Synthetic hydrogel carriers for muscle repair

A method of repairing muscle tissue in a human patient in need thereof,

• wherein the muscle tissue is diaphragm muscle tissue;
• wherein the patient has muscular dystrophy;comprising forming micropunctures on the muscle tissue with a substrate comprising microneedles and forming a hydrogel matrix in vivo on the muscle tissue having micropunctures, wherein the hydrogel matrix is formed in vivo by applying to the muscle tissue having micropunctures:
• a) a composition comprising a hydrophilic polymer conjugated to a plurality of adhesion peptides, wherein the hydrophilic polymer has the general formula:
• wherein ‘polymer’ represents polyethylene glycol, C represents a core, Q represents a linker, Z represents an adhesion peptide, wherein the adhesion peptide comprises the sequence GRGDSPC (SEQ ID NO:
• 1), CRGDS (SEQ ID NO:
• 2), CRGDSP (SEQ ID NO:
• 3), CPHSRN (SEQ ID NO:
• 4), CGWGGRGDSP (SEQ ID NO:
• 5), CGGSIDQVEPYSSTAQ (SEQ ID NO:
• 6), CGGRNIAEIIKDI (SEQ ID NO:
• 7), CGGDITYVRLKF (SEQ ID NO:
• 8), CGGDITVTLNRL (SEQ ID NO:
• 9), CGGRYVVLPR (SEQ ID NO:
• 10), CGGKAFDITYVRLKF (SEQ ID NO:
• 11), CGGEGYGEGYIGSR (SEQ ID NO:
• 12), CGGATLQLQEGRLHFXFDLGKGR, wherein X=Nle (SEQ ID NO:
• 13), CGGSYWYRIEASRTG (SEQ ID NO:
• 14), CGGGEFYFDLRLKGDKY (SEQ ID NO:
• 15), CKGGNGEPRGDTYRAY (SEQ ID NO:
• 16), CKGGPQVTRGDVFTMP (SEO ID NO:
• 17), CGGNRWHSIYITRFG (SEO ID NO:
• 18), CGGASIKVAVSADR (SEQ ID NO:
• 19), CGGTTVKYIFR (SEQ ID NO:
• 20), CGGSIKIRGTYS (SEQ ID NO:
• 21), CGGSINNNR (SEQ ID NO:
• 22), CGGSDPGYIGSR (SEQ ID NO:
• 23), CYIGSR (SEQ ID NO:
• 24), CGGTPGPQGIAGQGVV (SEQ ID NO:
• 25), CGGTPGPQGIAGQRVV (SEQ ID NO:
• 26), CGGMNYYSNS (SEQ ID NO:
• 27), CGGKKQRFRHRNRKG (SEQ ID NO:
• 28), CRGDGGGGGGGGGGGGGPHSRN (SEQ ID NO:
• 29), CPHSRNSGSGSGSGSGRGD (SEQ ID NO:
• 30), Acetylated-GCYGRGDSPG (SEQ ID NO:
• 31), ((GPP)5GPC) (SEQ ID NO:
• 32), CRDGS (SEQ ID NO:
• 33), cyclic RGD{Fd}C (SEQ ID NO:
• 34), CGGRKRLQVQLSIRT (SEQ ID NO:
• 35), CIKVAV (SEQ ID NO:
• 36), CGGAASIKVAVSADR (SEQ ID NO:
• 37), CGGKRTGQYKL (SEQ ID NO:
• 38), CGGTYRSRKY (SEQ ID NO:
• 39), CGGYGGGP(GPP)5GFOGERPP(GPP)4GPC (SEQ ID NO:
• 40), CGGKRTGQYKLGSKTGPGQK (SEQ ID NO:
• 41), QAKHKQRKRLKSSC (SEQ ID NO:
• 42), SPKHHSQRARKKKNKNC (SEQ ID NO:
• 43), CGGXBBXBX, wherein B=basic residue and X=hydropathic residue (SEQ ID NO:
• 44), and CGGXBBBXXBX, wherein B=basic residue and X=hydropathic residue (SEQ ID NO:
• 45), or a combination thereof,
• and
• b) a composition comprising a crosslinker;
• wherein at least one of the composition comprising the hydrophilic polymer and the composition comprising the crosslinker comprises a pro-myogenic agent, wherein C represents a group having the formula:
• wherein q is from 1-6;
• wherein the pro-myogenic agent comprises muscle stem cells and/or satellite cells, wherein the pro-myogenic agent further comprises a pro-myogenic protein comprising Wnt7a, FGF2, VEGF, IGF-1, GDNF, MG53, or a combination thereof;
• Q1 represents a group having the formula:
• wherein A is independently selected from O or NH, a is independently selected from 0 or 1, B is selected from hydrogen or methyl, and represents a link to a polyethylene glycol;
• and
• the crosslinker comprises 1,4-dithiothreitol poly(ethylene glycol) dithiol or a peptide having the sequence GCRDGPQG↓IWGQDRCG (SEQ ID NO:
• 46), GCRDGPQG↓IAGQDRCG (SEQ ID NO:
• 47), GCRDVPMS↓MRGGDRCG (SEQ ID NO:
• 48), GCRDIPVS↓LRSGDRCG (SEQ ID NO:
• 49), GCRDRPFS↓MIMGDRCG (SEQ ID NO:
• 50), GCRDVPLS↓LTMGDRCG (SEQ ID NO:
• 51), GCRDVPLS↓LYSGDRCG (SEQ ID NO:
• 52), GCRDIPES↓LRAGDRCG (SEQ ID NO:
• 53), GCRDSGESPAY↓YTADRCG (SEQ ID NO:
• 54), GCRDGGYAE↓LRMGGDRCG (SEQ ID NO:
• 55), GCRDGGPLG↓LYAGGDRCG (SEQ ID NO:
• 56), GCRDGPLG↓LWARDRCG (SEQ ID NO:
• 57), or a combination thereof.