Complex regional pain syndrome treatment using extracellular vesicle compositions

Abstract

Disclosed herein are methods of treating complex regional pain syndrome in a subject by administering a therapeutic MSC secretory group product prepared by a method comprising culturing a bone marrow-derived MSC under conditions comprising an oxygen tension of less than 5% and a culture medium having a pH of less than 7.

Description

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 507,207, filed June 9, 2023, which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Complex regional pain syndrome (CRPS) is a severely painful and disabling condition that can occur in a limb after a major trauma or surgery or can develop spontaneously. CRPS is a multisystem disease that incorporates different elements from the autonomic nervous system, however the biggest driver of symptomology is inflammation. Currently, there is no single proven effective treatment modality for patients with CRPS identified from clinical trials. There is a need for safe and effective treatments for CRPS. SUMMARY

[0003] Disclosed herein are methods of treating complex regional pain syndrome (CRPS) in a subject, one aspect of the disclosure is a method of treating complex regional pain syndrome (CRPS) in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 -In some embodiments, the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration. Also disclosed herein are methods of treating complex regional pain syndrome (CRPS) in a subject in need thereof, the methods comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration. In some embodiments, at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-. In some embodiments, the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration. In some embodiments, the subject has a reduction in Brief Pain Inventory (BPI) score after administration compared to prior to administration. In some embodiments, the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in BPI score after administration compared to prior to administration. In some embodiments, the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in BPI pain interference score after administration compared to prior to administration. In some embodiments, the subject has at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, at least a 85%, at least a 95%, or at least a 100% increase in range of motion assessment score after administration compared to prior to administration. In some embodiments, the subject has an increase in Jamar dynameter test assessment score after administration compared to prior to administration. In some embodiments, the increase in Jamar dynameter test assessment score is in the upper extremity. In some embodiments, the subject has grip strength equalization after administration. In some embodiments, the subject has at least a 5 kg, at least a 10 kg, at least a 15 kg, or at least a 20 kg increase in grip strength after administration compared to prior to administration. In some embodiments, the subject has at least a 50%, at least a 75%, at least a 100%, at least a 125%, at least a 150%, at least a 175%, at least a 200%, or at least a 210% increase in grip strength after administration compared to prior to administration. In some embodiments, the subject has an increase in grip strength in the affected limb. In some embodiments, the subject has an increase in grip strength in the contralateral limb. In some embodiments, the subject has an improvement in one or more of the following: limb range of motion, joint range of motion, sudomotor change, edema,allodynia and hypesthesia. In some embodiments, the subject has an improvement in Short Form 36 Health Survey Questionnaire (SF-36) scores after administration compared to prior to administration. In some embodiments, the improvement in SF-36 scores comprises one or more of: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health. In some embodiments, the subject has chronic intractable pain in one or more upper or lower extremities. In some embodiments, the subject has not experienced progressively increasing or changing pain in the 30 days prior to administration. In some embodiments, the subject experiences a reduction in pain flare, reduction in swelling, and / or reduction in burning sensation in the affected limb after administration compared to prior to administration. In some embodiments, the administration improves hair growth and / or nail growth in the affected limb of the subject. In some embodiments, the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, semaphorin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, biglycan, TIMP-2, SLITRK5, FAP, neuregulin, DPPII, clAP-1, pentraxin 3, visfatin, neutral endopeptidase, albumin, galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF R I, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, mesotachyprotein, calreticulin, bone activin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, trypsin 3, SIRP alpha, and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1 R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1,IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF R alpha, fetuin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, thrombomodulin, versican, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, skeletin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin 1, IGF-2R, ADAMTSL-1, proerythrin, plexin D1, DNMT3A, BCL-2, CL-P1, ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, neublastin, DPPII, cIAP-1, PDGF Rb, pentraxin 3, angiotensinogen, follistatin, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, visfatin, progranulin, PCSK2, GKN1, IL-18, neuraminidase, stabilin-2, IL-17 RD, albumin, follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galectin-1, troponin C, UNC5H3, FLRT2, CD314, semaphorin 6B, netrin-4, CD27 ligand, IL-20 R beta, semaphorin 6A, TSK, cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, galanin, activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, phosphatidylinositol glycan 2, MSP R, DSCAM,Proprotein convertase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, ubiquitin+1, ANGPTL4, TWEAK R, nidogen-1, CD2, kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, siglec-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), granzyme B, adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, lipocalin, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1 alpha, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, plexin A4, semaphorin 4D, ROBO2, PDX-1, APRIL, neuropilin, TMEM2, EMMPRIN, activin RIB, neuropilin 2, epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, lumican-2, sFRP-3, p53, EphB3, NCK1, semaphorin 7A, NKp80, prolactin, cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, pregnancy-associated plasma protein-2, aggrecan-3, jagged-1, AKR1C4, olfactomedin-2, osteoadherin, NKp44, thyroglobulin, IL-21R, chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, integrin alpha 5, VAMP-2, FLRG, Ret protooncogene, CD73, TRACP, proGRP, granzyme H, PRX2, p2'7, siglec-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V,Testican 2, Phosphoglycan 5, CD6, Sialoadhesin-2, Asparaginyl endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neurturin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Clusterin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Agrin-1, GUSB, Enigma-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Agrin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CFXIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1,POGLUT1, IL-1 ra, Pletin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Sialoadhesin-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Dystonin-3, Claudin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Phosphatidylinositol Glycan 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural Epithelial Stem Cell Protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Dystonin 2, Aggrecan, Syntaxin 4, VAMP-1, Claudin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurgulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13,E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, an endothelial cell-specific molecule, granulysin, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIFR alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Versican, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma R1, CrkL, B7-1, PARC, Draxin (Draxin), VE-cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12 p40, Total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13. In some embodiments, the extracellular vesicle comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p,hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d,hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p. In some embodiments, the composition is produced as follows: (a) culturing bone marrow-derived MSCs under conditions to produce an MSC conditioned medium: (i) an oxygen tension of less than 5%; and (ii) a medium having a pH of less than 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the medium is serum-free. In some embodiments, the medium has a glucose concentration of less than 4.5 g / L. In some embodiments, the subject is a human. In some embodiments, the bone marrow-derived MSCs are derived from human bone marrow. In some embodiments, the administering comprises intravenous administration. In some embodiments, the dose of the therapeutic MSC secretome composition administered to the subject is a cell equivalent dose of 0.7 to 7 million cells / kg. In some embodiments, the therapeutic MSC secretome composition comprises 4 x 10 10 to 10 x 10 10 cells / mL. In some embodiments, the therapeutic MSC secretome composition comprises 5 x 10 11 to 1.5 x 10 12extracellular vesicles. In some embodiments, the composition is administered monthly for two or more months, or once every 1, 2, or 3 or more months. In some embodiments, the composition is administered twice. In some embodiments, the composition is administered four days apart.

[0004] One aspect of the present disclosure is a method of making a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition for treating complex regional pain syndrome (CRPS) in a subject in need thereof, the method comprising: (a) culturing bone marrow-derived MSCs under conditions to produce MSC conditioned medium: (i) an oxygen tension of less than 5%; and (ii) a medium having a pH of less than 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the medium is serum-free. In some embodiments, the medium has a glucose concentration of less than 4.5 g / L. In some embodiments, at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 -In some embodiments, the bone marrow-derived MSCs are derived from human bone marrow. In some embodiments, the administering comprises intravenous administration. In some embodiments, the therapeutic MSC secretome composition further comprises one or more of the following proteins: Fetuin, NUP85, LAMP2, GPR115, Serpin F1, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Selectin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Versican, TIMP-2, SLITRK5, FAP, Sphingomyelinase, DPPII, clAP-1, Pentraxin 3, Adiponectin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF Rl, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Middle- size proteoglycan, Calreticulin, Osteoactivin, Asparaginyl endopeptidase, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, and Syndecan-4, and at least one protein selected from the group consisting of: Fetuin, IGFBP-4 IL-1 R6 GSTM1, NUP85, LAMP2, Transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, Ephrin-A4, CD109, Serpin F1, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Selectin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Versican, TIMP-2, TFPI, SOX2, SLITRK5,FAP, Dystroglycan, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Proerythrin, Plexin D1, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Sphingomyelinase, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Adiponectin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Netrin-2, IL-17 RD, Albumin, Follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, Norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTPIB, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol glycan 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Sialoadhesin-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSMR beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1,FGF-23, LAMA4, Lipid-regulating protein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmoglein, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neuropilin, Plexin-2, EMMPRIN, Activin RIB, Semaphorin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Versican-3, Jagged-1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Retinoic factor, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Salivary agglutinin-6, Dendritic cell-associated C-type lectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Phosphatidylinositol glycan 5, CD6, Salivary agglutinin-2, Asparaginyl endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neurturin, ILT4,uPAR, Axl, WIF-1, IL-7 Ra, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Sirtuin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Plexin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Plexin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31RA, Arginase 1, POGLUT1, IL-1ra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Dystonin-3, Plexin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S,LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Phosphatidylinositol Glycan 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural Epithelial Stem Cell Protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Neogenin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neuronal Granulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endothelial Cell Specific Molecule, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Fibulin-1,Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Versican, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-g R1, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Versican-4, IL-2 Rg, MICA, Dopamine decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12 p40, Total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13. In some embodiments, the extracellular vesicle comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a,hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p,hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.

[0005] One aspect of the disclosure is the use of the composition produced by any of the methods of the disclosure to treat complex regional pain syndrome (CRPS) in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration. In some embodiments, the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration. In some embodiments, the subject has a reduction in Brief Pain Inventory (BPI) score after administration compared to prior to administration. In some embodiments, the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in BPI score after administration compared to prior to administration. In some embodiments, the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in BPI pain interference score after administration compared to prior to administration. In some embodiments, the subject has at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, at least a 85%, at least a 95%, or at least a 100% increase in range of motion assessment score after administration compared to prior to administration. In some embodiments, the subject has an increase in Jamar dynameter test assessment score after administration compared to prior to administration. In some embodiments, the increase in Jamar dynameter test assessment score is in the upper extremity. In some embodiments, the subject has grip strength equalization after administration. In some embodiments, the subject has at least a 5 kg, at least a 10 kg, at least a 15 kg, or at least a 20 kg increase in grip strength after administration compared to prior to administration. In some embodiments, the subject has at least a 50%, at least a 75%, at least a 100%, at least a 125%, at least a 150%, at least a 175%, at least a 200%, or at least a 210% increase in grip strength after administration compared to prior to administration. In some embodiments, the subject has an increase in grip strength in the affected limb. In some embodiments, the subject has an increase in grip strength in the contralateral limb. In some embodiments, the subject has an improvement in one or more of the following: limb range of motion, joint range of motion, sudomotor nerve changes, edema, hyperalgesia, and hypoaesthesia after administration compared to prior to administration. In some embodiments, the subject has an improvement in Short Form 36 Health Survey Questionnaire (SF-36) questionnaire score after administration compared to prior to administration. In some embodiments, the improvement in SF-36 questionnaire score comprises one or more of the following: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health. In some embodiments, the subject has chronic refractory pain in one or more upper or lower extremities. In some embodiments, the subject has not experienced progressively increasing or changing pain in the 30 days prior to administration.In some embodiments, the subject experiences a reduction in onset of pain, a reduction in swelling, and / or a reduction in burning sensation in the affected limb after administration compared to prior to administration. In some embodiments, the administration improves hair growth and / or nail growth in the affected limb of the subject. In some embodiments, the dose of the therapeutic MSC secretome composition administered to the subject is a cell equivalent dose of 0.7 to 7 million cells / kg. In some embodiments, the therapeutic MSC secretome composition comprises 4 x 10 10 to 10 x 10 10 cells / mL. In some embodiments, the therapeutic MSC secretome composition comprises 5 x 10 11 to 1.5 x 10 12 extracellular vesicles. In some embodiments, the composition is administered monthly for two or more months, or once every 1, 2, or 3 or more months. In some embodiments, the composition is administered twice. In some embodiments, the composition is administered 4 days apart.

[0006] One aspect of the disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles to treat complex regional pain syndrome (CRPS) in a subject in need thereof, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-. In some embodiments, the composition is administered intravenously to the subject. In some embodiments, the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has a reduction in a brief pain inventory (BPI) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

[0007] One aspect of the present disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles in the treatment of complex regional pain syndrome (CRPS) in a subject in need thereof, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration of the therapeutic MSC secretome composition. In some embodiments, the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has a reduction in a brief pain inventory (BPI) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 -In some embodiments, the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, selectin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, versican, TIMP-2, SLITRK5, FAP, neuregulin, DPPII, clAP-1, pentaxin 3, visfatin, neutral endopeptidase, albumin, galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF Rl, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, mesotransferrin, calreticulin, osteoglycin, asparaginyl endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, trypsin 3, SIRP alpha, and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1 R6 GSTM1, NUP85, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF R alpha, selectin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, thrombomodulin, perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, versican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spatacsin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3,IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTS L-1, Proerythrin, Plexin D1, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Sphingomyelinase, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Adiponectin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Nidogen-2, IL-17 RD, Albumin, Follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, Norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Glycan 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Sialoadhesin-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSMR beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipocallin, AIF, SorCS2, SULT2A1, CD39L2,Insulin R, HIF-1 alpha, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmoglein, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neuropilin, Plexin-2, EMMPRIN, Activin RIB, Semaphorin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Periostin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Versican-3, Jagged-1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Retinoic factor, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Salivary agglutinin-6, Dendritic cell-associated C-type lectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Phosphatidylinositol glycan 5, CD6, Salivary agglutinin-2, Asparaginyl endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neurturin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1,FABP2, Clustern B3, MEPE, Activin RIIA, ANG-2, Cochlin, Sirtuin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Agrin-1, GUSB, Reelin-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Agrin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31RA, Arginase 1, POGLUT1, IL-1ra, MerTK, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Agrin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13,ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Glypican 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural Epithelial Stem Cell Protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Neogenin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neuronal Granulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endothelial Cell Specific Molecule, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229,insulin, synaptophysin 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, brevican, NAP-2, PU.1, EDAR, ADAMTS13, kynureninase, PTH1R, IFN-g R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, Procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-type lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, syndecan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, semaphorin 4G, IL-12 p40, total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galectin-8, CA4, cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, or IL-13. In some embodiments, the extracellular vesicle comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p,hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p,hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p. In some embodiments, the composition is produced as follows: (a) culturing bone marrow-derived MSCs under conditions to produce an MSC conditioned medium: (i) an oxygen tension of less than 5%; and (ii) a medium having a pH of less than 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the medium is serum-free. In some embodiments, the medium has a glucose concentration of less than 4.5 g / L. In some embodiments, the subject has a decrease in BPI score of at least 10%, at least 20%, at least 30%, or greater than 30% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has a decrease in BPI pain interference score of at least 10%, at least 20%, at least 30%, or greater than 30% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has an increase in range of motion assessment score of at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 95%, or at least 100% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has an increase in Jamar dynameter test assessment score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the increase in Jamar dynameter test assessment score is in the upper extremities. In some embodiments, the subject has hand grip equalization after administration of the therapeutic MSC secretome composition. In some embodiments, the subject has an increase in hand grip of at least 5 kg, at least 10 kg, at least 15 kg, or at least 20 kg after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has an increase in hand grip of at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has an increase in hand grip of at least 5 kg, at least 10 kg, at least 15 kg, or at least 20 kg after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject has an increase in hand grip of at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.an increase in grip strength of at least 200% or at least 210%. In some embodiments, the subject has an increase in grip strength in the affected limb. In some embodiments, the subject has an increase in grip strength in the control limb. In some embodiments, the subject has an improvement in one or more of the following after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition: range of motion of the limb, range of motion of the joint, sweat gland regulatory nerve changes, edema, hyperalgesia, and hypoaesthesia. In some embodiments, the subject has an improvement in Short Form 36-Item Health Survey Questionnaire (SF-36) questionnaire scores after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the improvement in SF-36 questionnaire scores comprises one or more of the following: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health. In some embodiments, the subject has chronic, intractable pain in one or more upper or lower extremities. In some embodiments, the subject has not experienced progressively increasing or changing pain in the 30 days prior to administration of the therapeutic MSC secretome composition. In some embodiments, the subject experiences a reduction in onset of pain, reduction in swelling, and / or reduction in burning sensation in the affected limb after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition. In some embodiments, the administration of the therapeutic MSC secretome composition improves hair growth and / or nail growth in the affected limb of the subject. INCORPORATION BY REFERENCE

[0008] Each of the patents, publications, and non-patent literature cited in the present application is hereby incorporated by reference in its entirety as if each was individually and specifically incorporated by reference. In the event of a conflict between the disclosure of the present specification and the disclosure of a publication or patent incorporated by reference, the disclosure of the present specification shall control. BRIEF DESCRIPTION OF DRAWINGS

[0009] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description, which sets forth illustrative embodiments, in which the disclosed principles are utilized, and the accompanying drawings of which make use of the patented principles (also herein “Figures” or “FIG.”): Figure 1Box-whisker plots showing the mean Visual Analog Scale (VAS) pain assessment results over the 6-month study period. The box identifies the 25th and 75th percentiles, the inner line identifies the median and the '+' identifies the mean. The upper and lower whiskers represent the maximum and minimum data values, respectively. Independent data points are shown as single dots (·). (*p < 0.05; **p < 0.01).

[0010] Figure 2 Plots showing Brief Pain Inventory (A, pain interference, and B, pain severity) assessment results over the 6-month study period. Plot and p-value labels are as shown in Figure 1

[0011] Figure 3 Plots showing SF-36 assessment results over the 6-month study period. Categories are A) Pain, B) Vitality / Fatigue, C) Social Functioning, D) Bodily Functioning, E) Bodily Restrictions, F) Emotional Restrictions, G) Emotional Well-Being, and H) General Health. Plot and p-value labels are as shown in Figure 1

[0012] Figure 4 Range of motion assessment results over the 6-month study period are shown as bar plots.

[0013] Figure 5 Jamar Dynameter test assessment results over the 6-month study period are quantified as bar plots. DETAILED DESCRIPTION

[0014] I. DEFINITIONS As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the content clearly dictates otherwise. It is also to be noted that the term "or" is generally employed in its sense of "and / or" unless the content clearly dictates otherwise. The terms "and / or" and "any and all combinations thereof" and their grammatical equivalents as used herein can be used interchangeably. These terms can express that any combination is specifically contemplated. For illustrative purposes, the following phrases, "A, B, and / or C" or "A, B, C, or any and all combinations thereof" can mean "A alone; B alone; C alone; A and B; B and C; A and C; and A, B, and C." The term "or" can be used in a conjunctive or disjunctive sense unless the context specifically dictates otherwise.

[0015] ​​The term "about" or "approximately" can refer to within an acceptable error range for a particular value, which will vary from one measurement to another, e.g., a standard deviation from the mean. For example, "about" can mean within 1 standard deviation, or more than 1 standard deviation. Alternatively, "about" can mean ranges approximately 20%, approximately 10%, approximately 5%, or approximately 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the terms can mean within normally-expected variations of the value. When particular values are described in the application and claims, the term "about" should be assumed to refer to within an acceptable error range for that particular value unless otherwise stated.

[0016] Throughout this application, numerical values are expressed in range format. It should be understood that the description in range format is merely for convenience and brevity and that one of ordinary skill in the art, given the entire disclosure, would understand that a range includes every possible sub-range. As an example, a range of "1 to 6" can be understood to include the values of 1, 2, 3, 4, 5, and 6, which are the discrete values within the range. However, the range can also be understood to include values such as 1.1, 1.2, 1.3, 1.4, 1.5, and so on, within the range of 1 to 6. The same principle applies to ranges of intermediate values, such as 1 to 3.5. In this disclosure and claims, the term "range" means a range "between" two values inclusive of the values. Unless otherwise stated, the description of a range includes the end values of the range in their integer form as if the range were expressed in its discrete form (e.g., a range of 1 to 6 includes the values of 1 and 6). It will be further understood that the endpoints of the ranges are specifically included (in the case of "between") within the range and can be independently included or excluded in various embodiments. Unless otherwise stated, the description of a range includes the end values of the range in their integer form as if the range were expressed in its discrete form (e.g., a range of 1 to 6 includes the values of 1 and 6). It will be further understood that the endpoints of the ranges are specifically included (in the case of "between") within the range and can be independently included or excluded in various embodiments.

[0017] As used in the specification and claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in the specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of the disclosure.

[0018] The terms "some embodiments," "implementation," "a method of implementation," or "other embodiments" used in this specification refer to specific features, structures, or characteristics described in relation to an embodiment that are included in at least some embodiments of this disclosure, but not necessarily in all embodiments. To aid in understanding this disclosure, several terms and phrases are defined below.

[0019] Certain explicit details in this description are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known techniques and methods are not shown or described in detail to avoid unnecessary obscurity in the description of embodiments. Unless the context otherwise requires, throughout this specification and the following claims, the word “comprising” and variations thereof (such as “comprises”, “comprising”) are understood to have an open, inclusive meaning, i.e., “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed disclosure.

[0020] Suitable methods and materials are described below, but methods and materials similar to or equivalent to those described herein may be used in practice or experimentation with this disclosure.

[0021] II. Therapeutic Composition Disclosed are components used to make the disclosed compositions as well as compositions themselves used in the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds can not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular MSC secretome (including but not limited to MSC exosomes (with or without growth factors) referred to herein as extracellular vesicle isolation products (EVIPs)) is disclosed and discussed and various modifications that can be made to a variety of molecules including the MSC secretome are discussed, then each and every combination and permutation of the MSC secretome and possible modifications is specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of combining molecules A-D, then even if each is not individually recited, each is individually and collectively contemplated to be a combination. Likewise, any subset or combination of these is also specifically contemplated. Thus, for example, the sub-group of A-E, B-F, and C-E is also specifically contemplated. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

[0022] The main nutritional properties of MSCs are the secretion of growth factors and exosomes to induce cell proliferation and angiogenesis. Exosomes express mitogenic proteins such as transforming growth factor-a (TGF-a), TGFp, hepatocyte growth factor (HGF), epithelial growth factor (EGF), basic fibroblast growth factor (FGF-2), and insulin-like growth factor- 1 (IGF-1). These increase fibroblast, epithelial, and endothelial cell division. Vascular endothelial growth factor (VEGF), IGF-1, EGF, and angiopoietin-1 are released to recruit endothelial lineage cells and initiate vascularization. MSCs aid in the regenerative environment through paracrine mechanisms and modulate the regenerative environment through anti-inflammatory mechanisms and immunomodulatory mechanisms. In response to inflammatory molecules such as interleukin-1 (IL-1), IL-6, IL-2, IL-12, tumor necrosis factor-a (TNF-a), and interferon-g (INF-g), MSCs secrete a range of growth factors and anti-inflammatory proteins with complex feedback mechanisms in many types of immune cells. Key immunomodulatory cytokines include prostaglandin 2, TGF-131, HGF, SDF-1, nitric oxide, indoleamine 2,3-dioxygenase, IL-4, IL-10, IL-1 receptor antagonist, and soluble tumor necrosis factor-a receptor. MSCs prevent the proliferation and function of many inflammatory immune cells, including T cells, natural killer cells, B cells, monocytes, macrophages, and dendritic cells. Although MSCs across species are able to modulate T cell activity, the mechanisms are not identical across mammalian species.

[0023] The chronic inflammatory environment is characterized by a persistent imbalance of T helper cell types and macrophage types. MSC exosomes indirectly promote the shift of TH1 cells to TH2 cells by decreasing INF-g and increasing IL-4 and IL-10. Restored TH1 / TH2 balance shows improved tissue regeneration in cartilage, muscle, and other soft tissue injuries, alleviates symptoms of autoimmune diseases, and has anti-diabetic effects. Similarly, the decrease in INF-g and secretion of IL-4 promotes the shift of macrophages from M1 type (pro-inflammatory, anti-angiogenic, and tissue growth inhibitory) to M2 type (anti-inflammatory, pro-remodeling, and tissue healing), which is a desired effect for healing and regeneration of bone, muscle, and nerves.

[0024] Disclosed herein are complex compositions of secreted biomolecules (proteins, lipids, and ribonucleic acids) and / or extracellular vesicles comprising the biomolecules derived from mesenchymal lineage cells. In one aspect, disclosed herein are compositions comprising a therapeutically effective amount of a MSC secretome (e.g., such as, including but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the compositions) and one or more biomolecules (e.g., such as, peptides, polypeptides, proteins, siRNAs, shRNAs, and / or microRNAs (miRNAs)).

[0025] In some embodiments, the therapeutic composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more of any combination of, or all of the following proteins: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, selectin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, lumican, TIMP-2, SLITRK5, FAP, neublastin, DPPII, cIAPl, pentaxilin 3, visfatin, neuraminidase, albumin, galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF Rl, htPAPP-A, eNOS, MSP R, TPPl, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, mesotransferrin, calreticulin, osteomodulin, asparaginyl endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, tryptase 3, SIRP alpha, and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1 R6 GSTM1, NUP85, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF Ralpha, profilin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSFRa, thrombomodulin, aggrecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, skeletin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin 1, IGF-2R, ADAMTSL-1, proerythrin, plexin D1, DNMT3A, BCL-2, CL-P1, ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, neublastin, DPPII, cIAP-1, PDGF Rb, pentraxin 3, angiotensinogen, follistatin, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, visfatin, progranulin, PCSK2, GKN1, IL-18, neuraminidase, stabilin-2, IL-17 RD, albumin, follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galectin-1, troponin C, UNC5H3, FLRT2, CD314, semaphorin 6B, netrin-4, CD27 ligand, IL-20 R beta, semaphorin 6A, TSK, cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, galanin, activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, phosphatidylinositol glycan 2, MSP R, DSCAM, matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, ubiquitin+1, ANGPTL4, TWEAKR, nestin-1, CD2, kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, siglec-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), granzyme B, adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, lipocalin, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1 alpha, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, plexin A4, semaphorin 4D, ROBO2, PDX-1, APRIL, neuropilin, TMEM2, EMMPRIN, activin RIB, neuropilin 2, epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, lumican-2, sFRP-3, p53, EphB3, NCK1, semaphorin 7A, NKp80, prolactin, cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, pregnancy-associated plasma protein-2, decorin-3, jagged-1, AKR1C4, olfactomedin-2, osteoadherin, NKp44, thyroglobulin, IL-21R, chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, integrin alpha5, VAMP-2, FLRG, midkine, CD73, TRACP, proGRP, granzyme H, PRX2, p2'7, siglec-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testican 2, phosphatidylinositol-glycan 5, CD6, siglec-2, asparaginyl endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, podoplanin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, biglycan, neurotrophin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activin RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, nectin-1, GUSB, nidogen-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17 RC, MIP-3b, cystatin C, cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, enteropeptidase, cathepsin E, TSLP, TCN2, GDF-15, epiregulin, GRKS, PD-1, serpin A4, ADAM23, NOV, galectin-2, neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphotactin, cystatin SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27Ra, Fas, IL-4Ra, kallikrein 14, matrilin-3, Olig2, kallikrein 12, CA13, IL-9, syndecan-3, MPIF-1, cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CFXIV, PYY, HGF, I-TAC, semaphorin 4C, SorCS3, Tie-1, IL-31 RA, arginase 1, POGLUT1, IL-1ra, podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, siglec-9, ICAM-3, cystatin SA, galectin-4, pepsinogen II, desmocollin-3, syndecan-4, SCF, serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, galectin-9, vWF-A2, TACE, activin RIM, cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol glycan 1, LAP (TGFbl), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Neogenin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neuronal Thread Protein, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endothelial Cell Specific Molecule, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIFR alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Short Aggrecan, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma R1, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dendritic Cell Associated C-type Lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, P1GF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Perlecan-4, IL-2Rg, MICA, Dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Brain signal protein 4G, IL-12 p40, Total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E / M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, and IL-13.

[0026] Extracellular vesicles (EVs) are membrane-bound small spheres containing proteins and RNAs (exosomes are a subset thereof). Exosomes are small (e.g., 20-150 nm) diameter lipid bilayer vesicles secreted by cells to initiate paracrine communication. Other EV populations are derived directly from the plasma membrane or formed during apoptosis (apoptotic bodies). Disclosed herein are compositions comprising a therapeutically effective amount of a MSC secretome (e.g., such as, including but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition). In some embodiments, the therapeutic composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more of any combination of, or all of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p,hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p.

[0027] Exemplary microRNA contents can include human miRNA sequences hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-214-3p, and hsa-miR-27a-3p, all of which have binding sites for TMPRSS2 in the miRNA.

[0028] In some embodiments, the therapeutic composition comprises extracellular vesicles having CD63 + CD9 - CD81 - phenotype. In some embodiments, at least 70, 75, 80, 85, 90, 91, 92, 93, 94, or 95% of the extracellular vesicles in the therapeutic composition are CD63 + CD9 - CD81 - . In some embodiments, at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, or 95% of the extracellular vesicles in the therapeutic composition are CD9 - . In some embodiments, at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, or 95% of the extracellular vesicles in the therapeutic composition are CD81 - .

[0029] In some embodiments, the MSCs cultured to produce the therapeutic composition have the ability to undergo in vitro tri-lineage differentiation toward adipocyte, osteoblast, and chondrocyte phenotypes. In some embodiments, the MSCs are positive for CD73, CD105, CD166, and CD90, and negative for CD14, CD31, CD34, and CD45.

[0030] It is understood and contemplated herein that the MSC secretome comprises exosomes and growth factors. The growth factors and exosomes can be heterologous or homologous. The growth factors and exosomes can be derived from any cell in the human body, such as from ectodermal cells, endodermal cells, or mesodermal cells. For example, the MSC secretome can comprise mesenchymal stem cell (MSC)-derived growth factors, MSC-derived exosomes, or both MSC-derived growth factors and exosomes. In some embodiments, the method further comprises adding at least one additive having exosomes and growth factors. Specifically, MSCs under appropriate wound healing conditions can produce suitable therapeutic agents, such as exosomes and growth factors, which can provide treatment for inflammatory lung diseases. In one aspect, disclosed herein is a composition, wherein the MSC secretome composition further comprises prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-131), hepatocyte growth factor (HGF), stromal cell-derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3-dioxygenase, interleukin-4 (IL-4), IL-6, interleukin-10 (IL-10), IL-1 receptor antagonist, and soluble TNF-a receptor, insulin-like growth factor, fibroblast growth factors (FGF) 1-23 (especially, FGF1 and FGF2), bone morphogenetic proteins (BMP) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a) macrophage stimulating protein (MSP), platelet-derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), insulin, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF, estrogen, and / or thyroid hormone.

[0031] Embodiments of the therapeutic compositions described herein can include proteins and microRNAs, some of which can be embedded in or surrounded by a lipid membrane to generate vesicles ranging in size from about greater than 20 nm to about 200 nm in size. The number of vesicles within the composition can be about 1 million to about 1 trillion vesicles per mL when suspended, or about 10 million to about 1 million when formulated as a lyophilized powder.

[0032] A. Delivery of drug carriers / drug products The therapeutic compositions described herein can be administered in vivo in a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the nucleic acid or vector without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier is naturally selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the individual, as is well known to those of skill in the art. The composition can be administered orally, parenterally (e.g., intravenous), by injection into a muscle, by injection into the peritoneal cavity, transdermally, extracorporeally, topically, etc., including local intranasal administration or administration by inhalation. As used herein, "local intranasal administration" means delivery of the composition into the nose and nasal passages through one or both nostrils, and can include delivery through a spray mechanism or droplet mechanism, or by nebulization of the nucleic acid or vector.

[0033] Administration of the composition by inhalation can be delivered through the nose or mouth via a spray or droplet mechanism, such as, for example, a metered dose inhaler, a dry powder inhaler, a nebulizer, a vaporization device, etc. It can also be delivered directly to any region of the respiratory system (e.g., the lungs) via a cannula. The exact amount of composition required will vary from subject to subject, depending on the species, age, weight, and general condition of the subject, the severity of the condition being treated, the mode of administration, and the like.

[0034] If parenteral administration of the composition is used, it is typically characterized by injection. The injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving or suspending in liquid prior to injection, or as emulsions. Parenteral administration can involve the use of sustained-release or continuous-release systems, so as to maintain a constant dosage.

[0035] Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th Ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic. Examples of pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer's solution, and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained-release preparations, such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those skilled in the art that certain carriers can be more preferred depending on, for instance, the route of administration and the concentration of the composition being administered.

[0036] Pharmaceutical carriers are known to those skilled in the art. These most typically will be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions of physiological pH. The compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those in the art.

[0037] In addition to the selected molecule, the pharmaceutical composition can include a carrier, thickening agent, diluent, buffer, preservative, surface active agent, and the like. The pharmaceutical composition can also include one or more active ingredients, such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.

[0038] The pharmaceutical composition can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including ophthalmic, vaginal, rectal, intranasal), oral, via inhalation, or parenteral, e.g., by intravenous drips, subcutaneous, intraperitoneal, or intramuscular injection. The disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.

[0039] Formulations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions. Examples of nonaqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous vehicles include water, alcoholic / aqueous solutions, emulsions or suspensions including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, glucose and sodium chloride, lactated Ringer's solution, or fixed oils. Intravenous vehicles include fluids and nutrient supplements, electrolyte supplements such as Ringer's dextrose-based solutions, and the like. Preservatives and other additives such as antimicrobials, antioxidants, chelating agents, and inert gases can also be present. Formulations for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like can be necessary or desirable.

[0040] Compositions for oral administration can include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable.

[0041] Some compositions can potentially be administered in the form of a pharmaceutically acceptable acid addition salt or base addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and an organic base such as mono-, di-, trialkylamines and arylamines and substituted ethanolamines.

[0042] B. Therapeutic uses The effective dose and schedule of administration for administering the compositions can be determined empirically and making such determinations is within the skill in the art. The dose range for administering the compositions is sufficiently broad to produce the desired effect in which the symptoms of the condition are affected. The dose should not be so large as to cause adverse side effects, such as unwanted cross-reactions, allergic reactions, and the like. Generally, the dose will vary with the age, condition, sex and extent of the disease in the patient, the route of administration or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The individual physician can determine the dosage for a particular patient. The dosage can vary and can be administered in one or more dose administrations daily, for one or several days, and / or in one or more dose administrations monthly, for two or more months, or once every 1, 2, or 3 months or more. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0043] C. Mesenchymal stem cells and therapeutic secretome compositions The therapeutic compositions disclosed herein utilize the MSC secretome and / or growth factors derived from mesenchymal stem cells (MSCs). In one aspect, disclosed herein are MSC secretome compositions (including, but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the compositions). The therapeutic compositions can be used for the treatment, inhibition, reduction, decrease, amelioration, and / or prevention of conditions such as, for example, complex regional pain syndrome (CRPS).

[0044] MSCs are multipotent cells capable of differentiating into multiple cell types including muscle cells, chondrocytes, adipocytes, and osteoblasts. Typically, these cells can be found in the placenta, umbilical cord blood, adipose tissue, bone marrow, or amniotic fluid, including perivascular tissue. As used herein, "MSC" refers to non-terminally differentiated cells including, but not limited to, multipotent stem cells, multipotent stromal cells, stromal vascular fraction cells, pericytes, perivascular cells, stromal cells, multipotent cells, multipotent cells, adipose-derived fibroblast-like cells, adipose-derived stromal vascular fraction, adipose-derived MSCs, bone marrow-derived fibroblast-like cells, bone marrow-derived stromal vascular fraction, bone marrow-derived MSCs, tissue-derived fibroblast-like cells, adult stem cells, adult stromal cells, keratinocytes, and / or melanocytes.

[0045] In addition to having differentiation potential, MSCs have immunomodulatory capacity that results in the expression of many different cytokines and growth factors. As used herein, "MSC preparation" or "MSC secretome composition" refers to a composition comprising MSC growth factors, MSC exosomes, extracellular vesicles, extracellular vesicle isolation products (EVIPs), or cell-free extracts of MSCs and / or MSC lysates obtained from human MSCs, fibroblast-like cells, and non-human animal MSCs including, but not limited to, MSCs from horses, cows, pigs, sheep, non-human primates, dogs, cats, rabbits, rats, and mice. In embodiments, the MSCs can be derived from the patient to whom the composition will be applied (autologous) or from another individual (allogeneic). The MSCs can be cultured for expansion to collect conditioned media or to increase the number of cells of the lysate or used fresh prior to incorporation into the compositions of the present disclosure. The MSC secretome composition, including but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or compositions comprising extracellular vesicles, can comprise about 0.00001 to about 20 wt.%, such as from about 0.01 to about 10 wt.% of mesenchymal stem cell (MSC) extract, MSC exosomes, or MSC growth factor preparation. The MSC preparation can comprise MSC conditioned media or MSC lysates from MSCs cultured for expansion. In some embodiments, the composition can further comprise from about 0.01 to about 10 wt.% of cell-free media conditioned by MSCs or MSC lineage cells, wherein the cells are cultured under normal hyperoxic culture conditions or under artificial wound healing conditions.

[0046] As disclosed herein, MSCs used to produce the disclosed MSC additives, including the MSC secretome composition frozen or powdered additives, can be selectively stimulated to produce MSC growth factors, secretomes, cytokines, chemokines, mesenchymal stem cell proteins, peptides, glycosaminoglycans, extracellular matrix (ECM), proteoglycans, secretomes, and exosomes. The growth factors and exosomes can be derived from any cell in the human body, such as from ectodermal cells, endodermal cells, or mesodermal cells. As used herein, MSC growth factors include, but are not limited to, prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-(31), hepatocyte growth factor (HGF), stromal cell-derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3-dioxygenase, interleukin-4 (IL-4), IL-6, interleukin-10 (IL-10), IL-1 receptor antagonist, and soluble TNF-a receptor, insulin-like growth factor, fibroblast growth factors (FGF) 1-23 (especially FGF1 and FGF2), bone morphogenetic proteins (BMP) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a) macrophage stimulating protein (MSP), platelet-derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), insulin, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and hormones including estrogen and thyroid hormone.

[0047] Culturing MSCs can occur under wound healing and / or hypoxic conditions. Hypoxic conditions can include about 1% to about 5% oxygen, reduced or no serum, reduced glucose, or various combinations of these elements. The combination of reduced nutrients and metabolites can trigger the cultured cells to produce wound healing and anti-inflammatory ECM proteins and growth factors to direct tissue healing. Directing tissue healing can be in the form of new ECM proteins, such as collagen and glycosaminoglycans (GAGs), as well as growth factors and cytokines. In one aspect, the MSC preparation, such as for example, the MSC secretome composition, includes MSC growth factors, MSC exosomes, and / or a cell extract of MSCs or MSC lysate obtained from MSCs cultured under standard high oxygen culture conditions (e.g., 21% oxygen) or MSCs cultured under artificial wound healing conditions, such as for example, 0.1% to about 5% oxygen.

[0048] As disclosed herein, artificial wound healing conditions mimic the growth conditions in real wounds, where reduced nutrient supply and reduced waste removal are typically caused by interruption of local blood circulation. This creates a harsh environment for the cells until new blood vessels are generated and blood circulation is restored. Thus, artificial wound healing conditions for culturing MSCs can include one or more of the following growth conditions: reduced glucose availability, reduced oxygen tension, reduced pH, and increased temperature.

[0049] In some embodiments, glucose availability can be reduced relative to a normal control (e.g., 4.5 g / L). Glucose in a modified medium that reduces glucose but does not harm the cells can be reduced by 0 to 50%, more preferably glucose is reduced by about 5% to 40%. For example, MSC artificial wound healing culture conditions can include a reduction in glucose of about 5% to about 15%, about 10% to about 20%, about 15% to about 25%, about 20% to about 30%, or about 25% to about 35%. In some embodiments, glucose is present at a concentration of about 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 g / L, or at a concentration within a range between any two of these values. In some embodiments, glucose is present at a concentration of less than or not more than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5 g / L.

[0050] In some embodiments, the oxygen tension can be reduced to oxygen levels that are hypoxic conditions. Normal atmospheric oxygen is about 21%, and any reduction is considered hypoxic. Thus, in one aspect, the MSCs can be cultured at 0.0% to 20.9% oxygen, from about 0.1% to about 0.5% oxygen, from about 0.1% to about 2.0%, from about 0.1% to about 5.0% oxygen, from about 0.5% to 5.0%, from about 1.0% to about 10% oxygen, from about 5.0% to about 10.0% oxygen; and about 10.0% to about 15.0%. Hypoxic conditions can be one aspect of artificial wound healing conditions.When MSCs are cultured to produce a therapeutic secretome composition comprising extracellular vesicles and / or growth factors secreted by MSCs, the oxygen tension can be between about 0.5% to 20.5% oxygen, for example, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, or 20.0% oxygen, or a range between any two of these values.

[0051] The pH can also decrease during MSC culture. The pH can be from about 6.0 to about 7.4, for example, from 6.0 to about 6.4, from about 6.2 to about 6.4, from about 6.2 to about 6.6, from about 6.4 to about 6.6, from about 6.4 to about 6.8, or from about 6.6 to about 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, or 7.4.

[0052] The temperature of the culture environment can be elevated relative to physiologically steady state temperature (e.g., 37°C). In one aspect, the culture conditions for MSCs can include from about 35°C to about 39°C, from about 35°C to about 36°C, from about 36°C to about 37°C, from about 37°C to about 38°C, from about 38°C to about 39°C, from about 39°C to about 40°C. In one aspect, the culture temperature can be 35.0, 35.1, 35.2, 35.3, 36.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0°C.

[0053] In some embodiments, the culture medium is serum-free. In some embodiments, the serum-free medium comprises platelet lysate. In some embodiments, the platelet lysate is human platelet lysate (HPL). In some embodiments, the serum-free medium comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by volume of HPL, or a range between any two of these values. In some embodiments, the medium comprises from 8% to 12%, 5% to 15%, or 9% to 11% by volume of HPL.

[0054] In one aspect, the MSC secretome composition (including, but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or compositions comprising extracellular vesicles) can further include a protective coating (such as, for example, cryoprotectant oligosaccharides and protein solutions) to reduce degradation of the growth factors. It can be appreciated and contemplated herein that the protective coating can be engineered as a polymer. A "polymer" refers to a relatively high molecular weight organic compound, natural or synthetic, whose structure can be represented by repeating small unit monomers. Non-limiting examples of polymers include polyethylene, rubber, cellulose. Synthetic polymers are generally formed from the addition or condensation polymerization of monomers. The term "copolymer" refers to a polymer formed from two or more different repeating units (monomer residues). For example, and without limitation, a copolymer can be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer. It is also contemplated that, in certain aspects, individual blocks of a block copolymer can themselves comprise a copolymer. The term "polymer" encompasses all forms of polymers, including, but not limited to, natural polymers, synthetic polymers, homopolymers, heteropolymers or copolymers, addition polymers, and the like. In one aspect, the gel matrix can include a copolymer, a block copolymer, a diblock copolymer, and / or a triblock copolymer. In one aspect, the protective coating can include a biocompatible polymer. In one aspect, the biocompatible polymer can be cross-linked. Such polymers can also be used to slowly release fat browning agents and / or fat modulating agents into the tissue. Biocompatible polymers as used herein include, but are not limited to, polysaccharides; hydrophilic polypeptides; polyamino acids such as poly-L-glutamic acid (PGS), gamma-polyglutamic acid, poly-L-aspartic acid, poly-L-serine, or poly-L-lysine; polyalkylene glycols and polyalkylene oxides such as polyethylene glycol (PEG), polypropylene glycol (PPG), and polyethylene oxide (PEO); poly(oxyethylated polyols); polyolefins; polyvinylpyrrolidone); poly(hydroxyalkyl methacrylamides); poly(hydroxyalkyl methacrylates); polysaccharides; poly(hydroxy acids); poly(vinyl alcohol), polyhydroxy acids such as poly(lactic acid), polyglycolic acid, and poly(lactic-co-glycolic acid); polyhydroxyalkanoates such as poly-3-hydroxybutyrate or poly-4-hydroxybutyrate; polycaprolactone; poly(ortho esters); polyanhydrides; poly(phosphazenes); poly(lactide-co-caprolactone); polycarbonates such as tyrosine polycarbonates; polyamides (including synthetic and natural polyamides), polypeptides, and poly(amino acids); polyesteramides; polyesters; poly(p-dioxanone); poly(alkylene alkylate); hydrophobic polyethers; polyurethanes; polyether esters; polyacetals; poly cyanoacrylates; polyacrylates; polymethyl methacrylate; polysiloxanes; poly(oxyethylene) / poly(oxypropylene) copolymers; polyketal; polyphosphoesters; polyhydroxyvalerate; polyalkylene oxalate; polyalkylene succinate; poly(maleic acid) and copolymers thereof.Biocompatible polymers can also include polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols (PVA), methacrylate PVAs (m-PVA), polyvinyl ethers, polyvinyl esters, polyhaloethylenes, polyvinylpyrrolidones, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylates and methacrylates, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxyethyl cellulose, cellulose triacetate, sodium cellulose sulfate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly( vinyl alcohol), poly(vinyl acetate), polyvinyl chloride, polystyrene, and polyvinylpyrrolidone, derivatives thereof, linear and branched copolymers and block copolymers thereof, and blends thereof. Exemplary biodegradable polymers include polyesters, poly(ortho esters), polyvinylamines, poly(caprolactone), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(anhydrides), poly(acrylic acid), polyglycolides, poly(urethanes), polycarbonates, polyphosphoesters, polyphosphazenes, derivatives thereof, linear and branched copolymers and block copolymers thereof, and mixtures thereof.

[0055] In some embodiments, the protective coating comprises a monosaccharide and a carbohydrate structure of a carbohydrate polymer, such as a disaccharide or a polysaccharide, including but not limited to non-reducing polysaccharides or disaccharides, and any combination thereof. Examples of carbohydrates that can be used in the protective coating include glucose, aldoses (D-allose, D-altrose, D-mannose, etc.), glucopyranose, pentahydroxyhexanals, a-D-glucopyranosyl-D-glucose, a-D-glucopyranosyl-dihydrate, polymers of P-D-glucopyranosyl units, P-D-fructopyranosyl a-D-glucopyranoside (anhydrous / dihydrate), f3-D-galactopyranosyl-D-glucose, a-D-glucopyranosyl-a-D-glucopyranoside (anhydrous / dihydrate), galactose, pentoses (ribose, xylose, lyxose), dextrose, dodeca monodeca hydrate, fructose, sucrose, lactose, maltose, trehalose, agarose, D-galactosyl-0-(1-4)-deoxy-L-galactosyl, cellulose, polymers of P-D-glucopyranosyl units, and starch, as well as polyhydroxy alcohols, polyols, sugar alcohols, erythritol, glycols, glycerol, xylitol, and sorbitol.

[0056] In some embodiments, the protective coating contains a biocompatible and / or biodegradable polyester or polyanhydride, such as poly(lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid). The particles can comprise one or more of the following: homopolymers comprising glycolic acid units (herein referred to as "PGA"), and lactic acid units (such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D,L-lactide 5, herein collectively referred to as "PLA"), and caprolactone units (such as poly(e-caprolactone), herein collectively referred to as "PCL"); and copolymers comprising lactic acid and glycolic acid units, such as various forms of poly(lactic-co-glycolic acid) and poly(lactide-co-glycolide), characterized by a ratio of lactic acid:glycolic acid, herein collectively referred to as "PLGA"; and polyacrylates and derivatives thereof. Exemplary polymers also include copolymers of polyethylene glycol (PEG) and the aforementioned polyesters, such as various forms of PLGA-PEG or PLA-PEG copolymers, herein collectively referred to as "PEGylated polymers." In certain embodiments, the PEG region can be covalently associated with the polymer via a cleavable linker to produce a "PEGylated polymer." In one aspect, the polymer comprises at least 60%, 65%, 70%, 75%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of acetal side groups.

[0057] The triblock copolymers disclosed herein include a core polymer such as, for example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), polyvinyl pyrrolidone-vinyl acetate copolymer, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), poly(lactic-co-glycolic acid) (PLGA), cellulose derivatives such as hydroxymethylcellulose, hydroxypropylcellulose, and the like. Examples of diblock copolymers that can be used in the protective coating disclosed herein include the following polymers such as, for example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), polyvinyl pyrrolidone-vinyl acetate copolymer, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), poly(lactic-co-glycolic acid) (PLGA).

[0058] In one aspect, the protective coating comprises (i.e., encapsulated, the encapsulated composition can further include lecithin or hydrolyzed lecithin as a carrier or as an encapsulating material. As used herein, lecithin and / or hydrolyzed lecithin coating includes a coating comprising phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and phosphatidic acid. The source of lecithin can be of plant or animal origin.

[0059] In one aspect, any of the polymers, monosaccharides, disaccharides, or polysaccharides used to form the protective coating by placing the MSC additive in an encapsulating solution can be at an appropriate concentration to form the protective coating. For example, the polymers, monosaccharides, disaccharides, or polysaccharides can be at any concentration between 0.01 mM and 10.0 M, for example, from about 0.01 M to about 0.1 M, from about 0.1 mM to about 1.0 M, from about 1.0 M to about 10.0 M.

[0060] In one aspect, the MSC secretome compositions disclosed herein (including, but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the compositions) can include any known ingredient typically found in the pharmaceutical arts, such as an agent for anti-free radicals; a bactericide; a chelating agent; a preservative; an alkalizing or acidifying agent; a fragrance; a surfactant; a filler; a natural product or extract of a natural product, such as aloe vera or green tea extract; a vitamin; or a coloring material. Other ingredients that can be combined with the powder can include an antioxidant, which can be selected from a variety of antioxidants. Suitable antioxidants include vitamins, such as vitamin C (L-ascorbic acid, magnesium ascorbate-2 phosphate, ascorbyl palmitate, tetrahexyldecyl ascorbate), vitamin E (tocotrienols), vitamin A (retinol, retinal, retinoic acid, provitamin A carotenoids such as beta-carotene), N-acetyl glucosamine or other derivatives of glucosamine. Other ingredients can include at least one essential fatty acid, such as S2-3, S2-6, and S2-9 polyunsaturated fatty acids, such as linoleic acid (LA), gamma-linoleic acid (GLA), alpha-linoleic acid (ALA), dihomo-gamma-linolenic acid (DGLA), arachidonic acid (ARA), and the like. The fatty acids can be derived from a variety of sources, including evening primrose oil, black currant oil, borage oil, or GLA modified safflower seed. Other ingredients can include a platelet-rich fibrin matrix, at least one ingredient that supports ECM production and hyaluronic acid production, such as N-acetyl glucosamine or other derivatives of glucosamine, ultra-low molecular weight (ULMW) hyaluronic acid, chondroitin sulfate, or keratin sulfate.

[0061] Producing a MSC secretome composition can include culturing MSCs collected from a donor to generate a culture medium under culture conditions, in some embodiments, the culture conditions include reduced oxygen and nutrients; stimulating the cultured cells to selectively secrete desired anti-inflammatory proteins, peptides, glycosaminoglycans, proteoglycans, exosomes, and secretomes by adjusting cell growth conditions; collecting, pooling the coagulation mixture with an encapsulation solution, and freezing the coagulation mixture, wherein the coagulation mixture comprises exosomes, peptides, proteins, cytokines, growth factors, extracellular matrix (ECM), proteoglycans, glycosaminoglycans; and chemokines selected from human MSCs, animal MSCs, multipotent stromal cells, and fibroblasts; pooling the coagulation mixture with an encapsulation solution, such as an oligosaccharide, like a trehalose solution or a protein solution, and freezing the mixture; and lyophilizing or freeze-drying the frozen mixture to generate a dry powder. Alternatively, MSCs can be lysed to collect all MSCs from the culture process to generate an extracted lysate; concentrating the extracted lysate and pooling the extracted lysate with an encapsulation solution, such as an oligosaccharide, like a trehalose solution or a protein solution, and freezing the mixture; and lyophilizing or freeze-drying the frozen mixture to generate a dry powder. The powder contains an analgesic MSC secretome and exosomes and a highly concentrated collection of extracellular matrix components specific to anti-inflammation.

[0062] The method further includes filtering-sterilizing, concentrating, freezing, or freeze-drying the MSC conditioned medium. In addition, the MSC culture medium can be combined with a cryoprotective agent prior to freezing.

[0063] There are various methods of lysing MSCs. Lysis can be achieved by the addition of a hypotonic solution or repeated freeze-thaw methods that disrupt the cell membrane. In addition, cells can be lysed while attached to a culture surface or in suspension. Cells can also be released enzymatically and / or lysed by mechanical homogenization.

[0064] Stimulating MSCs to selectively secrete desired anti-inflammatory proteins, peptides, glycosaminoglycans, proteoglycans, exosomes, and secretomes can be achieved by adjusting cell growth conditions, such as cell confluency, media additives, nutrient additives, oxygen levels, length of culture in these conditions, number of cell passages, or combinations thereof.

[0065] III. Methods of treating complex regional pain syndrome (CRPS) In some embodiments, the therapeutic compositions disclosed herein are used in a method of treating complex regional pain syndrome (CRPS) in a subject. Any of the therapeutic compositions described herein can be used in such a method. In some embodiments, the subject has chronic refractory pain in one or more upper or lower extremities. In some embodiments, the subject has not experienced progressively increasing or changing pain in the 30 days prior to treatment. In some embodiments, the subject experiences one or more of the following as a response to treatment: decreased pain, increased energy, decreased fatigue, increased social functioning, increased emotional well-being, increased physical functioning, decreased change in sudomotor nerves, decreased edema, decreased hyperalgesia, decreased hypoalgesia, improved motion, and / or improved grip strength. In some embodiments, the subject experiences an increase in range of motion in one or more joints as a response to treatment. In some embodiments, the subject experiences a decrease in pain onset, swelling, and / or burning as a response to treatment. In some embodiments, the treatment improves hair growth and / or nail growth in the affected limb of the subject. In some embodiments, the subject experiences a decrease in pain severity and / or a decrease in pain interference as a response to treatment.

[0066] In some embodiments, the investigational product of the present disclosure is administered to a CRPS patient in two doses. In some embodiments, 15 mL of the investigational product is administered per dose. In some embodiments, the investigational product is administered by intravenous infusion. In some embodiments, the investigational product is administered on consecutive days. In some embodiments, the investigational product is administered 1, 2, 3, 4, 5, 6, or 7 days apart. In some embodiments, the effects of the treatment last for at least 6 months or at least one year.

[0067] Also disclosed herein are methods of treating CRPS in a subject, comprising administering to the subject a composition comprising secreted extracellular vesicles containing a composition of any combination of proteins and / or miRNAs selected from the group consisting of: ferritin, NUP85, LAMP2, GPR115, Serpin F1, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Selectin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Versican, TIMP-2, SLITRK5, FAP, Sphingomyelinase, DPPII, cIAP-1, Pentraxin 3, Adiponectin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF R I, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Asparaginyl endopeptidase, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, and Syndecan-4, and at least one protein selected from the group consisting of: ferritin, IGFBP-4 IL-1 R6 GSTM1, NUP85, Transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, Ephrin-A4, CD109, Serpin F1, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Selectin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Versican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spondin,ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Proerythrin, Plexin D1, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Sphingomyelinase, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Adiponectin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Netrin-2, IL-17 RD, Albumin, Follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, Norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTPIB, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Glycan 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Sialoadhesin-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4,lipocalin, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1 alpha, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmoglein, SOX9, ST6GAL1, MEP1B, CD99-L2, plexin A4, semaphorin 4D, ROBO2, PDX-1, APRIL, neuropilin, plexin-2, EMMPRIN, agrin RIB, semaphorin 2, ephrin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, endomucin-2, sFRP-3, p53, EphB3, NCK1, semaphorin 7A, NKp80, prolactin, cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, pregnancy-associated plasma protein-2, decorin, jagged 1, AKR1C4, olfactomedin-2, osteoadherin, NKp44, thyroglobulin, IL-21R, chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, integrin alpha 5, VAMP-2, FLRG, Ret protooncogene, CD73, TRACP, proGRP, granzyme H, PRX2, p2'7, siglec-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testican 2, phosphatidylinositol-glycan 5, CD6, siglec-2, asparaginyl endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, podoplanin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, biglycan, neurotrophin, ILT4, uPAR, Axl, WIF-1,IL-7 Ra, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Sirtuin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Plexin-1, GUSB, Nestin-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 Ra, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Plexin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR a-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 Ra, Arginase 1, POGLUT1, IL-1 ra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Plexin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFA5, Galectin-9, vWF-A2, TACE, Activin RUB, Cathepsin S, LDL R,BMPR-IA, OX40, IL-3 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDT5, ROR2, EphB4, Phosphatidylinositol Glycan 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-bl, FABP4, RGM-A, RELT, TrkC, C5a, SREC-I, Neural Epithelial Stem Cell Protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Neogenin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neuronal Granulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RH, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCFR, Thromboregulin-5, IL-1 MI, Neuropilin-2, Cadherin-13, E-selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endothelial Cell Specific Molecule, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Fibulin-1, Reg4, ILT2, Mer,TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, synaptophysin 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, brevican, NAP-2, PU.1, EDAR, Adamalysin 13, Kynureninase, PTH1R, IFN-g R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Versican-4, IL-2 Rg, MICA, Dopamine decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12 p40, Total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, IL-13, hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p,hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p,hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p and hsa-miR-99b-5p. ,

[0068] In some embodiments, the therapeutic product is administered at a cell equivalent dose range of 0.7 to 7 million cells / kg. In some embodiments, the therapeutic product is administered at a cell equivalent dose of at least about, and at most about, or about 0.2, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, or 12.0 million cells / kg, or any two of these values. In some embodiments, the product is administered at a dose providing 9 x 10 11 Up to 1.2x10 12 One extracellular vesicle or 5x10 11 Up to 1.5x10 12 6x10 11 Up to 1.4x10 12 7x10 11 Up to 1.3x10 12 8x10 11 Up to 1.2x10 12 Or 8x10 11 Up to 1.3x10 12 A dose of extracellular vesicles is administered. In some embodiments, the product is administered to provide at least or at most 5 x 10-1 11 6x10 11 7x10 11 8x10 11 9x10 11 1x10 12 1.1x10 12 1.2x10 12 1.3x10 12 1.4x10 12 Or 1.5x10 12 A dose of 1 extracellular vesicle is administered. In some embodiments, the therapeutic product comprises 6 x 10-1 10 Up to 8x10 10 5x10 10 Up to 9x10 10 4x10 10 Up to 10x10 10 5.5x10 10 Up to 8.5x1010 or 6 x 10 10 to 8.5 x 10 10 cells / ml. In some embodiments, the therapeutic product comprises 6 x 10 10 to 8 x 10 10 extracellular vesicles or cells per milliliter and is administered in a dose of 10 to 20 ml. In some embodiments, the therapeutic product comprises 6 x 10 10 to 8 x 10 10 extracellular vesicles or cells per milliliter and is administered in a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml or a range between any two of these values.

[0069] In some embodiments, the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration. For example, the subject can have at least a 50%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% reduction in a VAS score after administration compared to prior to administration. In some embodiments, the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration.

[0070] In some embodiments, the subject has a reduction in Brief Pain Inventory (BPI) score after administration compared to prior to administration. In some embodiments, the subject has a reduction in BPI score of at least 10%, at least 20%, at least 30%, or greater than 30% after administration compared to prior to administration. For example, the subject can have a reduction in BPI score of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% after administration compared to prior to administration. In some embodiments, the subject has a reduction in BPI pain interference score of at least 10%, at least 20%, at least 30%, or greater than 30% after administration compared to prior to administration. For example, the subject can have a reduction in BPI pain interference score of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% after administration compared to prior to administration.

[0071] In some embodiments, the subject has an increase in range of motion assessment score of at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 95%, or at least 100% after administration compared to prior to administration. For example, the subject can have an increase in range of motion assessment score of at least 50%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or at least 100% after administration compared to prior to administration.

[0072] In some embodiments, the subject has an increase in Jamar dynameter test assessment score after administration compared to prior to administration. In some embodiments, the increase in Jamar dynameter test assessment score is in the upper extremity. In some embodiments, the subject has grip strength equalization after administration. In some embodiments, the subject has an increase in grip strength of at least 5 kg, at least 10 kg, at least 15 kg, or at least 20 kg after administration compared to prior to administration. In some embodiments, the subject has an increase in grip strength of at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, or at least 210% after administration compared to prior to administration. For example, the subject can have an increase in grip strength of at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or at least 300% after administration compared to prior to administration. In some embodiments, the subject has an increase in grip strength in the affected limb. In some embodiments, the subject has an increase in grip strength in the contralateral limb. In some embodiments, the subject has an improvement in one or more of the following after administration compared to prior to administration: limb range of motion, joint range of motion, sudomotor nerve changes, edema, hyperalgesia, and hypoaesthesia.

[0073] In some embodiments, the subject has an improvement in Short Form 36-Item Health Survey Questionnaire (SF-36) questionnaire score after administration compared to prior to administration. In some embodiments, the improvement in SF-36 questionnaire score includes one or more of the following: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health. In some embodiments, the subject has chronic refractory pain in one or more upper or lower extremities. In some embodiments, the subject has not experienced progressively increasing or changing pain in the 30 days prior to administration. In some embodiments, the subject experiences a reduction in pain flare, reduction in swelling, and / or reduction in burning sensation in the affected limb after administration compared to prior to administration. In some embodiments, administration improves hair growth and / or nail growth in the affected limb of the subject.

[0074] In some embodiments, subjects that can be treated with the therapeutic products and methods described herein can include any subject having or diagnosed with CRPS. In some embodiments, the subject can include a mammal. In some embodiments, the subject can include a human. In some embodiments, the subject can include a non-human mammal. Non-limiting examples of non-human mammals can include non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cows, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; experimental animals including rodents, such as mice, rats, and guinea pigs, and the like.

[0075] IV. Examples The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.); however, some errors and deviations can have occurred. Unless indicated otherwise, these examples are provided solely for illustrative purposes, and do not limit the scope of the claims as provided herein.

[0076] A. Example 1 - Generation of Therapeutic Compositions MSC secretome therapeutic compositions are prepared by the following method: human bone marrow-derived MSCs are cultured in culture vessels with growth media to expand the MSC population. The growth media is then removed and the cells are washed with PBS. The MSCs are then cultured under hypoxic conditions in a glucose-reduced media at a pH less than 7.0. The conditioned media is then collected and diafiltered, followed by filter sterilization. The method of production of the therapeutic product is performed under Good Manufacturing Practice and Current Good Tissue Practice.

[0077] The tetraspanin profile of the extracellular vesicles present in the therapeutic composition was determined and it was found that greater than 95% of the extracellular vesicles present in the therapeutic composition were CD63 + CD9 - CD81 - .

[0078] The protein content of the therapeutic product was determined and it was found that the following proteins were present: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, selectin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, versican, TIMP-2, SLITRK5, FAP, neuregulin, DPPII, cIAPl, pentaxin 3, visfatin, neutral endopeptidase, albumin, galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF Rl, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, meso- versican, calreticulin, osteoglycin, asparaginyl endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, tryptase 3, SIRP alpha and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1 R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF R alpha, selectin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, thrombomodulin, perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, versican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spiculin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3, IL-18BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Proerythrin, Clusterin D1, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Sphingomyelinase, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Adiponectin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Netrin-2, IL-17 RD, Albumin, Follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, Norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTPIB, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Glycan 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Cryptic-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Sialoadhesin-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSMR beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1(CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipid-regulating protein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmoglein, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neuropilin, Plexin-2, EMMPRIN, Activin RIB, Semaphorin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Tissue inhibitor of cysteine proteases B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Versican-3, Jagged-1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Retinoic midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Salivary agglutinin-6, Dendritic cell-associated C-type lectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, Cathepsin V, Testican-2, Phosphatidylinositol-glycan 5, CD6, Salivary agglutinin-2, Asparaginyl endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MISRII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, biglycan, neurotrophin, ILT4, uPAR, Axl, WIF-1, IL-7 Ra, GPR56, CEACAM-3, MCEMP1, FABP2, plectin B3, MEPE, activin RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, agrin-1, GUSB, nidogen-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17 RC, MIP-3b, cystatin C, cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, enteropeptidase, cathepsin E, TSLP, TCN2, GDF-15, epiregulin, GRKS, PD-1, serpin A4, ADAM23, NOV, galectin-2, neuron surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 Ra, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphotactin, cystatin SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Olig2, kallikrein 12, CA13, IL-9, agrin-3, MPIF-1, cystatin S, ADA, IL-2 Rb, GFR a-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CFXIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31RA, Arginase 1, POGLUT1, IL-1ra, MerTK, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Mucin-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Dystonin-3, Neogenin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Phosphatidylinositol Glycan 1, LAP (TGFb1), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural Epithelial Stem Cell Protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Dystonin-2, Aggrecan, Syntaxin 4, VAMP-1, Neogenin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurgulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNFRII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Pentraxin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endothelial cell-specific molecule, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Versican, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma R1, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Versican-4, IL-2 Rg, MICA, Dopamine decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12 p40, Total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, and IL-13.

[0079] The nucleic acid content of the therapeutic product was determined and it was found that the following nucleic acids were present: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p,hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p.

[0080] B. Example 2 - Safety Study of Complex Regional Pain Syndrome (CRPS) Treated with Human Bone Marrow Stem Cell-Derived Extracellular Vesicle Investigational Product In this example, the inventors report that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) is safe and exhibits efficacy in complex regional pain syndrome patients. Ten subjects received two intravenous infusions on days 1 and 4, each containing 15 mL of the investigational product. Assessments (visual analog scale for pain, Brief Pain Inventory, SF-36 questionnaire, range of motion analysis, Jamar dynamometer) were performed at baseline (day 0, prior to infusion), week 1, and months 1, 3, and 6 after the second infusion. No serious adverse events related to treatment with the investigational product occurred. Statistically significant improvements in pain and motor assessments occurred in the pool of subjects. The investigational product was found to be safe in patients with CRPS. The investigational product exhibited efficacy in treating CRPS symptoms. The investigational product appears to be a potential treatment that is safe and effective for CRPS.

[0081] ExoFlo TM The investigational product (IP) (as used herein) is a human BM-MSC-derived EV (hBM-MSC EV) preparation. The IP is a stable EV product with a broad array of characteristics, including advanced particle analysis, proteomic evaluation, and USP <71> sterility assurance. In addition, by being manufactured in a cGMP environment, the IP is a high-quality biopharmaceutical product that is stable in terms of dose and biological activity. Two peer-reviewed studies have demonstrated the safety of IV infusion administration of the IP to severe COVID-19 patients. The IP has also demonstrated efficacy in a subset of these critically ill patients.

[0082] Methods Ten subjects with CRPS, who met all the selection criteria and exclusion criteria, received 15 mL of the BM-MSC investigational product via intravenous route (IV) over 30 minutes on days 1 and 4 (two doses). The 15 mL of the investigational product was mixed with 85 mL of standard saline and the total of 100 mL of the mixture was administered via IV. This dosing regimen was chosen because it was previously shown to be safe. Measurements were taken at baseline prior to any dose, one week after the second dose, one month, three months, and six months after the second dose. During the trial, one subject lost follow-up and their information was excluded from the study results and analyses.

[0083] Measurement and statistical analysis The assessments performed included the visual analog scale for pain (VAS), Brief Pain Inventory, SF-36 questionnaire, range of motion (ROM) analysis, and Jamar dynamometer test. A one-way ANOVA with Geisser-Greenhouse correction was used for all results, followed by Dunnett’s multiple comparisons using GraphPad Prism 9.5.1.

[0084] Study design. Because CRPS affects more women than men (ratio range 2:3 - 4:1), females were well represented, as shown in Table 1. Diversity was not addressed in this pilot study.

[0085] Table 1: Gender and age demographics of subjects

[0086] * Patient follow-up lost Selection criteria Subjects enrolled must have primary symptoms of chronic refractory pain of the upper or lower extremity secondary to complex regional pain syndrome. Other possible etiologies of pain must be ruled out prior to enrolling in the study. Subjects must have a minimum VAS score of 6 in the area of maximal pain and have not achieved adequate pain reduction from at least two previous pharmacological or interventional therapies. Subjects must be greater than 18 years of age. Subjects have stable neurological function in the past 30 days. In the investigator's opinion, subjects must be mentally appropriate. Subjects are able to provide a written informed consent and agree to the follow-up schedule and protocol. Employee compensated participants must be of permanent and domiciled status.

[0087] Exclusion criteria Subjects are excluded if they have exhibited increasing or changing pain in the past 30 days. Subjects currently involved in a medical lawsuit are excluded. Subjects who have received glucocorticoid therapy in the past 30 days are excluded. Subjects are excluded if they are not stable on analgesic medication doses for 30 days. Subjects with cognitive, physical, or sensory impairment that, in the investigator's opinion, can limit the subject's ability to report are excluded. Subjects with active systemic infection are excluded. Subjects with significant medical comorbidities, in the investigator's opinion, are excluded. Subjects who have participated in another clinical study in the past 30 days are excluded. Subjects who have been diagnosed with cancer in the past two years are excluded. Female subjects who are pregnant, lactating, or planning to become pregnant are excluded. Employee compensated subjects who do not meet maximum medical benefit are excluded from the study.

[0088] Results Patient demographics: Seven of the ten patients were female, consistent with a 3-fold higher incidence in women than men (Table 1). The subjects' ages ranged from 22-72 years. The mean age was 55.8 years, also consistent with the prevalence of CRPS in older individuals. One subject was lost to follow-up.

[0089] Primary endpoint: None of the 10 subjects enrolled in the study reported any serious adverse events (SAEs) related to the treatment or investigational product. Two subjects contracted COVID-19 during the study but remained enrolled and completed the study. One subject developed congestive heart failure, but this was attributed to a pre-existing comorbidity and not the treatment regimen or investigational product.

[0090] Secondary endpoints: At baseline, the mean VAS score for the 9 subjects analyzed was 7.78 ( Figure 1 ). The mean VAS at 1, 3, and 6 months was 5.56, 5.5, and 4.89, respectively. Statistically significant improvement was observed as a group at all follow-up time points. At the 1-month follow-up, one subject reported a >50% VAS reduction. At the 3-month follow-up, three subjects reported a >50% VAS reduction. At the 6-month landmark, 4 of the remaining five subjects reported a >50% VAS reduction. The remaining subject reported VAS improvement to a lesser extent.

[0091] BPI pain scores were separated into pain interference scores and pain severity scores ( Figure 2 ). A trend toward improvement was observed during the study, but statistical significance was evident only for pain interference at the 3-month time point. The mean baseline values for both severity and interference were 6.99 and 7.61, respectively. When compared to baseline, further reductions were observed at 1, 3, and 6 months to 5.55 and 5.66, 4.90 and 4.59, and 4.94 and 5.16, respectively. At 6 months, there was a 29.23% and 32.22% reduction in pain severity and interference.

[0092] When calculating SF-36 scores, significant improvements were observed for the pain, vitality / fatigue, and social functioning indicators at the 3-month and 6-month follow-ups ( Figure 3 ). Significant improvements for the physical functioning and role-physical categories were evident at the 3-month time point. A trend toward improvement was seen for the role-emotional and mental health during the study, but these did not reach significance. A slight change was observed for the general health category.

[0093] Range of motion evaluations depend on the anatomical location of the affected joint. Data points were collected at baseline, 3 months, and 6 months landmarks ( Figure 4 ). Values were recorded in degrees and then compared to the normal rotation in degrees for a normal joint. When compared to a normal limb, seven of the nine subjects in the cohort had impaired range of motion in their limb affected by CRPS. On average, subjects had an 83.37% increase in their range of motion in their affected limb and 82% of their normal range of motion at the end of the study (Table 2).

[0094] Table 2: Range of Motion Assessment Results over the 6-month study period

[0095] Of the nine subjects in the study, only three had an impact on grip strength in the upper extremities (Jamar Test). Overall, there was an improvement in grip strength on the side affected by CRPS as well as their unaffected control side (p < 0.05). Figure 5 All subjects evaluated had grip strength equalization after 6 months (Table 3).

[0096] Table 3: Jamar Dynamax Test Assessment Results over the 6-month study period

[0097] Discussion This pilot study sought to evaluate the ExoFlo® treatment in patients with CRPS and assess the safety and efficacy of the treatment. TM Safety of the investigational product was the primary endpoint and the potential for the investigational product to promote improvement in symptoms associated with CRPS was explored as a secondary objective. No SAEs were reported throughout the entire 6-month follow-up period, meeting the primary endpoint. During the study, two subjects contracted COVID-19 and reported adverse complications with their CRPS diagnosis. One subject contracted COVID-19 between the 3-month and 6-month markers and had limb pain, color change, and swelling return to baseline. The other subject contracted COVID-19 between the 1-month and 3-month markers and stated that their neuropathic pain flare-up started again, but overall had a decrease in edema and burning sensation, and an increase in energy level. At the six-month marker, the same subject reported that the burning pain was completely gone. Of the patients who contracted COVID-19 during the study, one reported no change in pain interference and pain severity on the BPI scale. Between the 1-month and 3-month markers, one subject was diagnosed with congestive heart failure, but it is believed that the patient did not develop congestive heart failure as a result of treatment with the investigational product, but rather because of their pre-existing comorbidities and lifestyle habits. The same subject reported a 50% reduction in pain and overall had an increase in range of motion.

[0098] Functional assessments consistently showed positive patient response to treatment. Comparison of VAS scores from baseline to 6 months showed that, on average, all subjects had an improvement in pain. Overall, there was almost a 50% reduction in pain by the end of the study. One subject, who rated her pain as a 7 / 10 at baseline, reported no pain at the end of the study. One subject reported no change in pain from baseline to 6 months, but had a reduction in pain at the 1-month and 3-month follow-ups.

[0099] When evaluating BPI scores, on average, all subjects had a decrease in pain severity and pain interference. The greatest improvement seen in pain interference in daily life was a 32% decrease in overall pain interference by the end of the study. One subject reported no pain interference or severity at 3 months and at the end of the 6-month trial. All but two subjects reported a decrease in pain severity throughout the trial, and the remaining two subjects reported no change. All but one subject reported a decrease in pain interference at the end of the trial, and their pain levels did not increase, but remained the same. The same subject reported no change in pain severity or pain interference when compared to baseline. This same subject contracted COVID-19 during the 1- and 3-month markers of the study. Overall, most of the observed benefit was reported by the three-month marker, with a slight rebound in pain interference at the end of the 6-month trial.

[0100] Evaluation of SF-36 scores showed that all subjects showed improvement at the end of the 6-month clinical trial when compared to the original baseline scores. The most significant improvements were seen in pain, energy level, social functioning, and bodily functions, there was a positive trend in emotional well-being, and the smallest significant improvement was seen in general health. Of the nine subjects in the study, five reported zero emotional limitations at the end of the 6-month study. One patient reported zero physical limitations and zero limitations regarding pain at the 6-month marker.

[0101] On average, the percentage of normal range of motion in the joints affected by CRPS was 51% when compared to the normal anatomical degree of rotation of the unaffected limb. By the three-month marker, the percentage of normal range of motion was 81%, an 84.41% increase from baseline. At the six-month marker, the percentage of normal range of motion increased to 82%, a total increase of 83.37% from baseline. At the 6-month marker, two subjects had complete restoration of normal range of motion in their joints affected by CRPS. Most of the observed benefit in range of motion was observed by the 3-month marker. On average, all patients had an increase in range of motion at 6 months when compared to baseline. One subject did not receive a benefit from the treatment in range of motion in one motion (extension of their shoulder joint), but had an increase in flexion range of motion, and pronation abduction of the same joint. No subjects reported a decrease in range of motion throughout the study.

[0102] At baseline, the mean grip strength of the unaffected control limb was 29.33 kg, while that of the CRPS-affected limb was 21.33 kg. At the 1-month mark, this increased to 30.66 kg for the control side and 21.33 kg for the CRPS-affected side. At the 3-month mark, this increased to 35.67 kg and 34.67 kg, respectively. At the 6-month mark, this increased to 43.33 kg and 45 kg, respectively. Overall, grip strength increased by 147.73% in the control limb and by 210.94% in the CRPS-affected limb. All subjects showed increased grip strength on both their control and CRPS-affected sides. At 6 months, one subject had a stronger CRPS-affected side than their control side. These subjective and objective findings were consistent with reported improvements in limb and joint range of motion, as well as reduced changes in sweat gland regulation, edema, hyperalgesia, and hypoesthesia.

[0103] Two subjects reported almost no hair growth on their affected limbs prior to the study. Both subjects experienced increased hair growth during the study. One subject reported that by the end of the study, hair growth on the affected limbs had returned to normal compared to the unaffected limbs. One of the two subjects with insufficient hair growth also had issues with their nails. At the 6-month mark, they reported an overall increase in nail growth rate compared to before the start of the study.

[0104] In addition, one subject experienced complete resolution of CRPS symptoms and pain. They reported normalization of range of motion, complete resolution of pain, no pain interference in daily life, and no pain-related disturbances to physical function, physical limitations, emotional limitations, reduced energy, emotional health, social function, and general health.

[0105] in conclusion The investigational product was safe and well-tolerated in patients with CRPS. On average, all subjects experienced improvement after delivery of the investigational product.

Claims

1. A method of treating complex regional pain syndrome (CRPS) in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 - .

2. The method of claim 1, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration.

3. A method of treating complex regional pain syndrome (CRPS) in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration.

4. The method of claim 3, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 - .

5. The method of any one of claims 2-4, wherein the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration.

6. The method of any one of claims 1-5, wherein the subject has a reduction in a Brief Pain Inventory (BPI) score after administration compared to prior to administration.

7. The method of claim 6, wherein the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in a BPI score after administration compared to prior to administration.

8. The method of claim 6 or 7, wherein the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in a BPI pain interference score after administration compared to prior to administration.

9. The method of any one of claims 1-8, wherein the subject has at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, at least a 85%, at least a 95%, or at least a 100% increase in a range of motion assessment score after administration compared to prior to administration.

10. The method of any one of claims 1-9, wherein the subject has an increase in a Jamar dynameter test assessment score after administration compared to prior to administration.

11. The method of claim 10, wherein the increase in a Jamar dynameter test assessment score is in an upper extremity.

12. The method of claim 10 or 11, wherein the subject has grip strength equalization after administration.

13. The method of any one of claims 10-12, wherein the subject has an increase in grip strength of at least 5 kg, at least 10 kg, at least 15 kg, or at least 20 kg after administration compared to prior to administration.

14. The method of any one of claims 10-13, wherein the subject has an increase in grip strength of at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, or at least 210% after administration compared to prior to administration.

15. The method of any one of claims 10-14, wherein the subject has an increase in grip strength in the affected limb.

16. The method of any one of claims 10-15, wherein the subject has an increase in grip strength in a control limb.

17. The method of any one of claims 10 to 16, wherein the subject has one or more of the following improved after administration compared to prior to administration: range of motion of a limb, range of motion of a joint, sweat gland regulatory nerve changes, edema, hyperalgesia, and hypoaesthesia.

18. The method of any one of claims 1 to 17, wherein the subject has an improvement in Short Form 36-Item Health Survey Questionnaire (SF-36) questionnaire score after administration compared to prior to administration.

19. The method of claim 18, wherein the improvement in SF-36 questionnaire score comprises one or more of the following: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health.

20. The method of any one of claims 1 to 19, wherein the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, selectin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, versican, TIMP-2, SLITRK5, FAP, neuregulin, DPPII, clAP-1, pentaxin 3, visfatin, neprilysin, albumin, galectin-1, UNC5H3, IL-20R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, oncostatin, asparaginyl endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, trypsin 3, SIRP alpha, and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF R alpha, selectin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF.Ra, thrombomodulin, perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, skeletin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20Ra, glyoxalase II, trypsin 1, IGF-2R, ADAMTSL-1, proerythrin, plexin D1, DNMT3A, BCL-2, CL-P1, ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, neublastin, DPPII, cIAP-1, PDGFRb, pentraxin 3, angiotensinogen, follistatin, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, visfatin, progranulin, PCSK2, GKN1, IL-18, neuraminidase, stabilin-2, IL-17 RD, albumin, follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galectin-1, troponin C, UNC5H3, FLRT2, CD314, semaphorin 6B, netrin-4, CD27 ligand, IL-20 R beta, semaphorin 6A, TSK, cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, galanin, activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, phosphatidylinositol glycan 2, MSP R, DSCAM, matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, ubiquitin+1, ANGPTL4, TWEAK R, nidogen-1, CD2, kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipid Lowering Protein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, OX40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neuropilin, TMEM-2, EMMPRIN, Activin RIB, Semaphorin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Periostin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy Associated Plasma Protein-2, Versican-3, Jagged-1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Retinoic Factor, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dendritic Cell Associated C-Type Lectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican-2, Phosphatidylinositol Glycan 5, CD6, Siglec-2, Asparaginyl Endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1beta, TAFA1, Caloprotein, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neurturin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Plexin-1, GUSB, Nestin-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Plexin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31RA, arginase 1, POGLUT1, IL-1ra, MerTK, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, MBL-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Dystonin-3, Claudin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Phosphoglycan 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Dystonin-2, Aggrecan, Syntaxin-4, VAMP-1, Claudin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurgulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1RII, neuropilin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, an endothelial cell-specific molecule, granulysin, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, syntaxin 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, brevican, NAP-2, PU.1, EDAR, ADAMTS13, kynureninase, PTH1R, IFN-gamma R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-type lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, syndecan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, semaphorin 4G, IL-12 p40, total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galectin-8, CA4, cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, or IL-13.

21. The method of any one of claims 1 to 20, wherein the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25,hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.

22. The method of any one of claims 1 to 21, wherein the subject has chronic, intractable pain in one or more upper or lower extremities.

23. The method of any one of claims 1 to 22, wherein the subject has not experienced increasing or changing pain in the 30 days prior to administration.

24. The method of any one of claims 1 to 23, wherein the subject experiences a reduction in onset of pain, reduction in swelling, and / or reduction in burning sensation in the affected limb after administration compared to prior to administration.

25. The method of any one of claims 1 to 24, wherein the administration improves hair growth and / or nail growth in the affected limb of the subject.

26. The method of any one of claims 1 to 25, wherein the composition is produced as follows: (a) culturing bone marrow-derived MSCs to produce MSC conditioned media under the following conditions: (i) an oxygen tension of less than 5%; and (ii) a culture medium having a pH of less than 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).

27. The method of claim 26, wherein the culture medium is serum-free.

28. The method of claim 26 or 27, wherein the culture medium has a glucose concentration of less than 4.5 g / L.

29. The method of any one of claims 1 to 28, wherein the subject is a human.

30. The method of any one of claims 26 to 29, wherein the bone marrow-derived MSCs are derived from human bone marrow.

31. The method of any one of claims 1 to 30, wherein administration comprises intravenous administration.

32. The method of any one of claims 1 to 31, wherein the dose of the therapeutic MSC secretome composition administered to the subject is a cell equivalent dose of 0.7 to 7 million cells / kg.

33. The method of any one of claims 1 to 31, wherein the therapeutic MSC secretome composition comprises 4 x 10 10 to 10 x 10 10 cells / ml.

34. The method of any one of claims 1 to 31, wherein the therapeutic MSC secretome composition comprises 5 x 10 11 to 1.5 x 10 12 cells of extracellular vesicles.

35. The method of any one of claims 1 to 34, wherein the composition is administered monthly for two or more months, or once every 1, 2, or 3 months or more.

36. The method of any one of claims 1 to 34, wherein the composition is administered twice.

37. The method of claim 36, wherein the composition is administered four days apart.

38. A method of making a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition for treating complex regional pain syndrome (CRPS) in a subject in need thereof, the method comprising: (a) culturing bone marrow-derived MSCs under conditions to produce MSC conditioned medium: (i) an oxygen tension of less than 5%; and (ii) a medium having a pH of less than 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).

39. The method of claim 38, wherein the medium is serum-free.

40. The method of claim 38 or 39, wherein the medium has a glucose concentration of less than 4.5 g / L.

42. The method of any one of claims 38 to 41, wherein the bone marrow-derived MSCs are derived from human bone marrow.

41. The method of any one of claims 38-40, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 - .

43. The method of any one of claims 38 to 42, wherein administration comprises intravenous administration.

46. Use of the composition produced by the method of any one of claims 38 to 45 for treating complex regional pain syndrome (CRPS) in a subject in need thereof.

44. The method of any one of claims 38 to 43, wherein the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, selectin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, versican, TIMP-2, SLITRK5, FAP, neuregulin, DPPII, clAP-1, pentaxin 3, visfatin, neprilysin, albumin, galectin-1, UNC5H3, IL-20R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, oncostatin, asparaginyl endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, trypsin 3, SIRP alpha, and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF R alpha, selectin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF.Ra, thrombomodulin, perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, skeletin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20Ra, glyoxalase II, trypsin 1, IGF-2R, ADAMTSL-1, proerythrin, plexin D1, DNMT3A, BCL-2, CL-P1, ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, neublastin, DPPII, cIAP-1, PDGFRb, pentraxin 3, angiotensinogen, follistatin, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, visfatin, progranulin, PCSK2, GKN1, IL-18, neuraminidase, stabilin-2, IL-17 RD, albumin, follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galectin-1, troponin C, UNC5H3, FLRT2, CD314, semaphorin 6B, netrin-4, CD27 ligand, IL-20 R beta, semaphorin 6A, TSK, cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, galanin, activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, phosphatidylinositol glycan 2, MSP R, DSCAM, matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, ubiquitin+1, ANGPTL4, TWEAK R, nidogen-1, CD2, kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipid Lowering Protein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, OX40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neuropilin, TMEM-2, EMMPRIN, Activin RIB, Semaphorin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Periostin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy Associated Plasma Protein-2, Versican-3, Jagged-1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Retinoic Factor, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dendritic Cell Associated C-Type Lectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican-2, Phosphatidylinositol Glycan 5, CD6, Siglec-2, Asparaginyl Endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1beta, TAFA1, Caloprotein, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neurturin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Plexin-1, GUSB, Nestin-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Serpin C, Serpin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Serpin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Plexin-3, MPIF-1, Serpin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31RA, arginase 1, POGLUT1, IL-1ra, MerTK, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, MBL-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Dystonin-3, Claudin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Phosphoglycan 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Dystonin-2, Aggrecan, Syntaxin-4, VAMP-1, Claudin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurgulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1RII, neuropilin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, an endothelial cell-specific molecule, granulysin, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, syntaxin 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, brevican, NAP-2, PU.1, EDAR, ADAMTS13, kynureninase, PTH1R, IFN-gamma R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-type lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, syndecan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, semaphorin 4G, IL-12 p40, total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galectin-8, CA4, cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, or IL-13.

45. The method of any one of claims 38 to 44, wherein the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25,hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.

47. The use of claim 46, wherein the subject is a human.

48. The use of claim 46 or 47, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration compared to prior to administration.

49. The use of any one of claims 46 to 48, wherein the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration.

50. The use of any one of claims 46 to 49, wherein the subject has a reduction in a Brief Pain Inventory (BPI) score after administration compared to prior to administration.

51. The use of claim 50, wherein the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in the BPI score after administration compared to prior to administration.

52. The use of claim 50 or 51, wherein the subject has at least a 10%, at least a 20%, at least a 30%, or greater than a 30% reduction in the BPI pain interference score after administration compared to prior to administration.

53. The use of any one of claims 46 to 52, wherein the subject has at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, at least a 85%, at least a 95%, or at least a 100% increase in a range of motion assessment score after administration compared to prior to administration. ​ 54. The use of any one of claims 46-53, wherein the subject has an increased Jamar dynameter test evaluation score after administration as compared to prior to administration.

55. The use of claim 54, wherein the increased Jamar dynameter test evaluation score is in an upper extremity.

56. The use of claim 54 or 55, wherein the subject has grip strength equalization after administration.

57. The use of any one of claims 54-56, wherein the subject has an increased grip strength of at least 5 kg, at least 10 kg, at least 15 kg, or at least 20 kg after administration as compared to prior to administration.

58. The use of any one of claims 54-57, wherein the subject has an increased grip strength of at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, or at least 210% after administration as compared to prior to administration.

59. The use of any one of claims 54-58, wherein the subject has an increased grip strength in an affected limb.

60. The use of any one of claims 54-59, wherein the subject has an increased grip strength in a control limb.

61. The use of any one of claims 46-60, wherein the subject has an improvement in one or more of the following: range of extremity motion, range of joint motion, sweat gland regulatory nerve changes, edema, hyperalgesia, and hypoaesthesia after administration as compared to prior to administration.

62. The use of any one of claims 46-61, wherein the subject has an improvement in Short Form 36-Item Health Survey Questionnaire (SF-36) questionnaire score after administration as compared to prior to administration.

63. The use of claim 62, wherein the improvement in SF-36 questionnaire score comprises one or more of the following: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health.

64. The use of any one of claims 46-63, wherein the subject has chronic refractory pain in one or more upper or lower extremities.

65. The use of any one of claims 46-64, wherein the subject has not experienced increasing or changing pain in the 30 days prior to administration.

66. The use of any one of claims 46-65, wherein the subject experiences a reduction in pain onset, reduction in swelling, and / or reduction in burning sensation in an affected limb after administration as compared to prior to administration.

67. The use of any one of claims 46-66, wherein the administration improves hair growth and / or nail growth in an affected limb of the subject.

68. The use of any one of claims 46-67, wherein the dose of the therapeutic MSC secretome composition administered to the subject is a cell equivalent dose of 0.7 to 7 million cells / kg.

69. The method of any one of claims 46 to 67, wherein the therapeutic MSC secretome composition comprises 4 x 10 10 to 10 x 10 10 cells / ml.

70. The method of any one of claims 46 to 67, wherein the therapeutic MSC secretome composition comprises 5 x 10 11 to 1.5 x 10 12 cells of extracellular vesicles.

71. The method of any one of claims 38 to 70, wherein the composition is administered monthly for two or more months, or once every 1, 2, or 3 months or more.

72. The method of any one of claims 38 to 70, wherein the composition is administered twice.

73. The method of claim 72, wherein the composition is administered 4 days apart.

74. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles in the treatment of complex regional pain syndrome (CRPS) in a subject in need thereof, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-.

75. The use of claim 74, wherein the composition is administered intravenously to the subject.

76. The use of claim 74 or 75, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

77. The use of any one of claims 74 to 76, wherein the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration of the therapeutic MSC secretome composition.

78. The use of any one of claims 74 to 77, wherein the subject has a reduction in a brief pain inventory (BPI) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

79. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles in the treatment of complex regional pain syndrome (CRPS) in a subject in need thereof, wherein the subject has at least a 50% reduction in a pain visual analog scale (VAS) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

80. The use of claim 79, wherein the subject has a minimum VAS score of greater than 6 in the affected limb prior to administration of the therapeutic MSC secretome composition.

81. The use of claim 79 or 80, wherein the subject has a reduction in a brief pain inventory (BPI) score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

82. The use of any one of claims 79-81, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63 + CD9 - CD81 - .

83. The use of any one of claims 79 to 82, wherein the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serpin F1, OPN, PAI-1, DAPP1, cathepsin B, semaphorin 6C, PDGF R alpha, selectin, serpin B6, Dkk-3, thrombomodulin, PF4, MIF, periostin, furin, TIMP-1, decorin, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, versican, TIMP-2, SLITRK5, FAP, neuregulin, DPPII, clAP-1, pentaxin 3, visfatin, neprilysin, albumin, galectin-1, UNC5H3, IL-20R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, plexin A4, EMMPRIN, p53, semaphorin 7A, NKp80, cystatin B, osteoadherin, oncostatin, asparaginyl endopeptidase, TAZ, cathepsin L, RBP4, serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, trypsin 3, SIRP alpha, and syndecan-4, and at least one protein selected from the group consisting of ferritin, IGFBP-4 IL-1R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFbI, ephrin-A4, CD109, serpin F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, semaphorin 6C, IGF-2, PDGF R alpha, selectin, serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF.Ra, thrombomodulin, perlecan, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostin, furin, TIMP-1, PAPP-A, decorin, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, skeletin, ENPP-2, CD97, CTACK, integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20Ra, glyoxalase II, trypsin 1, IGF-2R, ADAMTSL-1, proerythrin, plexin D1, DNMT3A, BCL-2, CL-P1, ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, neublastin, DPPII, cIAP-1, PDGFRb, pentraxin 3, angiotensinogen, follistatin, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, visfatin, progranulin, PCSK2, GKN1, IL-18, neuraminidase, stabilin-2, IL-17 RD, albumin, follistatin-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galectin-1, troponin C, UNC5H3, FLRT2, CD314, semaphorin 6B, netrin-4, CD27 ligand, IL-20 R beta, semaphorin 6A, TSK, cytokeratin-8, CHST3, Mc1-1, DPPIV, SREC-II, norrin, JAM-C, Bc1-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, galanin, activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, phosphatidylinositol glycan 2, MSP R, DSCAM, matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, ubiquitin+1, ANGPTL4, TWEAK R, nidogen-1, CD2, kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PAR1, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipid Lowering Protein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, OX40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neuropilin, TMEM-2, EMMPRIN, Activin RIB, Semaphorin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Periostin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy Associated Plasma Protein-2, Versican-3, Jagged-1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Retinoic Factor, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dendritic Cell Associated C-Type Lectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican-2, Phosphatidylinositol Glycan 5, CD6, Siglec-2, Asparaginyl Endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1beta, TAFA1, Caloprotein, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neurturin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Plexin-1, GUSB, Nestin-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enterokinase, Cathepsin E, TSLP, TCN2, GDF-15, Epiregulin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neuronal surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Extracellular matrix protein-3, Olig2, Kallikrein 12, CA13, IL-9, Plexin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, Transmembrane serine 1 protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31RA, arginase 1, POGLUT1, IL-1ra, MerTK, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, MBL-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Dystonin-3, Claudin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Phosphoglycan 1, LAP (TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Dystonin-2, Aggrecan, Syntaxin-4, VAMP-1, Claudin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurgulin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-reactin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1RII, neuropilin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, an endothelial cell-specific molecule, granulysin, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibulin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, syntaxin 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, brevican, NAP-2, PU.1, EDAR, ADAMTS13, kynureninase, PTH1R, IFN-gamma R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-type lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, syndecan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, semaphorin 4G, IL-12 p40, total PSA, IL-15, MAP1D, Clq, TNF4, Dtk, endoglin, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galectin-8, CA4, cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, or IL-13.

84. The use of any one of claims 79 to 83, wherein the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25,hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.

85. The use of any one of claims 79 to 84, wherein the composition is produced as follows: (a) culturing bone marrow-derived MSCs to produce MSC conditioned media under the following conditions: (i) an oxygen tension of less than 5%; and (ii) a culture medium having a pH of less than 7; (b) harvesting the MSC conditioned media; and (c) administering the MSC conditioned media to the subject. (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).

86. The use of claim 85, wherein the culture medium is serum-free.

87. The use of claim 85 or 86, wherein the culture medium has a glucose concentration of less than 4.5 g / L.

88. The use of any one of claims 85-87, wherein the subject has a decrease in BPI score of at least 10%, at least 20%, at least 30%, or greater than 30% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

89. The use of claim 88, wherein the subject has a decrease in BPI pain interference score of at least 10%, at least 20%, at least 30%, or greater than 30% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

90. The use of any one of claims 85-89, wherein the subject has an increase in range of motion assessment score of at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 95%, or at least 100% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

91. The use of any one of claims 85-90, wherein the subject has an increase in Jamar dynameter test assessment score after administration of the therapeutic MSC secretome composition as compared to prior to administration of the therapeutic MSC secretome composition.

92. The use of claim 91, wherein the increase in Jamar dynameter test assessment score is in the upper extremities.

93. The use of claim 91 or 92, wherein the subject has grip strength equalization after administration of the therapeutic MSC secretome composition.

94. The use of any one of claims 91-93, wherein the subject has an increase in grip strength of at least 5 kg, at least 10 kg, at least 15 kg, or at least 20 kg after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

95. The use of any one of claims 91-94, wherein the subject has an increase in grip strength of at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, or at least 210% after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

96. The use of any one of claims 91-95, wherein the subject has an increase in grip strength in the affected limb.

97. The use of any one of claims 91-96, wherein the subject has an increase in grip strength in the contralateral limb.

98. The use of any one of claims 79-97, wherein the subject has one or more of the following improved: range of extremity motion, range of joint motion, eccrine modulating nerve changes, edema, hyperalgesia, and hypoaesthesia after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

99. The use of any one of claims 79-98, wherein the subject has an improvement in Short Form 36-Item Health Survey Questionnaire (SF-36) questionnaire score after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

100. The use of claim 99, wherein the improvement in SF-36 questionnaire score comprises one or more of the following: improvement in pain, improvement in energy level, improvement in social functioning, improvement in physical functioning, positive trend in emotional health, and improvement in general health.

101. The use of any one of claims 79-100, wherein the subject has chronic refractory pain in one or more upper or lower extremities.

102. The use of any one of claims 79-101, wherein the subject has not experienced increasing or changing pain in the 30 days prior to administration of the therapeutic MSC secretome composition.

103. The use of any one of claims 79-102, wherein the subject experiences a reduction in onset of pain, reduction in swelling, and / or reduction in burning sensation in the affected extremity after administration of the therapeutic MSC secretome composition compared to prior to administration of the therapeutic MSC secretome composition.

104. The use of any one of claims 79-103, wherein the administration of the therapeutic MSC secretome composition improves hair growth and / or nail growth in the affected extremity of the subject.

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