Hydrogels with biodegradable crosslinking

A hydrogel that is biodegradable under physiological conditions, wherein the hydrogel comprises one or more hyaluronic acid polymers crosslinked by a linker that decomposes by a beta elimination reaction,

• wherein said linker is of Formula (1):
• wherein for each linker of formula (1):
• m of formula (1) is 0 or 1;
• X of formula (1) is
• wherein
• T* is O, S, or NR6, wherein R6 is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• z is 1-6;
• Y is (OCH2CH2)p, wherein p is 1-100;
• and
• Z2 is a first functional group that is coupled to a first cognate functional group on a hyaluronic acid polymer;
• one of R1, R2, or R5 comprises a second functional group that is coupled to a second cognate functional group on a hyaluronic acid polymer,
• wherein each said first functional group and said second functional group comprises N3, NH2, NH—CO2tBu, SH, StBu, maleimide, CO2H, CO2tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, or acrylamide;
• with the proviso that:
• (1) when one of R5 of formula (1) comprises a second functional group that is coupled to a second cognate group of a hyaluronic acid polymer, the remaining R5 of formula (1) is H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl:
• and
• (a) R1 and R2 of formula (1) are independently CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• (b) R1 and R2 of formula (1) may be joined to form a 3-8 membered ring;
• (c) R1 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and R2 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• or
• (d) R2 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and R1 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• or
• (2) when R1 of formula (1) comprises a second functional group that is coupled to a second cognate group of a hyaluronic acid polymer:
• R2 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and each R5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• or
• (3) when R2 of formula (1) comprises a second functional group that is coupled to a second cognate group of a hyaluronic acid polymer:
• R1 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and each R5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• wherein
• R3 is selected from the group consisting of (i) H;
• (ii) optionally substituted alkyl;
• (iii) optionally substituted aryl;
• (iv) optionally substituted arylalkyl;
• (v) optionally substituted heteroaryl;
• (vi) optionally substituted heteroarylalkyl;
• (vii) OR9;
• and (viii) NR92;
• R4 is selected from the group consisting of (i) optionally substituted alkyl;
• (ii) optionally substituted aryl;
• (iii) optionally substituted arylalkyl;
• (iv) optionally substituted heteroaryl;
• and (v) optionally substituted heteroarylalkyl;
• and
• each R9 is independently H or optionally substituted alkyl, or both R9 groups taken together with the nitrogen to which they are attached form a heterocyclic ring.