are purified and derivatized. In some embodiments, the glycosaminoglycans are synthetically produced or synthesized by modified microorganisms, such as bacteria. In some embodiments, the glycosaminoglycans are synthetically modified from a naturally soluble state to a partially soluble, water-swellable, or hydrogel state.

[0095] A suitable method for achieving the desired particle size includes producing a gel made from crosslinked hyaluronic acid at the desired concentration and subjecting the gel to physical disruption, such as chopping, grinding, or forcing the gel through a filter with the appropriate particle size. The resulting gel particles are dispersed in a saline solution to produce a gel dispersion or slurry with particles of the desired size. This particle size can be achieved by producing a gel made from a viscoelastic medium at the desired concentration and subjecting the gel to physical disruption. Physical disruption can include chopping, grinding, filtering, or any combination thereof. The resulting gel particles can be dispersed in a saline solution to produce a gel dispersion or slurry with particles of the desired size.

[0096] In some embodiments, the particles have a specifically tailored density, hardness, or both. The density of the gel particles can be adjusted by adjusting the concentration of the viscoelastic medium, the amount and type of crosslinker, or both. Harder particles can be achieved by increasing the concentration of the viscoelastic medium in the gel. Gel particles of various hardness can be obtained by varying the hyaluronic acid concentration, for example, to 20, 25, 40, 50, and 100 mg / ml. Harder particles have lower viscoelasticity than softer particles and may have a longer in vivo half-life. The particles herein must retain sufficient viscoelastic properties to allow them to be safely injected.

[0097] In some embodiments, the implant contains both soft and hard gel particles. The soft and hard gel particles may be made from the same or different viscoelastic media. The resulting gel particle mixture combines the desired softness / hardness characteristics for use in radiation protection and long-term in vivo durability. In one embodiment, the soft gel particles contain 15-22 mg / ml cross-linked hyaluronic acid, and the hard gel particles contain 22-30 mg / ml cross-linked hyaluronic acid.

[0098] When the injectable vehicle is a hyaluronic acid vehicle, the hyaluronic acid concentration may be at least about 5 mg / ml. In some embodiments, the hyaluronic acid concentration is about 5 mg / ml to about 100 mg / ml. In some embodiments, the hyaluronic acid concentration is about 10 mg / ml to about 50 mg / ml. In some embodiments, the hyaluronic acid concentration is about 20 mg / ml. The cross-linked hyaluronic acid may be present as particles or beads of any shape.

[0099] In some embodiments, the method further comprises adding an image enhancement agent described herein to the spacer material, hi some embodiments, the method further comprises mixing an image enhancement agent described herein into the spacer material.

[0100] Method of injecting spacer material The subcutaneous spacer material herein is configured to form a cavity adjacent to a treated organ to prevent radiation or toxic damage to the organ adjacent to or adjacent to the treated organ. The subcutaneous spacer material herein may comprise a viscoelastic medium containing hyaluronic acid particles. The particle size and concentration of the hyaluronic acid within the spacer material can be adjusted to exhibit hardness, density, or both to enable consistent and uniform injection and cavity formation. Furthermore, based on the particle size, hardness, density, and concentration of the hyaluronic acid, a specific needle size may be used to deliver the spacer material to its intended in vivo location.

[0101] Provided herein are methods for injecting a spacing material. The spacing material may include a viscoelastic medium for therapeutic radiation protection in mammals, including humans. The spacing material may be suitable for subepidermal administration at sites in the mammal where therapeutic soft tissue protection from radiation or other toxic sources is desired. In particular, the particles are suitable for administration to tissues covered by exposed skin, such as facial tissue, because they do not cause bruising or other discoloration. The particles herein are suitable for administration to deep subcutaneous tissue, optionally in more than one layer, or submuscular / supraperiostal tissue. Administration to deep subcutaneous tissue or submuscular / supraperiostal tissue can further prevent or reduce migration of the particles away from the desired site.

[0102] The spacer material may be administered by subcutaneous injection in any suitable manner, for example, a skin incision may be made with a scalpel or sharp needle to facilitate percutaneous insertion of a large cannula for administration of the implant at the desired site.

[0103] The implant, consisting of viscoelastic medium particles and optionally other suitable components, can be administered as a single aliquot or multiple aliquot layers. Optionally, the viscoelastic medium can be replaced, refilled, or replenished by subsequent injections of the same or different viscoelastic medium. The injected volume is determined by the size of the desired cavity.

[0104] In some embodiments, the volume of the spacer material injected is about 1 ml to about 500 ml. In some embodiments, the volume of the spacer material injected is about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 25 ml, about 1 ml to about 50 ml, about 1 ml to about 100 ml, about 1 ml to about 150 ml, about 1 ml to about 200 ml, about 1 ml to about 250 ml, about 1 ml to about 300 ml, about 1 ml to about 400 ml, about 1 ml to about 500 ml, about 5 ml to about 10 ml, about 5 ml to about 25 ml, about 5 ml to about 50 ml, about 5 ml to about 100 ml, about 5 ml to about 150 ml, about 5 ml to about 2 00ml, approximately 5ml to approximately 250ml, approximately 5ml to approximately 300ml, approximately 5ml to approximately 400ml, approximately 5ml to approximately 500ml, approximately 10ml to approximately 25ml, approximately 10ml to approximately 50ml, approximately 10ml to approximately 100ml, approximately 10ml to approximately 150ml, approximately 10ml to approximately 200ml, about 10ml to about 250ml, about 10ml to about 300ml, about 10ml to about 400ml, about 10ml to about 500ml, about 25ml to about 50ml, about 25ml to about 100ml, about 25ml to about 150ml, about 25ml to about 200ml, about 2 5ml to 250ml, 25ml to 300ml, 25ml to 400ml, 25ml to 500ml, 50ml to 100ml, 50ml to 150ml, 50ml to 200ml, 50ml to 250ml, 50ml to 3 00ml, about 50ml to about 400ml, about 50ml to about 500ml, about 100ml to about 150ml, about 100ml to about 200ml, about 100ml to about 250ml, about 100ml to about 300ml, about 100ml to about 400ml, about 100ml to 5 00ml, about 150ml to about 200ml, about 150ml to about 250ml, about 150ml to about 300ml, about 150ml to about 400ml, about 150ml to about 500ml, about 200ml to about 250ml, about 200ml to about 300ml, about 200ml to about 400ml, about 200ml to about 500ml, about 250ml to about 300ml, about 250ml to about 400ml, about 250ml to about 500ml, about 300ml to about 400ml, about 300ml to about 500ml, or about 400ml to about 500ml.In some embodiments, the volume of spacer material injected is about 1 ml, about 5 ml, about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 150 ml, about 200 ml, about 250 ml, about 300 ml, about 400 ml, or about 500 ml. In some embodiments, the volume of spacer material injected is at least about 1 ml, about 5 ml, about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 150 ml, about 200 ml, about 250 ml, about 300 ml, or about 400 ml. In some embodiments, the volume of spacer material injected is at most about 5 ml, about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 150 ml, about 200 ml, about 250 ml, about 300 ml, about 400 ml, or about 500 ml.

[0105] Administration can be by any suitable method, such as via injection through a standard cannula and needle of appropriate size, where radiation protection is desired, such as the chin, cheek, or other area of ​​the face or body.

[0106] The spacer material herein can be injected through standard needles used in medicine, such as 20 gauge or larger needles. Alternatively, the spacer material containing hyaluronic acid can be injected using any of the following needle sizes:

[0107] [Table 1]

[0108] In some embodiments, the inner surface of the needle comprises protrusions, a mesh, a compressed portion, or any combination thereof. In some embodiments, gas bubbles are generated in the spacer material by injecting the spacer material past the protrusions, mesh, compressed portion, or any combination thereof. In some embodiments, the gas bubbles are microbubbles. In some embodiments, the mesh has a mesh spacing of about 20 μm to about 300 μm. In some embodiments, the size of the mesh spacing determines the size of the microbubbles generated thereby.

[0109] Standard Markers Developments in CT imaging can be used to exploit the stability of hyaluronic acid for use as a fiducial marker. Today's gold fiducial markers have too much artifact for MRI, but perform well with CT.

[0110] Image quality improvement Because polyethylene glycol, hyaluronic acid, and NASHA gel are difficult to visualize on CT scans, MRI, and transrectal ultrasound (TRUS), additives and compositions are designed to allow clinicians to precisely inject the organ spacer material described herein through real-time scan feedback. Furthermore, such scans can be used for radiation planning. Improved HA CT image quality is a critical feature, eliminating the need for a patient MRI, eliminating the cost and CT / MRI fusion step in treatment planning. Additionally, for boost and accelerated partial breast irradiation (APBI) planning, clear identification of seromas is crucial to enable accurate target volume contouring and initiation of cone-beam image-guided radiation therapy. However, because seromas are not always visible on CT simulation, many surgeries, such as those requiring full-thickness closure during surgery, are difficult to plan and may disqualify the patient from such APBI procedures. Intraoperative clip placement has been used to aid in such contouring, but it is often unreliable because high-Z clip materials distort the contour image and low-Z clip materials, such as tantalum, are invisible.

[0111] However, the image enhancement agents provided herein exhibit a Z-value that is sufficient to allow full visibility on CT and paramagnetic moment for visibility on MRI, but not too high to avoid degradation of seroma images. Further optimal visibility and image quality are achieved by varying the volume of the image enhancement agent injected while keeping the expansion of the treated volume to a minimum.

[0112] In one embodiment, the visualization additive includes iodine, which enhances CT imaging, but may not provide any benefit to MRI and TRUS imaging. Additionally, iodine may be an allergen.

[0113] In some embodiments, the visualization additive comprises a radiopaque compound selected from the group consisting of iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadolinium dimeglumine, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or any combination thereof. In some embodiments, the superparamagnetic iron oxide additive is superparamagnetic iron oxide nanoparticles. In some embodiments, the concentration of the visualization additive in the polyethylene glycol, hyaluronic acid, or both is about 1 mg / ml to about 10 mg / ml. In some embodiments, the visualization additive is present in the gel at about 0.5 mg / ml to about 6 mg / ml of the gel. In some embodiments, the concentration of the visualization additive in the spacer material is from about 0.1% to about 15%. In some embodiments, the concentration of the visualization additive in the spacer material is from 0.5 mg / ml to 1 mg / ml of gel, from 0.5 mg / ml to 1.5 mg / ml of gel, from 0.5 mg / ml to 2 mg / ml of gel, from 0.5 mg / ml to 2.5 mg / ml of gel, from 0.5 mg / ml to 3 mg / ml of gel, from 0.5 mg / ml to 3.5 mg / ml of gel, from 0.5 mg / ml to 4 mg / ml of gel, from 0.5 mg / ml to 4.5 mg / ml of gel, from 0.5 mg / ml to 5 mg / ml of gel, from 0.5 mg / ml to 5.5 mg / ml of gel, or from 0.5 mg / ml to 5 mg / ml of gel. 1~6mg / ml of gel, 1mg / ml of gel~1.5mg / ml of gel, 1mg / ml of gel~2mg / ml of gel, 1mg / ml of gel~2.5mg / ml of gel, 1mg / ml of gel~3mg / ml of gel, 1mg / ml of gel~3.5mg / ml of gel, 1mg / ml of gel~4mg / ml of gel, 1mg / ml of gel~4.5mg / ml of gel, 1mg / ml of gel~5mg / ml of gel, 1mg / ml of gel~5.5mg / ml of gel, 1mg / ml of gel~6mg / ml of gel, 1.5mg / ml of gel~2mg / ml of gel, 1.5mg / ml of gel~2.5mg / ml of gel, 1.5mg / ml to 3mg / ml of gel, 1.5mg / ml to 3.5mg / ml of gel, 1.5mg / ml to 4mg / ml of gel, 1.5mg / ml to 4.5mg / ml of gel, 1.5mg / ml to 5mg / ml of gel, 1.5mg / ml to 5.5mg / ml of gel, 1.5mg / ml to 6mg / ml of gel, 2mg / ml to 2.5mg / ml of gel, 2mg / ml to 3mg / ml of gel, 2mg / ml to 3.5mg / ml of gel, 2mg / ml to 4mg / ml of gel, 2mg / ml to 4.5mg / ml of gel, 2mg / ml to 5mg / ml of gel, 2mg / ml to 5.5mg / ml of gel, 2mg / ml to 6mg / ml of gel, 2.5mg / ml to 3mg / ml of gel, 2.5mg / ml to 3.5mg / ml of gel, 2.5mg / ml to 4mg / ml of gel, 2.5mg / ml to 4.5mg / ml of gel, 2.5mg / ml to 5mg / ml of gel, 2.5mg / ml to 5.5mg / ml of gel, 2.5mg / ml to 6mg / ml of gel, gel 3mg / ml to 3.5mg / ml of gel, 3mg / ml to 4mg / ml of gel, 3mg / ml to 4.5mg / ml of gel, 3mg / ml to 5mg / ml of gel, 3mg / ml to 5.5mg / ml of gel, 3mg / ml to 6mg / ml of gel, 3.5mg / ml to 4mg / ml of gel, 3.5mg / ml to 4.5mg / ml of gel, 3.5mg / ml to 5mg / ml of gel, 3.5mg / ml to 5.5mg / ml of gel, 3.5mg / ml to 6mg / ml of gel, 4mg The visualization additive is present in the gel at at least about 0.1% of the gel at 4.5 mg / ml to 5 mg / ml of gel, 4 mg / ml to 5.5 mg / ml of gel, 4 mg / ml to 6 mg / ml of gel, 4.5 mg / ml to 5 mg / ml of gel, 4.5 mg / ml to 5.5 mg / ml of gel, 4.5 mg / ml to 6 mg / ml of gel, 5 mg / ml to 5.5 mg / ml of gel, 5 mg / ml to 6 mg / ml of gel, or 5.5 mg / ml to 6 mg / ml of gel. In some embodiments, the visualization additive is present in the gel at about 0.In some embodiments, the visualization additive is present in the gel at about 0.5 mg / ml of the gel, about 1 mg / ml of the gel, about 1.5 mg / ml of the gel, about 2 mg / ml of the gel, about 2.5 mg / ml of the gel, about 3 mg / ml of the gel, about 3.5 mg / ml of the gel, about 4 mg / ml of the gel, about 4.5 mg / ml of the gel, about 5 mg / ml of the gel, about 5.5 mg / ml of the gel, or about 6 mg / ml of the gel. In some embodiments, the visualization additive is present in the gel at at least 0.5 mg / ml of the gel, about 1 mg / ml of the gel, about 1.5 mg / ml of the gel, about 2 mg / ml of the gel, about 2.5 mg / ml of the gel, about 3 mg / ml of the gel, about 3.5 mg / ml of the gel, about 4 mg / ml of the gel, about 4.5 mg / ml of the gel, about 5 mg / ml of the gel, or about 5.5 mg / ml of the gel. In some embodiments, the visualization additive is present in the gel at a maximum of about 1 mg / ml of gel, about 1.5 mg / ml of gel, about 2 mg / ml of gel, about 2.5 mg / ml of gel, about 3 mg / ml of gel, about 3.5 mg / ml of gel, about 4 mg / ml of gel, about 4.5 mg / ml of gel, about 5 mg / ml of gel, about 5.5 mg / ml of gel, or about 6 mg / ml of gel. Other examples of viscoelastic media treated for enhanced visualization are taught in WO2011084465, which is incorporated herein in its entirety.

[0114] In some embodiments, an additional visualization additive is added to the gel, wherein the additional visualization additive comprises a gas. In some embodiments, the gas is air, nitrogen, helium, oxygen, or any combination thereof. In some embodiments, the gas forms a plurality of bubbles within the spacer material. In some embodiments, the concentration of the additional visualization additive in the spacer material is about 0.1% to about 15%. In some embodiments, the microbubbles have a size of about 1 μm to about 100 μm. In some embodiments, the concentration of the visualization additive in the spacer material is at least about 0.1%. In some embodiments, the gas is injected into the spacer material. In some embodiments, the visualization additive has an outer width of at least about 20 microns. In some embodiments, the gas is injected into the spacer material while the spacer material is under pressure. In some embodiments, the visualization additive has a diameter of at least about 20 microns. In some embodiments, the spacer material is agitated in a gas-containing environment to form microbubbles. In some embodiments, the spacer material is pressurized and agitated in a gas-containing environment to form microbubbles. In some embodiments, the microbubbles are formed prior to injection of the spacer material into the subject. In some embodiments, the microbubbles are formed during injection of the spacer material into the subject. In some embodiments, the microbubbles are formed during injection of the spacer material into the subject, where the shape of the needle forms the microbubbles. In some embodiments, the microbubbles are formed in situ. In some embodiments, a cross-linked viscoelastic medium traps and stabilizes the microbubbles. In some embodiments, the gels described herein comprise an additional visualization additive, where the additional visualization additive comprises a gas without any other visualization additive.

[0115] In some embodiments, the viscoelastic medium is NASHA and the visualization additive is a known imaging (e.g., MRI) contrast agent. In some embodiments, the visualization additive is any one of the compounds disclosed herein. In some embodiments, the visualization additive comprises a gadolinium complex. In some embodiments, the gadolinium complex comprises gadopentetate dimeglumine. In some embodiments, a gel containing 5 mg / ml gadopentetate dimeglumine was prepared by weighing. In some embodiments, the visualization additive was mixed with the gel by manual stirring, and the resulting gel was centrifuged to remove air bubbles one day before use. In some embodiments, the visualization additive is superparamagnetic iron oxide.

[0116] Spacer material dissolving agent In one example, the spacer material can include polyethylene glycol, where the dissolving agent includes water. In another example, the spacer material can include hyaluronic acid, where the dissolving agent includes hyaluronidase. In another example, the dissolving agent can be used to treat. In another example, the dissolving agent can be used to treat melanoma, where the spacing can be temporarily over-inflated to allow for greater distance for a larger dose, and then returned to its original position for cosmetic purposes.

[0117] Subcutaneous spacer material The subcutaneous spacer material herein is configured to form an adjacent cavity to prevent radiation or toxic damage to organs adjacent to or in contact with the treated organ. The subcutaneous spacer material herein may comprise a viscoelastic medium containing polyethylene glycol particles. The size and concentration of the polyethylene glycol particles within the spacer material may be adjusted to exhibit hardness, density, or both to enable consistent and uniform injection and cavity formation.

[0118] In some embodiments, the implant comprises one or more particles of a viscoelastic medium dispersed in buffered saline, a suitable saline solution, or both. In some embodiments, the implant further comprises other additives, such as local anesthetics, anti-inflammatory drugs, antibiotics, and supportive agents (e.g., bone growth factors or cells). In some embodiments, a viscoelastic medium may also be included, which may be formed from the same material as the particles or a different material from the particles. In some embodiments, the viscoelastic medium is not present as particles.

[0119] Viscoelastic media according to embodiments herein can include gels, dispersions, solutions, suspensions, slurries, and mixtures thereof. In some embodiments, the media exists as a gel or a dispersion of gel-like particles. The viscoelastic media provided herein may be more resistant to biodegradation in vivo than natural polyethylene glycol. The long-term existence of a stable viscoelastic material is advantageous to patients because it allows for longer periods between treatments. The viscoelastic media herein are biocompatible, sterilized, and can exist as particles.

[0120] Advantageously, the viscoelastic medium herein is stable within physiological conditions, but may be transient under these conditions. In some embodiments, about 70% to about 90% of the viscoelastic medium remains in vivo for at least two weeks. In some embodiments, at least 70% of the viscoelastic medium remains in vivo for between about two weeks and two years. In some embodiments, at least 90% of the viscoelastic medium remains in vivo for between about two weeks and two years. The viscoelastic medium may naturally degrade after five years or more in vivo.

[0121] Viscoelastic media include, but are not limited to, polysaccharides and their derivatives. Suitable viscoelastic media include stabilized starch and its derivatives. Suitable viscoelastic media can also be selected from stabilized glycosaminoglycans and their derivatives, such as stabilized polyethylene glycol, stabilized chondroitin sulfate, stabilized heparin, and their derivatives. Suitable viscoelastic media also include stabilized dextrans and their derivatives, such as dextranomer. In some embodiments, the dextranomer has a molecular weight of about 40 kDa to about 70 kDa. In some embodiments, the dextranomer has a molecular weight of at most about 70 kDa. In some embodiments, the dextranomer has a molecular weight of at least 40 kDa. In some embodiments, the dextranomer comprises microspheres. In some embodiments, the microspheres have a diameter of about 80 μm to about 250 μm. In some embodiments, the microspheres have a diameter of at least 80 μm. In some embodiments, the microspheres have a diameter of at most about 250 μm. In some embodiments, the viscoelastic medium is cross-linked polyethylene glycol or its derivative. One example of a viscoelastic medium is non-animal stabilized polyethylene glycol. One type of suitable cross-linked polyethylene glycol can be obtained by cross-linking polyethylene glycol. The viscoelastic medium can also be a combination of two or more suitable viscoelastic mediums listed herein or known in the art. The viscoelastic medium can be non-animal derived.

[0122] The size of gel particles can depend on the ionic strength of the buffer, solution, carrier, or any combination thereof contained in and / or surrounding the gel particles. Thus, a given particle size can be assumed under physiological conditions, particularly isotonic conditions. In some embodiments, the gel particles contain and are dispersed in a physiological salt solution. In some embodiments, the gel particles are temporarily sized differently by exposing them to solutions of different tonicities. The particles will be within a given size range under physiological conditions when implanted subcutaneously in the body or when exposed to a physiological or isotonic salt solution (i.e., a solution with the same tonicity as the relevant biological fluid, such as serum).

[0123] In some embodiments, the particles have a specific, tailored size. Particle size can be achieved by producing a gel made with a viscoelastic medium at a desired concentration and subjecting the gel to physical disruption. Physical disruption includes: chopping, grinding, filtering, or any combination thereof. The resulting gel particles can be dispersed in a physiological saline solution, resulting in a gel dispersion or slurry with the desired particle size. Particle size can be determined by any suitable method, such as laser diffraction, microscopy, or filtration. In some embodiments, the specific shape of the gel particles is not important. The size of a spherical particle can be equal to its diameter. Size may be measured as an average size, a median size, a maximum size, or a minimum size.

[0124] In some embodiments, the particles have a size ranging from 1 to 2.5 mm, e.g., 1.5 to 2 mm, in the presence of physiological salt solution. In some embodiments, the particles have a size ranging from 2.5 to 5 mm, e.g., 3 to 4 mm, in the presence of physiological salt solution. At least 50% (v / v) of the particles may have a size of at least about 1 mm. At least 50% (v / v) of the particles may have a size of about 1 to 5 mm in the presence of physiological salt solution. In some embodiments, more than 70% (v / v) of the particles are within a given size limit under physiological conditions. In some embodiments, more than 90% (v / v) of the particles are within a given size limit under physiological conditions. Administration of an implant using methods according to embodiments herein comprising or consisting of larger particles in the 1 to 5 mm range under physiological conditions avoids or inhibits migration and / or displacement of the implant. Larger particles may exhibit less migration in vitro and may be more easily removed. In some embodiments, the viscoelastic medium is present as particles less than 0.1 mm in size.

[0125] In some embodiments, the particles have a size of about 0.1 mm to about 0.05 mm, about 0.05 mm to about 0.06 mm, about 0.05 mm to about 0.07 mm, about 0.05 mm to about 0.08 mm, about 0.05 mm to about 0.09 mm, about 0.05 mm to about 0.1 mm, about 0.06 mm to about 0.07 mm, about 0.06 mm to about 0.08 mm, about 0.06 mm to about 0.09 mm, about 0.06 mm to about 0.1 mm, about 0.07 mm to about 0.08 mm, about 0.07 mm to about 0.09 mm, about 0.07 mm to about 0.1 mm, about 0.08 mm to about 0.09 mm, about 0.08 mm to about 0.1 mm, or about 0.09 mm to about 0.1 mm. In some embodiments, the particles have a size of about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, or about 0.1 mm. In some embodiments, the particles have a size of at least about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, or about 0.09 mm. In some embodiments, the particles have a size of at most about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, or about 0.1 mm.

[0126] In some embodiments, the particles have a size of about 0.1 mm to about 10 mm, hi some embodiments, the particles have a size of about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 3 mm, about 0.1 mm to about 4 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 6 mm, about 0.1 mm to about 8 mm, about 0.1 mm to about 10 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm. m, about 0.2mm to about 1.5mm, about 0.2mm to about 2mm, about 0.2mm to about 3mm, about 0.2mm to about 4mm, about 0.2mm to about 5mm, about 0.2mm to about 6mm, about 0.2mm to about 8mm, about 0.2mm to about 10mm, about 0.5mm to about 1mm, about 0.5mm to about 1.5mm, about 0.5mm to about 2mm, about 0.5mm to about 3mm, about 0.5mm to about 4mm, about 0.5mm to about 5mm, about 0.5 mm~about 6mm, about 0.5 mm~about 8mm, about 0.5mm~about 10mm, about 1mm~about 1.5mm, about 1mm~about 2mm, about 1mm~about 3mm, about 1mm~about 4mm, about 1mm~about 5mm, about 1mm~about 6mm, about 1mm~about 8mm, about 1mm~about 10mm, Approximately 1.5mm to approximately 2mm, approximately 1.5mm to approximately 3mm, approximately 1.5mm to approximately 4mm, approximately 1.5mm to approximately 5mm, approximately 1.5mm to approximately 6mm, approximately 1.5mm to approximately 8mm, approximately 1.5mm to approximately 10mm, approximately 2mm to approximately 3mm, approximately 2mm to approximately 4mm In some embodiments, the particles have a size of about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, about 10 mm, about 2 mm to about 5 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 5 mm to about 6 mm, about 5 mm to about 8 mm, about 5 mm to about 10 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, or about 8 mm to about 10 mm. In some embodiments, the particles have a size of about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.In some embodiments, the particles have a size of at least about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, or about 8 mm, hi some embodiments, the particles have a size of at most about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 8 mm, or about 10 mm.

[0127] In some embodiments, the particles have a specific, tailored density, hardness, or both. The density of the gel particles can be adjusted by adjusting the concentration of the viscoelastic medium, adjusting the amount and type of crosslinker, or both. Harder particles can be achieved by increasing the concentration of the viscoelastic medium in the gel. Harder particles may be less viscoelastic than softer particles and may exhibit a longer half-life in vivo. The particles herein must retain sufficient viscoelasticity to be safely injected. In some embodiments, the implant includes both soft and harder gel particles. The soft and hard gel particles may be made of the same or different viscoelastic mediums. The resulting gel particle mixture combines the desired softness / hardness properties for use in radiation protection and long durability in vivo.

[0128] Method for forming spacer material The subcutaneous spacer material herein is configured to form a cavity adjacent to a treatment organ to prevent radiation or toxic damage to the organ adjacent or adjacent to the treatment organ. The subcutaneous spacer material herein may include a viscoelastic medium containing polyethylene glycol particles. The size and concentration of the polyethylene glycol particles within the spacer material may be adjusted to exhibit hardness, density, or both to enable consistent and uniform injection and cavity formation.

[0129] Provided herein are methods of forming spacer materials, the methods comprising forming an aqueous solution containing a water-soluble cross-linkable polysaccharide, initiating cross-linking of the polysaccharide in the presence of a multifunctional cross-linking agent, sterically hindering the cross-linking reaction to terminate before gelation occurs to produce an activated polysaccharide, and reintroducing sterically unhindered conditions to the activated polysaccharide to continue the cross-linking reaction until a viscoelastic gel is formed. In some embodiments, the step of initiating the cross-linking reaction in the presence of a multifunctional cross-linking agent can be carried out at a pH value that varies depending primarily on whether ether or ester reactions are to be promoted.

[0130] The crosslinker can be any crosslinker known in the art to be useful for biocompatible polysaccharides. However, crosslinkers include: aldehydes, epoxides, polyaziridyl compounds, glycidyl ethers, divinylsulfones, or any combination thereof. Glycidyl ethers represent a group that may be advantageously 1,4-butanediol diglycidyl ether. Some embodiments include hydrogels containing glycosaminoglycans extracted from natural sources that are purified and derivatized. In some embodiments, the glycosaminoglycans are synthetically produced or synthesized by engineered microorganisms, such as bacteria. In some embodiments, the glycosaminoglycans are synthetically modified from a naturally soluble state to a partially soluble, water-swellable, or hydrogel state.

[0131] A suitable method for obtaining the desired particle size includes producing a gel of cross-linked polyethylene glycol at the desired concentration and subjecting the gel to physical disruption, such as chopping, grinding, or forcing the gel to pass through a filter at the appropriate particle size. The resulting gel particles can be dispersed in a physiological saline solution, resulting in a gel dispersion or slurry with the desired particle size. Particle size can be achieved by producing a gel made with a viscoelastic medium at the desired concentration and subjecting the gel to physical disruption. Physical disruption includes: chopping, grinding, filtering, or any combination thereof. The resulting gel particles can be dispersed in a physiological saline solution, resulting in a gel dispersion or slurry with the desired particle size.

[0132] In some embodiments, the particles have a specific, tailored density, hardness, or both. The density of the gel particles can be adjusted by adjusting the concentration of the viscoelastic medium, adjusting the amount and type of crosslinker, or both. Harder particles can be achieved by increasing the concentration of the viscoelastic medium in the gel. For example, gel particles of various hardness can be obtained by varying the polyethylene glycol concentration to 20, 25, 40, 50, or 100 mg / ml. Harder particles may be less viscoelastic and may exhibit a longer half-life in vivo than softer particles. The particles herein must retain sufficient viscoelasticity to be safely injected.

[0133] In some embodiments, the implant contains both soft and harder gel particles. The soft and hard gel particles may be made of the same viscoelastic medium or different viscoelastic media. The resulting gel particle mixture combines the desired softness / hardness properties for use in radiation protection and long in vivo durability. In one embodiment, the soft gel particles contain 15-22 mg / ml cross-linked polyethylene glycol, and the hard gel particles contain 22-30 mg / ml cross-linked polyethylene glycol.

[0134] When the injectable medium is a polyethylene glycol medium, the polyethylene glycol concentration is at least about 5 mg / mL. In some embodiments, the polyethylene glycol concentration is about 5 mg / mL to about 100 mg / mL. In some embodiments, the polyethylene glycol concentration is about 10 mg / mL to about 50 mg / mL. In some embodiments, the polyethylene glycol concentration is about 20 mg / mL. The cross-linked polyethylene glycol can be present as particles or beads of any form.

[0135] In some embodiments, the concentration of polyethylene glycol in the spacer material is about 1 mg / ml to about 100 mg / ml, or about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 1 mg / ml to about 30 mg / ml, about 1 mg / ml to about 40 mg / ml, about 1 mg / ml to about 50 mg / ml, about 1 mg / ml to about 60 mg / ml to about 80 mg / ml, about 1 mg / ml to about 100 mg / ml, about 5 mg / ml to about 10 mg / ml, Approximately 5 mg / ml to approximately 15 mg / ml, approximately 5 mg / ml to approximately 20 mg / ml, approximately 5 mg / ml to approximately 25 mg / ml, approximately 5 mg / ml to 30 mg / ml, approximately 5 mg / ml to approximately 40 mg / ml, approximately 5 mg / ml to approximately 50 mg / ml, approximately 5 mg / ml to approximately 60 mg / m l, about 5 mg / ml to about 80 mg / ml, about 5 mg / ml to about 100 mg / ml, about 10 mg / ml to about 15 mg / ml, about 10 mg / ml to about 20 mg / ml, about 10 mg / ml to about 25 mg / ml, about 10 mg / ml to about 30 mg / ml, about 10 mg / ml ~40mg / ml, 10mg / ml~50mg / ml, 10mg / ml~60mg / ml, 10mg / ml~80mg / ml, 10mg / ml~100mg / ml, 15mg / ml~20mg / ml, 15mg / ml~25mg / ml, about 15mg / ml to about 30mg / ml, about 15mg / ml to about 40mg / ml, about 15mgmg / ml to about 50mg / ml, about 15mg / ml to about 60mg / ml, about 15mg / ml to about 80mg / ml, about 15mg / ml to about 100mg / ml, about 20 mg / ml~about 25mg / ml, about 20mg / ml~about 30mg / ml, about 20mg / ml~about 40mg / ml, about 20mg / ml~about 50mg / ml, about 20mg / ml~about 60mg / ml, about 20mg / ml~about 80mg / ml, about 20mg / ml~about 1 00mg / ml, about 25mg / ml to about 30mg / ml, about 25mg / ml to about 40mg / ml, about 25mg / ml to about 50mg / ml, about 25mg / ml to about 60mg / ml, about 25mg / ml to about 80mg / ml, about 25mg / ml to about 100mg / ml,about 30 mg / ml to about 40 mg / ml, about 30 mg / ml to about 50 mg / ml, about 30 mg / ml to about 60 mg / ml, about 30 mg / ml to about 80 mg / ml, about 30 mg / ml to about 100 mg / ml, about 40 mg / ml to about 50 mg / ml, about 40 mg / ml to about 60 mg / ml, about 40 mg / ml to about 80 mg / ml, about 40 mg / ml to about 100 mg / ml, about 50 mg / ml to about 60 mg / ml, about 50 mg / ml to about 80 mg / ml, about 50 mg / ml to about 100 mg / ml, about 60 mg / ml to about 80 mg / ml, about 60 mg / ml to about 100 mg / ml, or about 80 mg / ml to about 100 mg / ml. In some embodiments, the concentration of polyethylene glycol in the spacer material is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at least about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, or about 80 mg / mL. In some embodiments, the concentration of polyethylene glycol in the spacer material is at most about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, or about 100 mg / mL.

[0136] How to inject spacer material The subcutaneous spacer materials described herein are configured to form adjacent cavities to avoid radiation or toxic damage to organs proximal or adjacent to the treated organ. The subcutaneous spacer materials described herein may include a viscoelastic medium containing polyethylene glycol particles. The size and concentration of the polyethylene glycol particles within the spacer material can be tailored to exhibit hardness, density, or both to enable consistent and uniform injection and cavity formation. Furthermore, based on the size, hardness, density, and concentration of the polyethylene glycol particles, a specific needle size can be used to deliver the spacer material to its intended in vivo location.

[0137] Provided herein are methods for injecting spacer materials. The spacer material may comprise a viscoelastic medium for therapeutic radiation protection in mammals, including humans. The spacer material may be suitable for subcutaneous administration at sites where therapeutic soft tissue protection against radiation or other toxic sources is needed in the mammal. In particular, the particles are suitable for administration to tissues covered by exposed skin, such as facial tissue, because the particles do not cause bruising or other discoloration. The particles described herein are suitable for deep subcutaneous or submuscular / supraperiosteal administration, optionally in one or more layers. Deep subcutaneous, submuscular / supraperiosteal administration further prevents or reduces migration of the particles away from the desired site.

[0138] The spacer material can be administered by injection beneath the epidermis in any suitable manner, for example, an incision in the skin can be made with a scalpel or sharp needle to facilitate percutaneous insertion of a larger cannula for administration of the implant at the desired site.

[0139] The implant, consisting of particles of viscoelastic medium and optionally other suitable components, may be administered as a single aliquot or as layers of multiple aliquots. Optionally, the viscoelastic medium may be replaced, supplemented, or replenished with subsequent injections of the same or another viscoelastic medium. The amount injected is determined by the size of the desired cavity.

[0140] In some embodiments, the volume of spacer material injected is about 1 ml to about 500 ml. In some embodiments, the volume of spacer material injected is about 1 ml to about 5 ml, about 1 ml to about 10 ml, about 1 ml to about 25 ml, about 1 ml to about 50 ml, about 1 ml to about 100 ml, about 1 ml to about 150 ml, about 1 ml to about 200 ml, about 1 ml to about 250 ml, about 1 ml to about 300 ml, about 1 ml to about 400 ml, about 1 ml to about 500 ml, about 5 ml to about 10 ml, about 5 ml to about 25 ml, about 5 ml to about 50 ml, about 5 ml to about 100 ml, about 5 ml to about 150 ml, about 5 ml to about 2 00ml, approximately 5ml to approximately 250ml, approximately 5ml to approximately 300ml, approximately 5ml to approximately 400ml, approximately 5ml to approximately 500ml, approximately 10ml to approximately 25ml, approximately 10ml to approximately 50ml, approximately 10ml to approximately 100ml, approximately 10ml to approximately 150ml, approximately 10ml to approximately 200ml, about 10ml to about 250ml, about 10ml to about 300ml, about 10ml to about 400ml, about 10ml to about 500ml, about 25ml to about 50ml, about 25ml to about 100ml, about 25ml to about 150ml, about 25ml to about 200ml, about 2 5ml to 250ml, 25ml to 300ml, 25ml to 400ml, 25ml to 500ml, 50ml to 100ml, 50ml to 150ml, 50ml to 200ml, 50ml to 250ml, 50ml to 3 00ml, about 50ml to about 400ml, about 50ml to about 500ml, about 100ml to about 150ml, about 100ml to about 200ml, about 100ml to about 250ml, about 100ml to about 300ml, about 100ml to about 400ml, about 100ml to about 50 0 ml, about 150 ml to about 200 ml, about 150 ml to about 250 ml, about 150 ml to about 300 ml, about 150 ml to about 400 ml, about 150 ml to about 500 ml, about 200 ml to about 250 ml, about 200 ml to about 300 ml, about 200 ml to about 400 ml, about 200 ml to about 500 ml, about 250 ml to about 300 ml, about 250 ml to about 400 ml, about 250 ml to about 500 ml, about 300 ml to about 400 ml, about 300 ml to about 500 ml, or about 400 ml to about 500 ml.In some embodiments, the volume of spacer material injected is about 1 ml, about 5 ml, about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 150 ml, about 200 ml, about 250 ml, about 300 ml, about 400 ml, or about 500 ml. In some embodiments, the volume of spacer material injected is at least about 1 ml, about 5 ml, about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 150 ml, about 200 ml, about 250 ml, about 300 ml, or about 400 ml. In some embodiments, the volume of spacer material injected is at most about 5 ml, about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 150 ml, about 200 ml, about 250 ml, about 300 ml, about 400 ml, or about 500 ml.

[0141] Administration may be performed in any suitable manner, such as by injection with a standard cannula and needle of appropriate size, where radiation protection is desired, such as on the chin, cheek, or other part of the face or body.

[0142] The spacer material herein is injectable through standard needles used in medicine, such as 20 gauge or larger needles. Alternatively, the spacer material including polyethylene glycol can be injected using any of the following sizes of needles:

[0143] [Table 2]

[0144] In some embodiments, the interior surface of the needle comprises protrusions, a mesh, a constriction, or any combination thereof. In some embodiments, injecting the spacer material past the protrusions, mesh, constriction, or any combination thereof produces gas bubbles in the spacer material. In some embodiments, the gas bubbles are microbubbles. In some embodiments, the mesh has a mesh spacing of about 20 μm to about 300 μm. In some embodiments, the size of the mesh spacing determines the size of the microbubbles produced thereby.

[0145] Standard Markers Enhanced developments in CT imaging can be used to leverage the stability of polyethylene glycol for use as fiducial markers. Today's gold standard markers have too many artifacts in MRI but perform well in CT.

[0146] Image quality improvement Because polyethylene glycol (PEG) and NASHA gel are poorly visualized on CT scans, MRI, and transrectal ultrasound (TRUS), the additives and compositions are configured to allow clinicians to precisely inject the organ spacer material described herein using real-time scanning feedback. Furthermore, such scanning can be used for radiation planning. Enhanced HA CT imaging is a significant advantage, eliminating the need for a patient MRI, the cost, and the CT / MRI fusion step in treatment planning. Furthermore, for boost and accelerated partial breast irradiation (APBI) planning, clear identification of seromas is crucial to enable accurate target volume contouring and initiation of cone-beam image-guided radiation therapy. However, because seromas are not always visible on CT simulation, many surgeries, such as those requiring full-thickness closure during surgery, can be difficult to plan and disqualify patients from such APBI procedures. While intraoperative clip placement has been used to aid in such contouring, it is often unreliable, as high-Z clip materials distort the contour image and low-Z clip materials, such as tantalum, are invisible.

[0147] However, the image-enhancing agents provided herein exhibit Z values ​​that are high enough to allow full visibility on CT and sufficient paramagnetic moment for visibility on MRI, but that are too high to avoid imaging degradation of the seroma. Further optimal visibility and image quality is achieved by varying the amount of image-enhancing agent injected while maintaining minimal expansion of the treated volume.

[0148] In one embodiment, the visualization additive includes iodine, which enhances CT imaging but may not offer advantages over MRI and TRUS imaging. Furthermore, iodine can be an allergen. In some embodiments, the visualization additive includes a radiopaque compound selected from the group consisting of iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadolinium dimeglumine, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or any combination thereof. In some embodiments, the superparamagnetic iron oxide additive is superparamagnetic iron oxide nanoparticles. In some embodiments, the concentration of the visualization additive in the polyethylene glycol, hyaluronic acid, or both is about 1 mg / ml to about 10 mg / ml. In some embodiments, the visualization additive includes a gas. In some embodiments, the gas is air, nitrogen, helium, oxygen, or any combination thereof. In some embodiments, the gas forms a plurality of bubbles within the spacer material. In some embodiments, the microbubbles have a size of about 1 μm to about 100 μm. In some embodiments, the concentration of the visualization additive in the spacer material is about 0.1% to about 15%. In some embodiments, the concentration of the visualization additive in the spacer material is at least about 0.1%. In some embodiments, the visualization additive has an external width of at least about 20 microns. In some embodiments, the visualization additive has a diameter of at least 20 microns.

[0149] Spacer material solvent In some embodiments, the spacer materials herein can be configured to rapidly dissolve in the body after a period of time. Alternatively, application of a solvent can initiate removal of the spacer material. Such a solvent allows the spacer to dissipate, thereby allowing for a shorter, temporary, and larger interval to provide greater radiation protection, which then quickly dissipates to maintain quality of life, cosmetic effect, or both.

[0150] In one example, the spacer material comprises polyethylene glycol and the solvent comprises hyaluronidase, in another example, the solvent can be used to treat melanoma, where the spacing can be temporarily expanded excessively to create a greater distance for larger doses, and then collapsed for cosmetic purposes.

[0151] Terms and Definitions Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0152] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Any reference to "or" is intended to include "and / or" unless otherwise specified.

[0153] As used herein, the term "about" refers to an amount near 10%, 5%, or 1% of the stated amount, including increments therein.

[0154] As used herein, the term "about" in reference to a percentage refers to an amount that is 10%, 5%, or 1% more or less than the stated percentage, including increments therein.

[0155] As used herein, the phrases "at least one," "one or more," and "and / or" are expressions that are both conjunctive and disjunctive in operation. For example, each of the phrases "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," "one or more of A, B, or C," and "A, B, and / or C" means A only, B only, C only, both A and B, both A and C, both B and C, or both A, B, and C.

[0156] The term "radioprotection," as used herein, relates to any type of soft tissue augmentation, including, but not limited to, facial contouring (e.g., more prominent cheeks or chin), correction of concave deformities (e.g., post-traumatic, HIV-associated lipoatrophy), and correction of deep age-related facial wrinkles. Thus, radioprotection may be used solely for cosmetic purposes or for medical purposes, such as following trauma or degenerative disease.

[0157] The term "degraded" means that less than 20%, alternatively less than 10%, of the vehicle remains in the body.

[0158] The term "soft tissue," as used herein, refers to tissue that connects, supports, and surrounds other structures and organs of the body. Soft tissue includes muscle, fibrous tissue, and fat.

[0159] The terms "subepidermal administration" and "subcuticular administration," as used herein, refer to administration beneath the epidermis of the skin and include administration into the dermis, subcutaneous tissue, or deeper, such as submuscularly or periosteally (near bone tissue) where applicable.

[0160] As used herein, the term "therapeutic" refers to any type of preventative, palliative or curative treatment.

[0161] The term "superspacing," as used herein, refers to the dictionary definitions of the terms "super" and "spacing," as well as the definition of spacing that is extraordinary in conventional documents of similar tissue spacing of similarly located portions of a given subject.

[0162] As used herein, a physiological or isotonic solution is a solution having an osmolality in the range of about 200 to about 400 mOsm / L, about 250 to about 350 mOsm / L, or about 300 mOsm / L. For practical purposes, this osmolality can be achieved by preparation of a 0.9% (0.154 M) NaCl solution.

[0163] The term "implant," as used herein, broadly refers to any type of transplanted or implanted foreign or foreign material. Implants include objects or substances that are nearly identical to non-foreign or foreign materials. Implants are not limited to any particular shape. The final shape of the implant within the body is determined by one of skill in the art based on the purpose of the procedure.

[0164] The term "viscoelastic medium," as used herein, refers to a medium that exhibits a combination of viscous and elastic properties. Specifically, the viscoelastic medium is injectable through a 20-gauge or larger needle, such as a 10-20 gauge needle, by applying a pressure of 15-50 N. In particular, the medium or implant or drug containing the medium is suitable for subepidermal injection into a person in need at a desired site.

[0165] The term "stabilization," as used herein, refers to any form of chemical stabilization that renders the stabilized compound more stable to biodegradation than the parent compound under physiological conditions. Without being limited thereto, stabilized compounds include crosslinked and partially crosslinked compounds.

[0166] The term "derivative" of a polysaccharide, as used herein, means any suitable derivative thereof, including cross-linked polysaccharides such as sulfated polysaccharides and substituted polysaccharides.

[0167] Illustrative Embodiments Among the exemplary embodiments are: 1. A method for spacing a first tissue site of a subject from a second tissue site of a subject, the method comprising: (a) placing a viscoelastic medium in the space between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises non-animal stabilized hyaluronic acid ("NASHA") and a gadolinium complex. 2. The method of embodiment 1, further comprising monitoring or imaging the gap between the first tissue site and the second tissue site. 3. The method of embodiment 1 or 2, wherein the spacing between the first tissue site and the second tissue site ranges from about 0.1 cm to about 10 cm. 4. The method of any one of embodiments 1 to 3, wherein the gadolinium complex is present in the range of about 1 mg / ml to about 10 mg / ml. 5. The method of any one of embodiments 1 to 4, wherein the viscoelastic medium comprises a volume of about 1 ml to about 50 ml. 6. The method of any one of embodiments 1-5, wherein the viscoelastic medium is placed through a 10-25 gauge needle. 7. The method of any one of embodiments 1 to 6, wherein the viscoelastic medium comprises NASHA at a concentration ranging from about 5 mg / ml to about 100 mg / ml. 8. The method of any one of the preceding embodiments, wherein the viscoelastic medium comprises gel particles ranging in size from about 0.2 mm to about 5 mm. 9. The method of any one of embodiments 1-8, wherein the viscoelastic medium is placed subcutaneously or subepidermally. 10. The method of any one of embodiments 1-9, wherein the first tissue site and the second tissue site are selected from the group consisting of breast, head and neck, cervix, vagina, base of spine, skin, pancreas, liver, or lung of a subject. 11. The method of any one of embodiments 2 to 10, wherein the imaging comprises real-time imaging. 12. The method of any one of embodiments 2-11, wherein the viscoelastic medium is configured to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium. 13. The method of any one of embodiments 2-12, wherein the imaging comprises MRI, CT, ultrasound, or a combination thereof. 14. The method of any one of embodiments 2-13, wherein the viscoelastic medium is bioabsorbable. 15. A method of spacing a first tissue site on a subject from a second tissue site on a subject, the method comprising: (a) placing a viscoelastic medium in the space between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises one or more visualization additives. 16. The method of embodiment 15, further comprising monitoring or imaging the gap between the first tissue site and the second tissue site. 17. The method of embodiment 15 or 16, wherein the spacing between the first tissue site and the second tissue site ranges from about 0.1 cm to about 10 cm. 18. The method of any one of embodiments 15-17, wherein the visualization additive is present in a volume sufficient to produce contrast when imaged by an imaging method. 19. The method of any one of embodiments 15 to 18, wherein the viscoelastic medium comprises a volume of about 1 ml to about 50 ml. 20. The method of any one of embodiments 15-19, wherein the viscoelastic medium is placed through a 10-25 gauge needle. 21. The method of any one of embodiments 15 to 20, wherein the viscoelastic medium comprises hyaluronic acid, polyethylene glycol, or dextranomer at a concentration ranging from about 5 mg / ml to about 100 mg / ml. 22. The method of any one of embodiments 15-21, wherein the viscoelastic medium comprises gel particles ranging in size from about 0.08 mm to about 5 mm. 23. The method of any one of embodiments 15 to 22, wherein the viscoelastic medium is placed subcutaneously or subepidermally. 24. The method of any one of embodiments 15-23, wherein the first tissue site and the second tissue site are selected from the group consisting of breast, head and neck, cervix, vagina, base of spine, skin, pancreas, liver, or lung of a subject. 25. The method of any one of embodiments 16 to 24, wherein the imaging comprises real-time imaging. 26. The method of any one of embodiments 16 to 25, wherein the viscoelastic medium is configured to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium. 27. The method of any one of embodiments 16 to 26, wherein the imaging comprises MRI, CT, ultrasound, or a combination thereof. 28. The method of any one of embodiments 18 to 27, wherein the imaging method comprises MRI, CT, ultrasound, or a combination thereof. 29. The method of any one of embodiments 15 to 28, wherein the viscoelastic medium does not substantially move before and during the imaging. 30. The method of any one of embodiments 15-29, wherein the visualization additive comprises one or more nanoparticles. 31. The method of any one of embodiments 15-30, wherein the visualization additive comprises a precious metal. 32. The method of embodiment 31, wherein the precious metal comprises iron or gold. 33. The method of any one of embodiments 15-32, wherein the viscoelastic medium is bioabsorbable. 34. The method of any one of embodiments 15-29, wherein the visualization additive comprises iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or a combination thereof. 35. A method for preventing or reducing damage to tissue adjacent to a site of radiation therapy in a subject undergoing radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the site of radiation therapy, wherein the bioabsorbable viscoelastic medium comprises a visualization additive. 36. The method of embodiment 35, wherein the injection displaces the tissue a distance in the range of about 0.1 cm to about 10 cm. 37. The method of any one of embodiments 35-36, wherein the viscoelastic medium comprises gel particles. 38. The method of any one of embodiments 35 to 37, wherein the gel particles comprise hyaluronic acid or a derivative thereof. 39. The method of any one of embodiments 35 to 38, wherein the injection comprises a volume of about 1 ml to about 50 ml. 40. The method of any one of embodiments 35-39, wherein the injection is performed through a 10-25 gauge needle. 41. The method of any one of embodiments 35 to 40, wherein the concentration of hyaluronic acid is in the range of about 5 mg / ml to about 100 mg / ml. 42. The method of any one of embodiments 35-41, wherein the size of the gel particles ranges from about 0.2 mm to about 5 mm. 43. The method of any one of embodiments 35 to 42, wherein the injection is subcutaneous or subepidermal. 44. The method of any one of embodiments 35 to 43, wherein movement of the viscoelastic medium is avoided or reduced. 45. The method of any one of embodiments 35-44, wherein the visualization additive comprises one or more nanoparticles. 46. ​​The method of any one of embodiments 35-45, wherein the nanoparticles comprise a precious metal. 47. The method of any one of embodiments 35-46, wherein the dose of radiation therapy in contact with tissue adjacent to the site of radiation therapy is reduced by about 10% to about 80%. 48. The method of any one of embodiments 35-47, wherein the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. 49. The method of any one of embodiments 35-48, further comprising administration of hyaluronidase at the site of said radiation therapy. 50. The method of any one of embodiments 35 to 49, wherein the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. 51. The method of any one of embodiments 35 to 50, wherein the administration of the hyaluronidase occurs from about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium. 52. The method of any one of embodiments 35-51, further comprising imaging the site of radiation treatment. 53. The method of embodiment 52, wherein the miscellaneous image comprises sequential imaging. 54. The method of any one of embodiments 52-53, wherein the imaging comprises MRI, CT scan, ultrasound, or a combination thereof. 55. A method of reducing a radiation therapy dose to tissue adjacent to a site of radiation therapy in a subject receiving radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the site of radiation therapy. 56. The method of embodiment 55, wherein the injection displaces the tissue a distance in the range of about 0.1 cm to about 10 cm. 57. The method of embodiment 55 or 56, wherein the viscoelastic medium comprises gel particles. 58. The method of any one of embodiments 55 to 57, wherein the gel particles comprise hyaluronic acid or a derivative thereof. 59. The method of any one of embodiments 55 to 58, wherein the injection comprises a volume of about 1 ml to about 50 ml. 60. The method of any one of embodiments 55-59, wherein the injection is performed through a 10-25 gauge needle. 61. The method of any one of embodiments 55 to 60, wherein the concentration of hyaluronic acid is in the range of about 5 mg / ml to about 100 mg / ml. 62. The method of any one of embodiments 55-61, wherein the gel particles have a size ranging from about 0.2 mm to about 5 mm. 63. The method of any one of embodiments 55 to 62, wherein the injection is subcutaneous or subepidermal. 64. The method of any one of embodiments 55 to 63, wherein movement of the viscoelastic medium is avoided or reduced. 65. The method of any one of embodiments 55-64, wherein the viscoelastic medium further comprises one or more nanoparticles. 66. The method of any one of embodiments 55-65, wherein the nanoparticles comprise a precious metal. 67. The method of any one of embodiments 55 to 66, wherein the radiation therapy dose is reduced by about 10% to about 80%. 68. The method of any one of embodiments 55-67, wherein the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of the subject. 69. The method of any one of embodiments 55-68, further comprising administration of hyaluronidase at the site of said radiation therapy. 70. The method of any one of embodiments 55 to 69, wherein the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%. 71. The method of any one of embodiments 55 to 70, wherein the administration of the hyaluronidase occurs from about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium. 72. A method for temporary superspacing of tissue adjacent to a site of radiation therapy, the method comprising a formulation comprising a large amount of degradable nanoparticles encapsulating cross-linked hyaluronic acid or a derivative thereof and hyaluronidase. 73. The method of embodiment 72, wherein the amount of degradable nanoparticles encapsulating hyaluronidase is directly proportional to the desired distance of superspacing relative to the desired duration of superspacing. 74. The method of embodiment 72 or 73, comprising injecting a bioabsorbable viscoelastic medium into a blood vessel, wherein the blood vessel is directly connected to the tumor. 75. The method of any one of embodiments 72-74, wherein the viscoelastic medium comprises gel particles. 76. The method of any one of embodiments 72 to 75, wherein the gel particles comprise hyaluronic acid or a derivative thereof. 77. The method of any one of embodiments 72 to 76, wherein the injection comprises a volume of about 1 ml to about 50 ml. 78. The method of any one of embodiments 72 to 77, wherein the injection is performed through a 10-25 gauge needle. 79. The method of any one of embodiments 72 to 78, wherein the concentration of hyaluronic acid is in the range of about 5 mg / ml to about 100 mg / ml. 80. The method of any one of embodiments 72-79, wherein the gel particles have a size ranging from about 0.2 mm to about 5 mm. 81. The method of any one of embodiments 72 to 80, wherein blood flow to the tumor is avoided or reduced. 82. The method of any one of embodiments 72 to 81, wherein movement of the viscoelastic medium is avoided or reduced. 83. The method of any one of embodiments 72-82, further comprising administration of hyaluronidase at the site of said radiation therapy. 84. The method of any one of embodiments 72 to 83, wherein the administration of the hyaluronidase is performed about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium. 85. The method of any one of embodiments 72-84, further comprising the step of excising remaining tumor cells from the subject. 86. A composition comprising a viscoelastic medium and a visualization additive. 87. The composition of embodiment 86, wherein the visualization additive is present in a volume sufficient to produce contrast when imaged by an imaging method. 88. The composition of embodiment 86 or 87, wherein the viscoelastic medium comprises a volume of about 1 ml to about 50 ml. 89. The composition of any one of embodiments 86-88, wherein the viscoelastic medium is configured for placement through a 10-25 gauge needle. 90. The composition of any one of embodiments 86 to 89, wherein the viscoelastic medium comprises hyaluronic acid, polyethylene glycol, or dextranomer at a concentration ranging from about 5 mg / ml to about 100 mg / ml. 91. The composition of any one of embodiments 86-90, wherein the viscoelastic medium comprises gel particles ranging in size from about 0.08 mm to about 5 mm. 92. The composition of any one of embodiments 86-91, wherein the visualization additive configures the viscoelastic medium to be imaged, wherein the imaging comprises real-time imaging. 93. The composition of any one of embodiments 86-92, wherein the visualization additive configures the viscoelastic medium to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium. 94. The composition of any one of embodiments 86 to 93, wherein the visualization additive configures the viscoelastic medium to be imaged, wherein the imaging comprises MRI, CT, ultrasound, or a combination thereof. 95. The composition of any one of embodiments 87-94, wherein the imaging method comprises MRI, CT, ultrasound, or a combination thereof. 96. The composition of any one of embodiments 86-95, wherein the viscoelastic medium is configured to be substantially non-migrating upon displacement. 97. The composition of any one of embodiments 86-96, wherein the visualization additive comprises one or more nanoparticles. 98. The composition of any one of embodiments 86-97, wherein the visualization additive comprises a precious metal. 99. The composition of embodiment 98, wherein the precious metal comprises iron or gold. 100. The composition of any one of embodiments 86-99, wherein the viscoelastic medium is bioabsorbable. 101. The composition of any one of embodiments 86-96, wherein the visualization additive comprises iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or a combination thereof. [Example]

[0168] The following illustrative examples are representative of embodiments of the software applications, systems, and methods described herein and are not meant to be limiting in any way.

[0169] Example 1 - Spacer injection between the head of the pancreas and the duodenum In one example, an absorbable hydrogel containing hyaluronic acid microparticles was injected into the space between the head of the pancreas (HOP) and the third portion of the duodenal loop using an 18-gauge needle. The duodenal-HOP interface was identified using an endoscopic ultrasound (EUS) connected to an ultrasound workstation, and then hydrogel was injected into this peripancreatic space in 1 mL increments using a 19-gauge fine-needle aspiration needle until the desired space was created. The EUS scope was then adjusted (slightly telescoped) around the target area to provide the shape and conformability to create the desired space around the tumor, with total injection volumes ranging from 1.0 mL to 27 mL.

[0170] A visible separation was created between the HOP and duodenum to confirm the hydrogel's position and measure the distance created between the duodenum and HOP. The average separation distance due to hydrogel placement was determined by averaging the measured thickness of the gel on each CT slice, where the gel was visualized on post-injection simulated CT scans acquired at a slice thickness of 2 mm. The average thickness of the spacer on post-injection CT scans was 1.1 cm (0.9 cm-1.2 cm) and 0.9 cm (0.8 cm-1.1 cm) in EUS cadaver specimens 1 and 2, respectively.

[0171] FIG. 5A is an exemplary image of a computed tomography scan before injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5B is an exemplary image of a computed tomography scan after injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5C is an exemplary image of a whole histological specimen before injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5D is an exemplary image of a computed tomography scan before open injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5E is an exemplary image of a computed tomography scan after open injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5F is an exemplary image of a whole histological specimen before open injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5G is an exemplary image of a computed tomography scan before endoscopic injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5H is an exemplary image of a computed tomography scan after endoscopic injection of a hydrogel spacer between the pancreas head and the duodenum. FIG. 5I is an exemplary image of a whole histological specimen after endoscopic hydrogel spacer injection between the pancreatic head and duodenum. FIG. 6A is a first exemplary image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining. FIG. 6B is a second exemplary image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining. FIG. 6C is a first exemplary high-magnification image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining. FIG. 6D is a third exemplary image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining. FIG. 6E is a second exemplary high-magnification image of a formalin-fixed, paraffin-embedded section after hematoxylin-eosin staining. FIG. 7A is a first exemplary stereotactic body radiotherapy treatment plan before hydrogel spacer placement. Figure 7B is a first exemplary stereotactic body radiation treatment plan after placement of a hydrogel spacer, Figure 7C is a second exemplary stereotactic body radiation treatment plan before placement of a hydrogel spacer, and Figure 7D is a second exemplary stereotactic body radiation treatment plan after placement of a hydrogel spacer.FIG. 8A is an exemplary baseline image of a duodenal computed tomography and stereotactic body radiotherapy plan. FIG. 8B is an exemplary image of a duodenal computed tomography and stereotactic body radiotherapy plan with 2 mm spacing. FIG. 8C is an exemplary image of a duodenal computed tomography and stereotactic body radiotherapy plan with 3 mm spacing. FIG. 8D is an exemplary image of a duodenal computed tomography and stereotactic body radiotherapy plan with 5 mm spacing. FIG. 8E is an exemplary image of a duodenal computed tomography and stereotactic body radiotherapy plan with 8 mm spacing. FIG. 8F is an exemplary image of a duodenal computed tomography and stereotactic body radiotherapy plan with 15 mm spacing.

[0172] Example 2 - Subcutaneous Breast Spacer Injection In one example, ultrasound-guided spacer injection of iodinated polyethylene glycol (PEG) was performed to create a spacer thickness of more than 5 mm. After defining the clinical target volume, pre- and post-injection CT scans were used. Skin toxicity indicators were calculated based on the maximum dose per small skin volume (D 0.2 cc) and the presence of hot spots (equivalent to 1 cm2 of skin - 90%). After breast removal, a spacer was injected directly under the skin, and an extra 5 mm of space was created between the skin and the superficial fascial layer of the breast by hydrodissection.

[0173] Interventional success was 90.9%. Hydrodissection was feasible in 63.6% of cases. The median system utility scale score was 82.5 for PEG (p<0.001). The mean D0.2cc was 80.8 Gy without a spacer and 53.7 Gy with a spacer (p<0.001). Skin hot spots were 40.9% without a spacer and zero with a spacer (p<0.001).

[0174] The success rate of spacer injections was high (91%) at the marker.

[0175] Example 3 - Injection of a subcutaneous esophageal spacer In one example, the gel was prepared as a 10 ml viscous mixture of 1 mg / ml hyaluronic acid (HA) and 0.8 ml of contrast agent composed of 300 mg / ml iodine. After local anesthesia of the subcutaneous tissue with lidocaine and under ultrasound and CT guidance, a 21-gauge needle was inserted at the puncture point lateral to the trachea at the level of the upper end of the sternum and advanced to the gel injection site. The needle penetrated first through the skin; second, the subcutaneous tissue between the two ends of the platysma muscle in the superficial cervical fascia (superficial cervical fascia, SCF); third, the relatively tough surrounding layer of the deep cervical fascia (DCF), including the suprasternal space filled with adipose connective tissue and the transverse jugular vein (the space of Burns), and the adipose tissue beneath this fascia; and fourth, the pretracheal layer of the DCF spanning the peritracheal space, which is continuous with the paraesophageal adipose tissue. To safely advance the needle, the trachea was manually shifted approximately 5-10 mm to the right or left, as needed. Using this route, the needle passed medially between the sternohyoid and sternothyroid bands to avoid muscle contraction affecting the needle. Once the needle tip reached the predetermined injection point, gel was injected to create a gap, separating the esophagus from the target. The created gap was confirmed by CT.

[0176] Example 4 - Reduction of Radiation Therapy Dose to Tissues Adjacent to the Site of Radiation Therapy for Pancreatic Cancer Two patients with pancreatic cancer are treated with radiation therapy. One patient received a PEG-based spacer injection using the technique described in Example 1. Utilizing the injection technique from Example 1, a spacing ranging from 0.9 cm to 1.2 cm was created between the radiation therapy site and the duodenum. The radiation dose in tissues adjacent to the radiation therapy site was reduced by 40% in patients who received a spacer compared to patients who did not receive a spacer.

[0177] Example 5 - Reduction of radiation therapy dose to tissue adjacent to the site of radiation therapy for esophageal cancer Two patients with esophageal cancer are treated with radiation therapy. One patient received a PEG-based spacer injection using the technique described in Example 1. Utilizing the injection technique from Example 4, a spacing ranging from 0.9 cm to 1.2 cm was created between the radiation therapy site and the duodenum. The radiation dose in tissues adjacent to the radiation therapy site was reduced by 20% in patients who received a spacer compared to patients who did not receive a spacer.

[0178] Example 6 - Removable Hyaluronic Acid Spacer Utilizing the techniques described in Examples 4 and 5, a patient urgently needs reduction in spacer size after radiation therapy due to pressure generated by the spacer on the patient's esophagus, the caring physician injects about 1 ml to about 10 ml of hyaluronidase, at about 1 U to about 100 U, until the desired volume of the spacer is achieved.

[0179] Example 7 - Erasable PEG-based spacer Utilizing the techniques described in Examples 4 and 5, a patient urgently needs a reduction in spacer size after radiation therapy due to pressure generated by the spacer on the patient's esophagus, the caring physician injects about 1 ml to about 50 ml of water until the desired volume of the spacer is achieved.

[0180] Example 8 - Shrinking Hyaluronic Acid Super Spacer The injection technique of Example 4 is adapted to accommodate a dual syringe. One syringe contains the desired volume of cross-linked hyaluronic acid particles, while the other syringe contains degradable nanoparticles containing hyaluronidase, which are soluble in hyaluronic acid. The concentration of degradable nanoparticles contained within the syringe is determined by the desired length of radiation therapy. A larger spacing distance is achieved compared to the use of a spacer without degradable nanoparticles containing hyaluronidase, because the spacer shrinks before tissue damage due to significant tissue displacement occurs or before undesirable external changes occur in the subject's anatomy. This result is only possible with a shrinking superspacer.

[0181] Example 9 - Use of a contracted hyaluronic acid superspacer in subjects with melanoma on the scalp A subject has a melanoma tumor located on the scalp. The tumor measures 0.4 cm x 0.8 cm x 0.2 cm. Radiation therapy is selected as the desired treatment. The treating physician determines that radiation therapy will require approximately 10 minutes. The treating physician desires to use a higher radiation therapy dose than conventional methods, depending on the tumor's condition. The injection technique described in Examples 4 and 7 is adapted for subcutaneous injection into the scalp. A volume of approximately 3 ml to approximately 6 ml is injected, spacing the tumor from the subject's brain. A specific percentage of this volume is composed of degradable nanoparticles containing hyaluronidase. This breaks down connective tissue adjacent to the skull, spacing the brain from the tumor by a distance that creates an undesirable appearance. However, as soon as the spacer is injected into the space between the brain and the tumor, the spacer begins to shrink. Radiation therapy is administered, and the subject's brain is exposed to a 20% reduced radiation therapy dose compared to subjects not receiving a spacer. The radiotherapy session is completed and the subject's scalp looks like that of a subject who did not receive the spacer because the degradable nanoparticles have degraded the spacer.

[0182] Example 10 - PEG-based shrinking superspacer The injection technique of Example 4 is adapted to accommodate a dual syringe. One syringe contains the desired volume of cross-linked PEG particles, while the other syringe contains water-containing degradable nanoparticles soluble in hyaluronic acid. The concentration of the degradable nanoparticles contained in the syringe is determined by the desired length of radiation therapy. Compared to the use of a spacer without water-containing degradable nanoparticles, a larger spacing distance is achieved because the spacer shrinks before tissue damage due to significant tissue displacement occurs or before undesirable external changes occur in the subject's anatomy. This result is only possible with a shrinking superspacer.

[0183] Example 11 - Use of a PEG-based shrinking superspacer in subjects with melanoma on the scalp A subject has a melanoma tumor located on the scalp. The tumor measures 0.4 cm x 0.8 cm x 0.2 cm. Radiation therapy is selected as the desired treatment. The treating physician determines that radiation therapy will require approximately 10 minutes. The treating physician desires to use a higher radiation therapy dose than conventional methods, depending on the tumor's condition. The injection technique described in Examples 4 and 7 is adapted for subcutaneous injection into the scalp. A volume of approximately 3 ml to approximately 6 ml is injected to space the tumor from the subject's brain. A specific percentage of this volume is composed of degradable nanoparticles containing water. This spaces the brain from the tumor at a distance that would damage connective tissue adjacent to the skull and create an undesirable appearance. However, as soon as the spacer is injected into the space between the brain and the tumor, it begins to shrink. Radiation therapy is administered, and the subject's brain is exposed to a 20% reduced radiation therapy dose compared to subjects not receiving a spacer. The radiotherapy session is completed and the subject's scalp looks like that of a subject who did not receive the spacer because the degradable nanoparticles have degraded the spacer.

[0184] Example 12 - Use of improved tissue spacers for interventional oncology 7.4 g of poloxamer 407 and 0.2 g of polyethylene glycol-modified polylactic acid (PLA-PEG) were added to 20 ml and 10 ml of pure water, and the mixture was left at 25°C for 3 days to completely dissolve the polymer. The two were then mixed and stirred to obtain a gel dispersion, which was then distilled under low pressure and water. The spacer was then dried, sealed, and stored at 4°C.

[0185] The hydrogel is directly inserted into the blood vessels directly connected to the tumor. Cancer is treated by the hydrogel, cutting off the blood supply to the tumor, causing the tumor to become ischemic, hypoxic, and necrotic. Furthermore, cancer tissue necrosis continues to stimulate the body's immune system, which can eliminate distant metastases (preferably in melanoma), and targeted arterial supply mixed with chemotherapy delivers an embolic agent to the tumor, both of which cut off the blood supply, but also slow the release of chemotherapy drugs, which plays a role in the short-term effectiveness of local chemotherapy, resulting in tumor lysis.

[0186] Example 13 - Incorporation of iodine into PEG PEG-SG (having 2.3 SG units per molecule) containing an iodine core was synthesized. The PEG-I molecule was 6400 daltons, of which iodine was 381 daltons (5.9%). Thus, for example, at this iodine content, the percent solids of PEG-I in the hydrogel were 1.68% and 3.36%, resulting in iodine concentrations of 0.1% and 0.2% in the resulting matrix. Table II of WO2011084465, incorporated herein in its entirety, shows how the PEG-I concentration can be manipulated to obtain the percent iodine content, which can then be related to the CT value.

[0187] Example 14 - Preparing Gadopentetate Dimeglumine with NASHA-Gel A gel containing 5 mg / ml gadopentetate dimeglumine was prepared by weighing gadopentetate dimeglumine (Magnevist 469 mg / ml (0.5 mmol Gd / ml, Shering)) and thoroughly mixing it with NASHA-gel (20 mg HA / ml, Q-Med) by manual stirring. The resulting gel was centrifuged to remove air bubbles.

[0188] The release of the gadolinium complex from the gel was measured using a USP-paddle system. NMR and ICP-MS were used to monitor the release of the gadolinium complex. 2D spin echo (SE) and 3D gradient echo (FFE) sequences were generated, both with and without fatty acid saturation (FS). MRI was also performed on the gel releasing the gadolinium complex for various time periods. The initial release of the gadolinium complex was relatively rapid, and the rate closely matched the diffusion rate of small drug molecules (Figure 18A). ICP-MS analysis after 7 and 24 hours of release showed that 82% and 85% of the gadolinium had been released (Figure 18B), suggesting that a small amount of gadolinium interacted and was released at a much slower rate. MRI measurements on the gel showed that at the first time points (30 and 90 minutes), the NASHA-Gel exhibited strong contrast compared to water and oil. After that time (8 hours up to 4 days), the contrast became much weaker but was still visible compared to NASHA-Gel without the gadolinium complex, indicating that a small amount of gadolinium appears to be interacting with the NASHA-Gel. However, the amount is not sufficient to provide a contrast that is useful for in vivo MRI. The signal intensities in the MRI measurements are summarized in Table 1 below.

[0189] [Table 3]

[0190] Example 15 - Creating an Omni-Opac Spacer Using Any of the Materials Described Herein A viscoelastic medium comprising any one or combination of materials described herein is developed into particles sized to be drawn into a syringe. A thin (20 gauge or greater) needle is attached to the syringe, where a portion of the interior surface of the needle comprises a mesh structure configured to generate highly uniform microbubbles within the viscoelastic medium that are extruded through the mesh.

[0191] MRI was performed on gels containing a viscoelastic medium with microbubbles for different time periods. Initial visualization of the gels with microbubbles was relatively consistent with other gels combined with the radiopaque agents described herein. At 30 and 90 minutes, the gels with microbubbles exhibited strong contrast compared to water and oil, comparable to gels with the radiopaque agents described herein. Over time (8 hours to up to 4 days), the contrast of the gels with microbubbles maintained sufficient quality to provide useful contrast for in vivo MRI, CT, ultrasound, or other imaging modalities known in the art, and to be administered to various gels described herein containing any one of the radiopaque agents described herein, including microbubbles or combinations thereof. These gels will maintain sufficient contrast for in vivo imaging in real time, at 30 minutes, 90 minutes, and up to 8 hours and up to 4 days.

[0192] Example 16 - Cavity visualization In another example, a skin incision is made at the desired site using a scalpel and the viscoelastic medium from Example 15 is administered by injection subepidermally, where microbubbles are formed as the viscoelastic medium passes through the mesh structure of the needle into the injection site. The mesh structure has a diameter of about 0.001 mm. 2 ~about 1.5mm 2 The mesh structure includes spacing of approximately 0.001 mm. 2 ~about 0.005mm 2 , approximately 0.001 mm2 ~approximately 0.01mm 2 Approximately 0.001mm 2 ~approximately 0.05mm 2 Approximately 0.001mm 2 ~approximately 0.06mm 2 Approximately 0.001mm 2 ~approximately 0.07mm 2 Approximately 0.001mm 2 ~approximately 0.08mm 2 Approximately 0.001mm 2 ~approximately 0.09mm 2 Approximately 0.001mm 2 ~approximately 0.1mm 2 Approximately 0.001mm 2 ~approximately 0.5mm 2 Approximately 0.001mm 2 ~approximately 1mm 2 Approximately 0.001 mm 2 ~approximately 1.5mm 2 Approximately 0.005mm 2 ~approximately 0.01mm 2 Approximately 0.005mm 2 ~approximately 0.05mm 2 Approximately 0.005mm 2 ~approximately 0.06mm 2 Approximately 0.005mm 2 ~approximately 0.07mm 2 Approximately 0.005mm 2 ~approximately 0.08mm 2 Approximately 0.005mm 2 ~approximately 0.09mm 2 Approximately 0.005mm 2 ~approximately 0.1mm 2 Approximately 0.005mm 2 ~approximately 0.5mm 2 Approximately 0.005mm 2 ~approximately 1mm 2 Approximately 0.005mm 2 ~approximately 1.5mm 2 Approximately 0.01mm 2 ~approximately 0.05mm 2 Approximately 0.01mm 2 ~approximately 0.06mm 2 Approximately 0.01mm 2 ~approximately 0.07mm 2 Approximately 0.01mm 2 ~approximately 0.08mm 2, approximately 0.01 mm 2 ~approx. 0.09mm 2 , approximately 0.01 mm 2 ~about 0.1mm 2 , approximately 0.01 mm 2 ~about 0.5mm 2 , approximately 0.01 mm 2 ~about 1mm 2 , approximately 0.01 mm 2 ~about 1.5mm 2 , about 0.05mm 2 ~approx. 0.06mm 2 , about 0.05mm 2 ~approx. 0.07mm 2 , about 0.05mm 2 ~approx. 0.08mm 2 , about 0.05mm 2 ~approx. 0.09mm 2 , about 0.05mm 2 ~about 0.1mm 2 Approximately 0.05mm 2 ~about 0.5mm 2 Approximately 0.05mm 2 ~about 1mm 2 , about 0.05mm 2 ~about 1.5mm 2 , approximately 0.06 mm 2 ~approx. 0.07mm 2 , approximately 0.06 mm 2 ~approx. 0.08mm 2 , approximately 0.06 mm 2 ~approx. 0.09mm 2 , approximately 0.06 mm 2 ~about 0.1mm 2 , approximately 0.06 mm 2 ~about 0.5mm 2 , approximately 0.06 mm 2 ~about 1mm 2 , approximately 0.06 mm 2 ~about 1.5mm 2 , approximately 0.07 mm 2 ~approx. 0.08mm 2 Approximately 0.07 mm 2 ~approx. 0.09mm 2 Approximately 0.07 mm 2 ~about 0.1mm 2 Approximately 0.0 mm 2 ~about 0.5mm 2 , approximately 0.07 mm 2~about 1mm 2 , approximately 0.07 mm 2 ~about 1.5mm 2 , approximately 0.08 mm 2 ~approx. 0.09mm 2 , approximately 0.08 mm 2 ~about 0.1mm 2 , approximately 0.08 mm 2 ~about 0.5mm 2 , approximately 0.08 mm 2 ~about 1mm 2 , approximately 0.08 mm 2 ~about 1.5mm 2 , approximately 0.09 mm 2 ~about 0.1mm 2 , approximately 0.09 mm 2 ~about 0.5mm 2 , approximately 0.09 mm 2 ~about 1mm 2 , approximately 0.09 mm 2 ~about 1.5mm 2 , about 0.1mm 2 ~about 0.5mm 2 , about 0.1mm 2 ~about 1mm 2 , about 0.1mm 2 ~about 1.5mm 2 Approximately 0.5mm 2 ~about 1mm 2 , about 0.5mm 2 ~about 1.5mm 2 , or about 1 mm 2 ~about 1.5mm 2 The mesh structure includes spacing of approximately 0.001 mm. 2 , about 0.005mm 2 , approximately 0.01 mm 2 , about 0.05mm 2 , approximately 0.06 mm 2 , approximately 0.07 mm 2 , approximately 0.08 mm 2 , approximately 0.09 mm 2 , about 0.1mm 2 , about 0.5mm 2 , about 1mm 2 , or about 1.5 mm 2 The mesh structure includes a spacing of at least about 0.001 mm. 2 , about 0.005mm 2 , approximately 0.01 mm2 , about 0.05mm 2 , approximately 0.06 mm 2 , approximately 0.07 mm 2 , approximately 0.08 mm 2 , approximately 0.09 mm 2 , about 0.1mm 2 , about 0.5mm 2 , or about 1 mm 2 The mesh structure has a maximum spacing of approximately 0.005 mm. 2 , approximately 0.01 mm 2 , about 0.05mm 2 , approximately 0.06 mm 2 , approximately 0.07 mm 2 , approximately 0.08 mm 2 , approximately 0.09 mm 2 , about 0.1mm 2 , about 0.5mm 2 , about 1mm 2 , or about 1.5 mm 2 The viscoelastic medium is injected into the patient's treatment site, where the viscoelastic medium contains homogeneous microbubbles. MRI, CT, ultrasound, or any combination thereof is then performed on the treatment site to determine the formation of a cavity by the spacer material between the treated organ and the proximal tissue location. The gel is configured to be visualized in real time, at 30 minutes, 90 minutes, and up to 8 hours and up to 4 days after injection. The gel is configured so that the microbubbles remain sufficiently visible for in vivo imaging in all modalities for up to 4 days.

[0193] Example 17 - Preparing Gadopentetate Dimeglumine in NASHA-Gel Gels containing greater than 5 mg / ml, greater than 6 mg / ml, greater than 7 mg / ml, greater than 8 mg / ml, greater than 9 mg / ml, or greater than 10 mg / ml of gadopentetate dimeglumine are prepared by weighing gadopentetate dimeglumine and thoroughly mixing it with NASHA-gel (20 mg HA / ml, Q-Med) by manual stirring. The resulting gel is centrifuged to remove air bubbles.

[0194] The release of the gadolinium complex from the gel was measured using a USP-paddle system. NMR and ICP-MS were used to monitor the release of the gadolinium complex. 2D spin echo (SE) and 3D gradient echo (FFE) sequences were generated, both with and without fat saturation (FS). MRI was also performed on the gels releasing the gadolinium complex for various time periods. The initial release of the gadolinium complex should be relatively rapid, and the rate should closely match the diffusion rate of small drug molecules. ICP-MS analysis after 7 and 24 hours of release showed that 80% of the gadolinium was released by 1 hour after addition, suggesting that a small amount of gadolinium interacted and was released at a much slower rate. MRI measurements on the gels showed that at the first time points (30 and 90 minutes), the NASHA-Gel exhibited strong contrast compared to water and oil. After that time (8 hours up to 4 days), the contrast becomes much weaker but is still visible compared to NASHA-Gel without the gadolinium complex. Furthermore, the gadolinium complex is retained in the gel in a dose-dependent manner (more gadolinium results in higher MRI contrast), indicating that a small amount of gadolinium appears to interact with the NASHA-Gel. Gels containing greater than 5 mg / ml, greater than 6 mg / ml, greater than 7 mg / ml, greater than 8 mg / ml, greater than 9 mg / ml, or greater than 10 mg / ml of gadopentetate dimeglumine provide useful contrast for in vivo MRI at later time points.

[0195] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It will be understood that various alternatives to the embodiments of the present disclosure described herein may be utilized in practicing the present disclosure.

Claims

1. 1. A method of spacing a first tissue site on a subject from a second tissue site on a subject, the method comprising: (a) disposing a viscoelastic medium in a spaced relationship between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises non-animal stabilized hyaluronic acid ("NASHA") and a gadolinium complex.

2. The method of claim 1 , further comprising monitoring or imaging the gap between the first tissue site and the second tissue site.

3. The method of claim 1 or 2, wherein the spacing between the first tissue site and the second tissue site ranges from about 0.1 cm to about 10 cm.

4. The method of any one of claims 1 to 3, wherein the gadolinium complex is present in a range of about 1 mg / ml to about 10 mg / ml.

5. The method of any one of claims 1 to 4, wherein the viscoelastic medium comprises a volume of about 1 ml to about 50 ml.

6. The method of any one of claims 1 to 5, wherein the viscoelastic medium is placed through a 10-25 gauge needle.

7. The method of any one of claims 1 to 6, wherein the viscoelastic medium comprises NASHA at a concentration ranging from about 5 mg / ml to about 100 mg / ml.

8. The method of any one of claims 1 to 7, wherein the viscoelastic medium comprises gel particles ranging in size from about 0.2 mm to about 5 mm.

9. The method according to any one of claims 1 to 8, wherein the viscoelastic medium is placed subcutaneously or subepidermally.

10. 10. The method of any one of claims 1-9, wherein the first tissue site and the second tissue site are selected from the group consisting of breast, head and neck, cervix, vagina, base of spine, skin, pancreas, liver, or lung of a subject.

11. The method of any one of claims 2 to 10, wherein imaging comprises real-time imaging.

12. 12. The method of any one of claims 1 to 11, wherein the viscoelastic medium is configured to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium.

13. The method of any one of claims 2 to 12, wherein the imaging comprises MRI, CT, ultrasound, or a combination thereof.

14. The method according to any one of claims 2 to 13, wherein the viscoelastic medium is bioabsorbable.

15. 1. A method of spacing a first tissue site on a subject from a second tissue site on a subject, the method comprising: (a) disposing a viscoelastic medium in a spaced relationship between the first tissue site and the second tissue site, wherein the viscoelastic medium comprises one or more visualization additives.

16. The method of claim 1 , further comprising monitoring or imaging the gap between the first tissue site and the second tissue site.

17. 17. The method of claim 15 or 16, wherein the spacing between the first tissue site and the second tissue site ranges from about 0.1 cm to about 10 cm.

18. The method of any one of claims 15 to 17, wherein the visualization additive is present in an amount sufficient to produce contrast when imaged by an imaging modality.

19. The method of any one of claims 15 to 18, wherein the viscoelastic medium comprises a volume of about 1 ml to about 50 ml.

20. The method of any one of claims 15 to 19, wherein the viscoelastic medium is placed through a 10-25 gauge needle.

21. 21. The method of any one of claims 15 to 20, wherein the viscoelastic medium comprises hyaluronic acid, polyethylene glycol, or dextranomer at a concentration ranging from about 5 mg / ml to about 100 mg / ml.

22. The method of any one of claims 15 to 21, wherein the viscoelastic medium comprises gel particles ranging in size from about 0.08 mm to about 5 mm.

23. The method of any one of claims 15 to 22, wherein the viscoelastic medium is placed subcutaneously or subepidermally.

24. 24. The method of any one of claims 15-23, wherein the first tissue site and the second tissue site are selected from the group consisting of breast, head and neck, cervix, vagina, base of spine, skin, pancreas, liver, or lung of a subject.

25. The method of any one of claims 16 to 24, wherein the imaging comprises real-time imaging.

26. 26. The method of any one of claims 15 to 25, wherein the viscoelastic medium is configured to be imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium.

27. The method of any one of claims 16 to 26, wherein the imaging comprises MRI, CT, ultrasound, or a combination thereof.

28. The method of any one of claims 18 to 27, wherein the imaging modality comprises MRI, CT, ultrasound, or a combination thereof.

29. The method of any one of claims 15 to 28, wherein the viscoelastic medium is substantially immobile prior to and during the imaging.

30. The method of any one of claims 15 to 29, wherein the visualization additive comprises one or more nanoparticles.

31. The method of any one of claims 15 to 30, wherein the visualization additive comprises a precious metal.

32. 32. The method of claim 31 , wherein the precious metal comprises iron or gold.

33. The method of any one of claims 15 to 32, wherein the viscoelastic medium is bioabsorbable.

34. 30. The method of any one of claims 15-29, wherein the visualization additive comprises iohexol, metrizamide, iopamidol, (3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid), meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or a combination thereof.

35. 1. A method for preventing or reducing damage to tissue adjacent to a site of radiation therapy in a subject undergoing radiation therapy, the method comprising injecting a bioabsorbable viscoelastic medium at the site of radiation therapy, wherein the bioabsorbable viscoelastic medium comprises a visualization additive.

36. 36. The method of claim 35, wherein the injection displaces the tissue a distance in the range of about 0.1 cm to about 10 cm.

37. The method of any one of claims 35 to 36, wherein the viscoelastic medium comprises gel particles.

38. The method of any one of claims 35 to 37, wherein the gel particles comprise hyaluronic acid or a derivative thereof.

39. 39. The method of any one of claims 35 to 38, wherein the injection comprises a volume of about 1 ml to about 50 ml.

40. 40. The method of any one of claims 35 to 39, wherein the injection is performed through a 10-25 gauge needle.

41. 41. The method of any one of claims 35 to 40, wherein the concentration of the hyaluronic acid is in the range of about 5 mg / ml to about 100 mg / ml.

42. 42. The method of any one of claims 35 to 41, wherein the size of the gel particles ranges from about 0.2 mm to about 5 mm.

43. 43. The method of any one of claims 35 to 42, wherein the injection is subcutaneous or subepidermal.

44. The method of any one of claims 35 to 43, wherein movement of the viscoelastic medium is avoided or reduced.

45. The method of any one of claims 35 to 44, wherein the visualization additive comprises one or more nanoparticles.

46. The method of any one of claims 35 to 45, wherein the nanoparticles comprise a noble metal.

47. 47. The method of any one of claims 35 to 46, wherein the dose of radiation therapy contacting tissue adjacent to the site of radiation therapy is reduced by about 10% to about 80%.

48. 48. The method of any one of claims 35-47, wherein the site of radiation therapy is selected from the group consisting of the breast, head and neck, cervix, vagina, base of the spine, skin, pancreas, liver, or lung of a subject.

49. 49. The method of any one of claims 35-48, further comprising administration of hyaluronidase at the site of said radiation therapy.

50. 50. The method of any one of claims 35 to 49, wherein the volume of the viscoelastic medium at the site of radiation therapy is reduced by about 1% to about 95%.

51. 51. The method of any one of claims 35 to 50, wherein the administration of hyaluronidase occurs about 0.1 hours to about 24 hours after injection of the bioabsorbable viscoelastic medium.

52. 52. The method of any one of claims 35 to 51, further comprising imaging the site of radiation therapy.

53. 53. The method of claim 52, wherein the imaging comprises serial imaging.

54. 54. The method of any one of claims 52 or 53, wherein the imaging comprises MRI, CT scan, ultrasound, or a combination thereof.

55. A composition comprising a viscoelastic medium and a visualization additive.

56. 56. The composition of claim 55, wherein the visualization additive is present in an amount sufficient to produce contrast when imaged by an imaging modality.

57. 57. The composition of claim 55 or 56, wherein the viscoelastic medium comprises a volume of about 1 ml to about 50 ml.

58. 58. The composition of any one of claims 55 to 57, wherein the viscoelastic medium is configured for placement through a 10-25 gauge needle.

59. 59. The composition of any one of claims 55 to 58, wherein the viscoelastic medium comprises hyaluronic acid, polyethylene glycol, or dextranomer at a concentration ranging from about 5 mg / ml to about 100 mg / ml.

60. 60. The composition of any one of claims 55 to 59, wherein the viscoelastic medium comprises gel particles ranging in size from about 0.08 mm to about 5 mm.

61. 61. The composition of any one of claims 55 to 60, wherein the visualization additive is configured to allow the viscoelastic medium to be imaged, wherein the imaging comprises real-time imaging.

62. 62. The composition of any one of claims 55-61, wherein the visualization additive is configured such that the viscoelastic medium is imaged within 30 minutes, within 90 minutes, within 4 hours, within 8 hours, or within 4 days of placement of the viscoelastic medium.

63. 63. The composition of any one of claims 55-62, wherein the visualization additive is configured to allow the viscoelastic medium to be imaged, wherein the imaging comprises MRI, CT, ultrasound, or a combination thereof.

64. 64. The composition of any one of claims 56 to 63, wherein the imaging modality comprises MRI, CT, ultrasound, or a combination thereof.

65. 65. The composition of any one of claims 55 to 64, wherein the viscoelastic medium is configured to be substantially immobile upon displacement.

66. 66. The composition of any one of claims 55 to 65, wherein the visualization additive comprises one or more nanoparticles.

67. 67. The composition of any one of claims 55 to 66, wherein the visualization additive comprises a precious metal.

68. 68. The composition of claim 67, wherein the precious metal comprises iron or gold.

69. The composition of any one of claims 55 to 68, wherein the viscoelastic medium is bioabsorbable.

70. 70. The composition of any one of claims 55-69, wherein the visualization additive comprises iohexol, metrizamide, iopamidol, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, triiodobenzoic acid, erythrosine, ioversol, gadolinium, gadopentetate carbon-coated zirconium beads, calcium hydroxylapatite, superparamagnetic iron oxide, or a combination thereof.

Images