Superabsorbent, freeze dried hydrogels for medical applications
Methods are provided for making freeze dried hydrogel and structures therefrom that may be introduced into a patient's body for medical applications. Precursor components are combined to initiate crosslinking. The combined precursor components are placed in a chilled tray, and allowed to crosslink to a desired level of complete crosslinking before and/or after being placed onto the tray. The partially crosslinked hydrogel is frozen and freeze dried. After freeze drying, the hydrogel is conditioned to substantially complete crosslinking, and formed into one or more structures, e.g., plugs, hemostatic, or other medical devices. For example, the hydrogel may be cut, machined, rolled, folded, compressed, and/or cored into that may be loaded into delivery devices that may be introduced into a body to implant or otherwise deliver the structures into the body, e.g., to seal a puncture or other passage through tissue.
1. A method for making superabsorbent hydrogel, comprising:
forming a mixture by combining precursor components to initiate covalent crosslinking of the precursor components;
placing the combined precursor components onto a chilled tray or container;
freezing the mixture before the covalent crosslinking is complete; and
freeze drying the frozen mixture to form the hydrogel,
wherein the precursor components comprise a first electrophilic precursor that comprises electrophilic functional groups and a second nucleophilic precursor that comprises nucleophilic functional groups chosen from the group consisting of amines and thiols, with the electrophilic functional groups and nucleophilic functional groups chemically reacting with each other to form covalent bonds to crosslink the precursor components.
2. The method of claim 1 , further comprising conditioning the hydrogel after freeze drying.
3. The method of claim 2 , wherein the hydrogel substantially completes crosslinking when the hydrogel is conditioned.
4. The method of claim 3 , wherein the hydrogel has substantially no unreacted reactive ester end groups after the hydrogel is conditioned.
5. The method of claim 1 , wherein the mixture is frozen on the tray or container.
6. The method of claim 1 , further comprising forming the freeze dried hydrogel into one or more structures.
7. The method of claim 6 , wherein the one or more structures are formed by at least one of cutting, machining, rolling, coring, and compressing the hydrogel.
8. The method of claim 1 , wherein crosslinking of the precursor components is initiated in an aqueous phase.
9. The method of claim 1 , wherein the hydrogel substantially completes the covalent crosslinking when the mixture is freeze dried.
10. The method of claim 1 , wherein the precursor components comprise a highly branched active PEG.
11. The method of claim 10 , wherein the nucleophilic precursor comprises an oligopeptide with two or more lysine groups.
12. A method for making hydrogel, comprising:
combining precursor components to initiate covalent crosslinking of the precursor components to form a hydrogel;
placing the hydrogel onto a tray or container chilled below the freezing point of the combined precursor components;
freezing the hydrogel before crosslinking is complete;
freeze drying the frozen hydrogel; and
conditioning the freeze dried hydrogel to substantially complete the covalent crosslinking of the precursor components
wherein the precursor components comprise a first electrophilic precursor that comprises electrophilic functional groups and a second nucleophilic precursor that comprises nucleophilic functional groups chosen from the group consisting of amines and thiols, with the electrophilic functional groups and nucleophilic functional groups chemically reacting with each other to form covalent bonds to crosslink the precursor components.
13. The method of claim 12 , further comprising forming the hydrogel into one or more structures.
14. The method of claim 12 , wherein the hydrogel is placed onto the tray or container before the covalent crosslinking is complete.
15. The method of claim 12 , wherein the hydrogel is placed onto the tray or container after a predetermined amount of the covalent crosslinking has occurred.
16. The method of claim 12 , wherein the hydrogel is placed onto the tray or container immediately upon combining the precursor components, and wherein the hydrogel is maintained on the tray or container at a predetermined temperature until a predetermined percentage of complete covalent crosslinking is achieved, whereupon the hydrogel is freeze dried.
17. The method of claim 12 , wherein conditioning the hydrogel comprises one or more conditioning steps selected from the group comprising:
exposing the hydrogel to a controlled-humidity environment;
further drying the hydrogel using heat;
exposing the hydrogel to a controlled gas environment;
exposing the hydrogel to an aerosolized buffer solution; and
desiccating the hydrogel.
18. The method of claim 17 , wherein the hydrogel is conditioned using multiple successive stages, each stage comprising one or more of the conditioning steps.
19. The method of claim 12 , wherein the step of freeze drying the hydrogel comprises:
a first stage comprising exposing the hydrogel to a freeze drying temperature and a vacuum; and
a second stage comprising at least one of increasing the freeze drying temperature, and reducing the vacuum.
20. The method of claim 19 , wherein the second stage comprises reducing the vacuum for a second stage duration, and wherein the freeze drying temperature is increased at least intermittently during the second stage duration.
21. The method of claim 20 , wherein the freeze drying temperature is increased at a steady rate during the second stage duration.
22. The method of claim 12 , wherein the hydrogel substantially completes covalent crosslinking when the hydrogel is conditioned.
23. The method of claim 22 , wherein the hydrogel has substantially no unreacted reactive ester end groups after the hydrogel is conditioned.