{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:47:02Z","timestamp":1768506422433,"version":"3.49.0"},"posted":{"date-parts":[[2023,5,25]]},"group-title":"Bioengineering","reference-count":61,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,5,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Critical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks or\n                  <jats:italic>de novo<\/jats:italic>\n                  growth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model. The gelatin hydrogel is functionalized with a peptide derived from the extracellular epitope of Type 1 cadherins. Mechanistically, these \u201cGelCad\u201d hydrogels promote arteriogenesis by recruiting smooth muscle cells to vessel structures in both\n                  <jats:italic>ex vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  assays. In a murine femoral artery ligation model of CLI, delivery of\n                  <jats:italic>in situ<\/jats:italic>\n                  crosslinking GelCad hydrogels was sufficient to restore limb perfusion and maintain tissue health for 14 days, whereas mice treated with gelatin hydrogels had extensive necrosis and autoamputated within 7 days. A small cohort of mice receiving the GelCad hydrogels were aged out to 5 months and exhibited no decline in tissue quality, indicating durability of the collateral arteriole networks. Overall, given the simplicity and off-the-shelf format of the GelCad hydrogel platform, we suggest it could have utility for CLI treatment and potentially other indications that would benefit from arteriole development.\n                <\/jats:p>","DOI":"10.1101\/2023.05.24.542150","type":"posted-content","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T07:40:14Z","timestamp":1685000414000},"source":"Crossref","is-referenced-by-count":0,"title":["Growth factor-free, peptide-functionalized gelatin hydrogel promotes arteriogenesis and attenuates tissue damage in a murine model of critical limb ischemia"],"prefix":"10.64898","author":[{"given":"Corinne W.","family":"Curry","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah M.","family":"Sturgeon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian J.","family":"O\u2019Grady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis K.","family":"Yates","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Kjar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayden A.","family":"Paige","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas S.","family":"Mowery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ketaki A.","family":"Katdare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riya V.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Mlouk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison R.","family":"Stiefbold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sidney","family":"Vafaie-Partin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuyuki","family":"Kawabata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel M.","family":"McKee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie Moore-","family":"Lotridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrienne","family":"Hawkes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiro","family":"Kusunose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine N.","family":"Gibson-Corley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Schmeckpeper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan G.","family":"Schoenecker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles F.","family":"Caskey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ethan S.","family":"Lippmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023052710450663000_2023.05.24.542150v1.1","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.3390\/ijms22052335","article-title":"Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia","volume":"22","year":"2021","journal-title":"Int. J. Mol. Sci"},{"key":"2023052710450663000_2023.05.24.542150v1.2","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2147\/VHRM.S209241","article-title":"The burden of critical limb ischemia: a review of recent literature","volume":"15","year":"2019","journal-title":"Vasc. Health Risk Manag. Volume"},{"key":"2023052710450663000_2023.05.24.542150v1.3","doi-asserted-by":"crossref","first-page":"e002938","DOI":"10.1161\/JAHA.115.002938","article-title":"Critical Limb Ischemia: Current Trends and Future Directions","volume":"5","year":"2016","journal-title":"J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis"},{"key":"2023052710450663000_2023.05.24.542150v1.4","doi-asserted-by":"crossref","unstructured":"S. Kinlay , Management of Critical Limb Ischemia, Circ. Cardiovasc. Interv. 9 (2016). https:\/\/doi.org\/10.1161\/CIRCINTERVENTIONS.115.001946.","DOI":"10.1161\/CIRCINTERVENTIONS.115.001946"},{"key":"2023052710450663000_2023.05.24.542150v1.5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.029092"},{"key":"2023052710450663000_2023.05.24.542150v1.6","doi-asserted-by":"crossref","first-page":"3S","DOI":"10.1016\/j.jvs.2019.02.016","article-title":"Global vascular guidelines on the management of chronic limb-threatening ischemia","volume":"69","year":"2019","journal-title":"J. Vasc. Surg"},{"key":"2023052710450663000_2023.05.24.542150v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2006.12.037"},{"key":"2023052710450663000_2023.05.24.542150v1.8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1001\/jamasurg.2013.4277","article-title":"Relationship Between Regional Spending on Vascular Care and Amputation Rate","volume":"149","year":"2014","journal-title":"JAMA Surg"},{"key":"2023052710450663000_2023.05.24.542150v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.avsg.2008.02.017"},{"key":"2023052710450663000_2023.05.24.542150v1.10","doi-asserted-by":"publisher","DOI":"10.1177\/0003319712464514"},{"key":"2023052710450663000_2023.05.24.542150v1.11","doi-asserted-by":"crossref","first-page":"2003119","DOI":"10.1002\/advs.202003119","article-title":"Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia","volume":"8","year":"2021","journal-title":"Adv. Sci"},{"key":"2023052710450663000_2023.05.24.542150v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(02)00259-1"},{"key":"2023052710450663000_2023.05.24.542150v1.13","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1016\/S0140-6736(02)08937-7","article-title":"Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial","volume":"359","year":"2002","journal-title":"The Lancet"},{"key":"2023052710450663000_2023.05.24.542150v1.14","first-page":"1933","volume":"108","year":"2003","journal-title":"Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease: A Phase II Randomized, Double-Blind, Controlled Study of Adenoviral Delivery of Vascular Endothelial Growth Factor 121 in Patients With Disabling Intermittent Claudication, Circulation"},{"key":"2023052710450663000_2023.05.24.542150v1.15","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.17.11.2793"},{"key":"2023052710450663000_2023.05.24.542150v1.16","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.79.1.62"},{"key":"2023052710450663000_2023.05.24.542150v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nm848"},{"key":"2023052710450663000_2023.05.24.542150v1.18","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1016\/S0140-6736(11)60394-2","article-title":"Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia","volume":"377","year":"2011","journal-title":"The Lancet"},{"key":"2023052710450663000_2023.05.24.542150v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2018.01.005"},{"key":"2023052710450663000_2023.05.24.542150v1.20","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.91.11.2687"},{"key":"2023052710450663000_2023.05.24.542150v1.21","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2006.17.683"},{"key":"2023052710450663000_2023.05.24.542150v1.22","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1089\/wound.2017.0760","article-title":"Inspired by Nature: Hydrogels as Versatile Tools for Vascular Engineering","volume":"7","year":"2018","journal-title":"Adv. Wound Care"},{"key":"2023052710450663000_2023.05.24.542150v1.23","doi-asserted-by":"publisher","DOI":"10.1021\/cr000108x"},{"key":"2023052710450663000_2023.05.24.542150v1.24","doi-asserted-by":"crossref","first-page":"10908","DOI":"10.1021\/acs.chemrev.0c00923","article-title":"Chemically Modified Biopolymers for the Formation of Biomedical Hydrogels","volume":"121","year":"2021","journal-title":"Chem. Rev"},{"key":"2023052710450663000_2023.05.24.542150v1.25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.biomaterials.2015.06.009","article-title":"Enhanced therapeutic neovascularization by CD31-expressing cells and embryonic stem cell-derived endothelial cells engineered with chitosan hydrogel containing VEGF-releasing microtubes","volume":"63","year":"2015","journal-title":"Biomaterials"},{"key":"2023052710450663000_2023.05.24.542150v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1404605111"},{"key":"2023052710450663000_2023.05.24.542150v1.27","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.actbio.2019.01.057","article-title":"Gelatin-based micro-hydrogel carrying genetically engineered human endothelial cells for neovascularization","volume":"95","year":"2019","journal-title":"Acta Biomater"},{"key":"2023052710450663000_2023.05.24.542150v1.28","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1021\/acs.biomac.8b00331","article-title":"Heparin Functionalized Injectable Cryogel with Rapid Shape-Recovery Property for Neovascularization","volume":"19","year":"2018","journal-title":"Biomacromolecules"},{"key":"2023052710450663000_2023.05.24.542150v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-005-5644-2"},{"key":"2023052710450663000_2023.05.24.542150v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2014.05.010"},{"key":"2023052710450663000_2023.05.24.542150v1.31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1159\/000479869","article-title":"VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits","volume":"54","year":"2017","journal-title":"J. Vasc. Res"},{"key":"2023052710450663000_2023.05.24.542150v1.32","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-010-0067-0"},{"key":"2023052710450663000_2023.05.24.542150v1.33","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s10856-019-6232-z","article-title":"Tethering QK peptide to enhance angiogenesis in elastin-like recombinamer (ELR) hydrogels","volume":"30","year":"2019","journal-title":"J. Mater. Sci. Mater. Med"},{"key":"2023052710450663000_2023.05.24.542150v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.201101163"},{"key":"2023052710450663000_2023.05.24.542150v1.35","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1089\/ten.tea.2013.0357","article-title":"Avidity-Controlled Delivery of Angiogenic Peptides from Injectable Molecular-Recognition Hydrogels","volume":"20","year":"2014","journal-title":"Tissue Eng. Part A"},{"key":"2023052710450663000_2023.05.24.542150v1.36","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.biomaterials.2016.04.032","article-title":"Treatment of hind limb ischemia using angiogenic peptide nanofibers","volume":"98","year":"2016","journal-title":"Biomaterials"},{"key":"2023052710450663000_2023.05.24.542150v1.37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.302953"},{"key":"2023052710450663000_2023.05.24.542150v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2007.08.040"},{"key":"2023052710450663000_2023.05.24.542150v1.39","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000036416.14084.5A"},{"key":"2023052710450663000_2023.05.24.542150v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.02.023"},{"key":"2023052710450663000_2023.05.24.542150v1.41","doi-asserted-by":"publisher","DOI":"10.1109\/TUFFC.2005.1561668"},{"key":"2023052710450663000_2023.05.24.542150v1.42","doi-asserted-by":"crossref","unstructured":"M.E. Padgett , T.J. McCord , J.M. McClung , C.D. Kontos , Methods for Acute and Subacute Murine Hindlimb Ischemia, J. Vis. Exp. (2016) 54166. https:\/\/doi.org\/10.3791\/54166.","DOI":"10.3791\/54166-v"},{"key":"2023052710450663000_2023.05.24.542150v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2008.08.077"},{"key":"2023052710450663000_2023.05.24.542150v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501444102"},{"key":"2023052710450663000_2023.05.24.542150v1.45","doi-asserted-by":"crossref","first-page":"E3","DOI":"10.3171\/FOC.2008.25.11.E3","article-title":"Activated autologous macrophage implantation in a large-animal model of spinal cord injury: Laboratory investigation","volume":"25","year":"2008","journal-title":"Neurosurg. Focus"},{"key":"2023052710450663000_2023.05.24.542150v1.46","doi-asserted-by":"crossref","first-page":"5811","DOI":"10.1021\/acsbiomaterials.0c00885","article-title":"Development of an N-Cadherin Biofunctionalized Hydrogel to Support the Formation of Synaptically Connected Neural Networks","volume":"6","year":"2020","journal-title":"ACS Biomater. Sci. Eng"},{"key":"2023052710450663000_2023.05.24.542150v1.47","doi-asserted-by":"crossref","first-page":"6771","DOI":"10.1002\/adfm.201401110","article-title":"In Situ Crosslinkable Gelatin Hydrogels for Vasculogenic Induction and Delivery of Mesenchymal Stem Cells","volume":"24","year":"2014","journal-title":"Adv. Funct. Mater"},{"key":"2023052710450663000_2023.05.24.542150v1.48","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000202677.55012.a0"},{"key":"2023052710450663000_2023.05.24.542150v1.49","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00047.2007"},{"key":"2023052710450663000_2023.05.24.542150v1.50","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.bone.2014.07.002","article-title":"The temporal and spatial development of vascularity in a healing displaced fracture","volume":"67","year":"2014","journal-title":"Bone"},{"key":"2023052710450663000_2023.05.24.542150v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1101-1029"},{"key":"2023052710450663000_2023.05.24.542150v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.09.013"},{"key":"2023052710450663000_2023.05.24.542150v1.53","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.biomaterials.2017.06.012","article-title":"Controlled release of basic fibroblast growth factor for angiogenesis using acoustically-responsive scaffolds","volume":"140","year":"2017","journal-title":"Biomaterials"},{"key":"2023052710450663000_2023.05.24.542150v1.54","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41467-020-14480-0","article-title":"Microchannel network hydrogel induced ischemic blood perfusion connection","volume":"11","year":"2020","journal-title":"Nat. Commun"},{"key":"2023052710450663000_2023.05.24.542150v1.55","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000079027.44309.53"},{"key":"2023052710450663000_2023.05.24.542150v1.56","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvn278"},{"key":"2023052710450663000_2023.05.24.542150v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2005.12.017"},{"key":"2023052710450663000_2023.05.24.542150v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.01.004"},{"key":"2023052710450663000_2023.05.24.542150v1.59","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12123"},{"key":"2023052710450663000_2023.05.24.542150v1.60","first-page":"20","article-title":"Hydrogel microparticles for biomedical applications","volume":"5","year":"2020","journal-title":"Nat. Rev. Mater"},{"key":"2023052710450663000_2023.05.24.542150v1.61","doi-asserted-by":"crossref","first-page":"5415","DOI":"10.1002\/adma.201103046","article-title":"Surfaces That Sequester Serum-Borne Heparin Amplify Growth Factor Activity","volume":"23","year":"2011","journal-title":"Adv. Mater"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.05.24.542150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:41:56Z","timestamp":1768452116000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.05.24.542150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,25]]},"references-count":61,"URL":"https:\/\/doi.org\/10.1101\/2023.05.24.542150","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.biomaterials.2023.122397","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,5,25]]},"subtype":"preprint"}}