Lung volume reduction therapy using crosslinked non-natural polymers
View Patent ↗One aspect of the invention relates to a hydrogel comprising a non-natural polymer comprising a plurality of pendant nucleophilic groups and a crosslinker comprising at least two pendant electrophilic groups. Another aspect of the invention relates to a hydrogel comprising a non-natural polymer comprising a plurality of pendant electrophilic groups and a crosslinker comprising at least two pendant nucleophilic groups. Yet another aspect of the invention relates to a method for reducing lung volume in a patient comprising the step of administering a hydrogel composition as described herein. Further, hydrogels of the invention may be used to achieve pleurodesis, seal brochopleural fistulas, seal an air leak in a lung, achieve hemostasis, tissue sealing (e.g., blood vessels, internal organs), or any combination thereof. In certain embodiments, the compositions and methods described herein are intended for use in the treatment of patients with emphysema.
1. A method for treating a lung of a patient, comprising:
advancing a catheter into a region of a patient's lung;
mixing outside of the lung a first solution comprising a non-natural polymer with a second solution comprising a cross-linker, thereby initiating crosslinking to form a hydrogel;
mixing outside of the lung the hydrogel with a gas to form a hydrogel foam; and
delivering the hydrogel foam through the catheter to the region of the lung;
wherein crosslinking of the hydrogel foam is completed at the region of the lung;
the non-natural polymer consists essentially of a plurality of subunits independently selected from the group consisting of
wherein independently for each occurrence X is (—C(R) 2 ) n —, —(CH 2 OCH 2 ) n CH 2 —, —(CH 2 ) n -(cycloalkyl)-(CH 2 ) n —, or —(CH 2 ) n -(aryl)-(CH 2 ) n —;
R is H or lower alkyl;
Y is —NHR′, —OH or —SH;
R′ is hydrogen, NH 2 , aliphatic, aromatic, heterocyclic, cycloaliphatic or a saturated heterocyclic moiety; and
n is 1-20.
2. The method of claim 1 , wherein the hydrogel foam causes lung volume reduction.
3. The method of claim 1 , wherein crosslinking of the hydrogel foam is completed at the region of the lung less than 10 minutes after initiating crosslinking of the hydrogel.
4. The method of claim 1 , wherein crosslinking of the hydrogel foam is completed at the region of the lung between 1 and 5 minutes after initiating crosslinking of the hydrogel.
5. The method of claim 1 , wherein crosslinking of the hydrogel foam is completed at the region of the lung between 1 and 3 minutes after initiating crosslinking of the hydrogel.
6. The method of claim 1 , wherein the foam is formed by mixing the hydrogel and the gas with turbulence.
7. The method of claim 1 , wherein the catheter comprises an inflatable occlusion balloon at a distal end; and wherein the balloon is maintained in an inflated state at the region of the lung until crosslinking of the hydrogel foam is completed.
8. The method of claim 1 , wherein the volume of the gas is between 2 and 5 times larger than the volume of the hydrogel; and wherein the volume of the hydrogel foam is between 3 and 6 times larger than the volume of the hydrogel before mixing with the gas.
9. The method of claim 1 , wherein the non-natural polymer comprises a plurality of pendant nucleophilic groups.
10. The method of claim 1 , wherein about 60 mol % to about 99 mol % of the subunits are
11. The method of claim 1 , wherein Y is NHR′; and R′ is H.
12. The method of claim 1 , wherein X is —(C(R) 2 ) n —; and R is H.
13. The method of claim 1 , wherein X is —(C(R) 2 ) n —; R is H; Y is NHR′; and R′ is H.
14. The method of claim 1 , wherein the cross-linker comprises at least two pendant electrophilic groups.
15. The method of claim 14 , wherein said electrophilic groups are selected from the group consisting of aziridines, episulfides, cyclic sulfates, carbonates, imines, esters, lactones, halides, epoxides, hydroxysuccinimidyl esters, maleimides, iodoacetamides, phosphates, sulfates, sulfonates, ketones and aldehydes.
16. The method of claim 1 , wherein said cross-linker is a polyaldehyde.
17. The method of claim 1 , wherein said cross-linker is a dialdehyde.
18. The method of claim 1 , wherein said cross-linker is glutaraldehyde.