US-12622982-B2 - Implants and biodegradable tissue markers

Abstract

Implantable materials may be used in an iatrogenic site. Applications include radioopaque materials for fiducial marking.

Inventors

• Patrick Campbell
• Amarpreet S. Sawhney

Assignees

• INCEPT, LLC

Dates

Publication Date

20260512

Application Date

20220107

Claims (20)

1. 1 . A method for radiation therapy comprising imaging margins of a hydrogel spacer using ultrasound, wherein the hydrogel spacer is at a site between a first tissue location and a second tissue location to increase a distance between the first tissue location and the second tissue location, the site being chosen to decrease radiation at the first tissue location when the second tissue location receives a dose of therapeutic radiation, wherein the hydrogel spacer comprises a polysaccharide.
2. 2 . The method of claim 1 , wherein the polysaccharide is hyaluronic acid.
3. 3 . The method of claim 1 , wherein the hydrogel spacer comprises an ultrasound contrast agent.
4. 4 . The method of claim 1 , wherein the first tissue location is associated with the rectum and the second tissue location is associated with the prostate gland.
5. 5 . The method of claim 1 , wherein the hydrogel spacer is echolucent under ultrasound imaging.
6. 6 . The method of claim 1 , wherein the hydrogel spacer, as placed in the tissue, has a volume between 1 and 40 ml.
7. 7 . The method of claim 1 , wherein the polysaccharide is enzymatically biodegradable.
8. 8 . The method of claim 1 , wherein the polysaccharide is covalently-crosslinked.
9. 9 . The method of claim 1 , wherein the polysaccharide is a glycosaminoglycan.
10. 10 . The method of claim 9 , wherein the glycosaminoglycan is crosslinked with a reactive precursor species having electrophilic functional groups.
11. 11 . The method of claim 1 , wherein the polysaccharide comprises esterified hyaluronic acid.
12. 12 . The method of claim 1 , wherein the hydrogel spacer comprises hydrogel particles.
13. 13 . The method of claim 12 , wherein the hydrogel particles comprise a collection of covalently-crosslinked, biodegradable hydrogel particles comprising the polysaccharide.
14. 14 . The method of claim 13 , wherein the collection of particles is completely biodegradable at a time between about 30 and about 365 days.
15. 15 . The method of claim 12 , wherein the hydrogel particles are formed by a process comprising breaking up a hydrogel polymer matrix.
16. 16 . The method of claim 15 , wherein the hydrogel particles are formed by a process comprising forcing the hydrogel polymer matrix through a mesh.
17. 17 . The method of claim 12 , wherein the hydrogel particles have a size range from 1 micron to 500 microns.
18. 18 . The method of claim 1 , wherein the hydrogel spacer further comprises a linear polymer.
19. 19 . The method of claim 18 , wherein the hydrogel spacer exhibits shear thinning behavior.
20. 20 . The method of claim 18 , wherein the linear polymer comprises polyethylene glycol.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 16/999,703, filed Aug. 21, 2020, which is a continuation of U.S. patent application Ser. No. 16/296,795, filed Mar. 8, 2019, which is a continuation of U.S. patent application Ser. No. 15/613,555, filed Jun. 5, 2017, which is a continuation of U.S. patent application Ser. No. 15/066,707, filed Mar. 10, 2016, which is a continuation of U.S. patent application Ser. No. 14/465,202, filed Aug. 21, 2014, which is a divisional of U.S. patent application Ser. No. 13/750,570, filed Jan. 25, 2013, which is a divisional of U.S. patent application Ser. No. 12/968,527, filed Dec. 15, 2010, which claims the benefit of U.S. Provisional Application No. 61/286,450, filed Dec. 15, 2009, each of which are hereby incorporated by reference herein in their entirety. TECHNICAL FIELD The technical field, in general, relates to stabilizing and visualizing tissue gaps left by surgical removal of cancerous tissues; certain embodiments include polymeric microparticles with attached radioopaque markers. BACKGROUND According to the American Cancer Society, in 2009 it is estimated there will be more than 192,000 and 62,000 new cases of invasive and in situ breast cancer, respectively, with more with over 40,000 deaths in the United States alone. Once detected, most breast cancers, including ductal carcinoma in situ (DCIS), are removed surgically either by a modified radical mastectomy, or via lumpectomy. Following lumpectomy, patents are then typically treated with either chemotherapy followed by 5-7 weeks of whole breast external beam radiation therapy (EBRT), or by 5-7 days of accelerated partial breast irradiation (APBI) followed by either chemotherapy or no further treatment. SUMMARY Implants are described herein that conformally fill surgical sites. Conformal filling of the sites with a radioopaque material provides for later identification and monitoring of the site and its tissue margins. Good visualization allows for careful post-operative follow-up of cancer patients who have had cancerous tissue removed. In the first place, filling substantially all of the site provides a bulky mass that resists permanent deformation and migration of the margins. Further, the margins can be visualized because the site is substantially full and the implant is thus coterminous with the tissue margins. One embodiment of an implant involves filling a site with flowable precursors that set-up to make a hydrogel implant that provides for ready visualization of margins of the implant site. The implant immobilizes and may adhere to the tissue edges, so that the edges can be followed and subsequently treated. A process for making the implant involves reacting precursors with each other that form the implant when they react with each other. A crosslinked hydrogel can be formed in-situ that supports tissue around a lumpectomy site to stabilize the tissue at the margins of the lumpectomy so the margins can be precisely targeted by subsequent treatments, for instance, radiation or ablation. Another embodiment of the invention provides filling the site with small particles that are small, pliable, and slippery so that they flow easily into the site and its irregularities, pack closely, and provide good visualization of the margins. Radioopaque agents may be included with the implants, either covalently attached or mixed within the materials. A conformal filling approach is a considerable improvement over the use of clips, which provide poor resolution of the site's margins. Conformal filling also improves over a do-nothing approach which is also a conventional practice that allows a void to remain at the surgical site to be filled with a seroma. Seromas can be symptomatic, often requiring drainage, and are known to change size following surgery, preventing targeting for partial breast irradiation. The implants may be formulated to be stable until no longer needed, and then biodegrade. The implants may also be used with or without radioopaque agents. An in situ formed hydrogel can seal tissue margins to reduce seroma formation. Further, the use of hydrogel as a continuous phase or as a particulate form may result in improved cosmesis since the hydrogel fills the cavity and prevents its deformation. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is an illustration of the prior art for removing a tumor from a tissue. FIG. 1B is an illustration of the prior art for removing a tumor from a tissue. FIG. 2A illustrates placement of matrix precursors in an iatrogenic site using a dual-barreled applicator. FIG. 2B depicts an alternative applicator for placing a plurality of particles into the site of FIG. 2A. FIG. 3A is an image of a hydrogel placed in an iatrogenic site with clear definition of the lumpectomy cavity on kilovoltage CT. FIG. 3B is a T2-weighted MRI image of the site of FIG. 3A. FIG. 3C is a kilovoltage cone-beam CT image of the site of FIG. 3A. F