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120. Haentjens P, Magaziner J, Colón-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. *Ann Intern Med.* 2010;152(6):380-390.

121. Hu F, Jiang C, Shen J, Tang P, Wang Y. Preoperative predictors for mortality following hip fracture surgery: a systematic review and meta-analysis. *Injury.* 2012;43(6):676-685. doi:10.1016/j.injury.2011.05.017

122. Campana V, Milano G, Pagano E, et al. Bone substitutes in orthopaedic surgery: from basic science to clinical practice. *J Mater Sci Mater Med.* 2014;25(10):2445-2461. doi:10.1007/s10856-014-5240-2

123. Decision Resources G. Medtech 360 - Bone Graft Substitutes, Market Insights, Global 2019. 2019.

124. Miron RJ, Sculean A, Cochran DL, et al. Twenty years of enamel matrix derivative: the past, the present and the future. *J Clin Periodontol.* 2016;43(8):668-683. doi:10.1111/jcpe.12546

125. Hsu WL, Oldfield CJ, Xue B, et al. Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding. *Protein Sci.* 2013;22(3):258-273. doi:10.1002/pro.2207

126. Sculean A, Chiantella GC, Windisch P, Donos N. Clinical and histologic evaluation of human intrabony defects treated with an enamel matrix protein derivative (Emdogain). *Int J Periodontics Restorative Dent.* 2000;20(4):374-381.

127. Heden G. A case report study of 72 consecutive Emdogain-treated intrabony. *Restorative Dent.* 2000;20:127-139.

128. Rasperini G, Silvestri M, Schenk RK, Nevins ML. Clinical and histologic evaluation of human gingival recession treated with a subepithelial connective tissue graft and enamel matrix derivative (Emdogain): a case report. *Int J Periodontics Restorative Dent.* 2000; 20(3):269-275.

129. Sculean A, Windisch P, Keglevich T, Chiantella GC, Gera I, Donos N. Clinical and histologic evaluation of human intrabony defects treated with an enamel matrix protein derivative combined with a bovine-derived xenograft. *Int J Periodontics Restorative Dent.* 2003; 23(1):47-55.

130. Jones JR. Review of bioactive glass: from Hench to hybrids. *Acta Biomater.* 2013;9(1):4457-4486. doi:10.1016/j.actbio.2012.08.023

131. van Dijk LA, Barrere-de Groot F, Rosenberg A, et al. MagnetOs, Vitoss, and Novabone in a multi-endpoint study of posterolateral fusion: a true fusion or not? *Clin Spine Surg.* 2020;33(6):E276-E287. doi:10.1097/BSD.0000000000000920

132. Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of polymer 407 pharmaceutical and pharmacological characteristics. *Pharm Res.* 2006;23(12):2709-2728. doi:10.1007/s11095-006-9104-4

133. Dumortier G, El Kateb N, Sahli M, Kedjar S, Boulliat A, Chaumeil JC. Development of a thermogelling ophthalmic formulation of cysteine. *Drug Dev Ind Pharm.* 2006;32(1):63-72. doi:10.1080/036390405 00390934

134. Kirschner HJ, Obermayr F, Schaefer J, Lieber J. Treatment of benign bone defects in children with silicate-substituted calcium phosphate (SiCaP). *Eur J Pediatr Surg.* 2012;22(2):143-147. doi:10.1055/s- 0032-1308699

135. Gruskin E, Doll BA, Futrell FW, Schmitz JP, Hollinger JO. Demineralized bone matrix in bone repair: history and use. *Adv Drug Deliv Rev.* 2012;64(12):1063-1077. doi:10.1016/j.adr.2012.06.008

136. Haugen HJ, Lyngstadaas SP, Rossi F, Perale G. Bone grafts: which is the ideal biomaterial? *J Clin Periodontol.* 2019;46(Suppl 21):92-102. doi:10.1111/jcpe.13058

137. Martin BI, Mirza SK, Spina N, Spiker WR, Lawrence B, Brodke DS. Trends in lumbar fusion procedure rates and associated hospital costs for degenerative spinal diseases in the United States, 2004 to 2015. *Spine (Phila Pa 1976).* 2019;44(5):369-376. doi:10.1097/ BRS.00000000000002822

138. Teraguchi M, Yoshimura N, Hashizume H, et al. Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. *Osteoarthr Cartil.* 2014;22(1):104-110. doi:10.1016/j. joca.2013.10.019

139. Mobbs RJ, Sivabalan P, Li J. Minimally invasive surgery compared to open spinal fusion for the treatment of degenerative lumbar spine pathologies. *J Clin Neurosci.* 2012;19(6):829-835. doi:10.1016/j. jocn.2011.10.004

140. Rajaee SS, Kanim LE, Bae HW. National trends in revision spinal fusion in the USA: patient characteristics and complications. *Bone Joint J.* 2014;96-B(6):807-816. doi:10.1302/0301-620X.96B6.31149

141. Bohner M, Miron RJ. A proposed mechanism for material-induced heterotopic ossification. *Mater Today.* 2019;22:132-141.

142. Maazouz Y, Chizzola G, Dobelin N, Bohner M. Cell-free, quantitative mineralization measurements as a proxy to identify osteoinductive bone graft substitutes. *Biomaterials.* 2021;275:120912. doi: 10.1016/j.biomaterials.2021.120912

143. Epstein NE. Pros, cons, and costs of INFUSE in spinal surgery. *Surg Neurol Int.* 2011;2:10. doi:10.4103/2152-7806.76147

144. Putz C, Wiedenhöfer B, Gerner HJ, Hüttinger K, Fürstenberg CH. Spinal fusion of an unstable atlantoaxial fracture in a completely tetraplegic patient using silicate-substituted calcium phosphate. *Eur J Trauma Emerg Surg.* 2010;36(2):169-175.

145. Licina P, Coughlan M, Johnston E, Pearcy M. Comparison of silicate-substituted calcium phosphate (Actifuse) with recombinant human bone morphogenetic Protein-2 (Infuse) in posterolateral instrumented lumbar fusion. *Global Spine J.* 2015;5(6):471-478. doi:10.1055/s-0035- 1566230

146. Newell N, Little JP, Christou A, Adams MA, Adam CJ, Masouros SD. Biomechanics of the human intervertebral disc: a review of testing techniques and results. *J Mech Behav Biomed Mater.* 2017;69:420- 434. doi:10.1016/j.jmbbm.2017.01.037

147. Chen YC, Su WY, Yang SH, Gefen A, Lin FH. In situ forming hydrogels composed of oxidized high molecular weight hyaluronic acid and gelatin for nucleus pulposus regeneration. *Acta Biomater.* 2013; 9(2):5181-5193. doi:10.1016/j.actbio.2012.09.039

148. Tavana S, Masouros SD, Baxan N, Freedman BA, Hansen UN, Newell N. The effect of degeneration on internal strains and the mechanism of failure in human intervertebral discs analyzed using digital volume correlation (DVC) and ultra-high field MRI. *Front Bio- eng Biotechnol.* 2021;8:610907.

149. Durdag E, Ayden O, Albayrak S, Atci IB, Armagan E. Fragmentation to epidural space: first documented complication of Gelsix(TM.). *Turk Neurosurg.* 2014;24(4):602-605. doi:10.5137/1019-5149. JTN.9328-13.1

150. Thier S, Baumann F, Weiss C, Fickert S. Feasibility of arthroscopic autologous chondrocyte implantation in the hip using an injectable hydrogel. *Hip Int.* 2018;28(4):442-449. doi:10.5301/hipint.5000580

151. Blanke F, Oehler N, Haenle M, Lenz R, Vogt S, Tischer T. All- arthroscopic hydrogel-based autologous chondrocyte transplanta- tion in the knee joint: good clinical and magnetic resonance imaging outcome after 24 months. *Art Ther.* 2021;37(6):1892-1899.e1. doi: 10.1016/j.arthro.2021.01.038

152. Tschugg A, Diepers M, Simone S, et al. A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of phase I—a short report. *Neu- rosurg Rev.* 2017;40(1):155-162. doi:10.1007/s10143-016-0781-0

153. Tschugg A, Michnacs F, Strowitzki M, Meisel HJ, Thome C. A prospective multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disc plus autologous disc chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disc to avoid secondary disease: study protocol for a
119. Grønskag AB, Romundstad P, Forsmo S, Langhammer A, Schei B. Excess mortality after hip fracture among elderly women in Norway. The HUNT study. *Osteoporos Int.* 2012;23(6):1807-1811. doi: 10.1007/s00198-011-1811-y

120. Haentjens P, Magaziner J, Colón-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. *Ann Intern Med.* 2010;152(6):380-390.

121. Hu F, Jiang C, Shen J, Tang P, Wang Y. Preoperative predictors for mortality following hip fracture surgery: a systematic review and meta-analysis. *Injury*. 2012;43(6):676-685. doi:10.1016/j.injury.2011.05.017

122. Campana V, Milano G, Pagano E, et al. Bone substitutes in orthopaedic surgery: from basic science to clinical practice. *J Mater Sci Mater Med.* 2014;25(10):2445-2461. doi:10.1007/s10856-014-5240-2

123. Decision Resources G. Medtech 360 – Bone Graft Substitutes, Market Insights, Global 2019. 2019.

124. Miron RJ, Sculean A, Cochran DL, et al. Twenty years of enamel matrix derivative: the past, the present and the future. *J Clin Periodontol.* 2016;43(8):668-683. doi:10.1111/jcpe.12546

125. Hsu WL, Oldfield CJ, Xue B, et al. Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding. *Protein Sci.* 2013;22(3):258-273. doi:10.1002/pro.2207

126. Sculean A, Chiantella GC, Windisch P, Donos N. Clinical and histologic evaluation of human intrabony defects treated with an enamel matrix protein derivative (Emdogain). *Int J Periodontics Restorative Dent.* 2000;20(4):374-381.

127. Heden G. A case report study of 72 consecutive Emdogain-treated intrabony. *Restorative Dent.* 2000;20:127-139.

128. Rasperini G, Silvestri M, Schenk RK, Nevins ML. Clinical and histologic evaluation of human gingival recession treated with a subepithelial connective tissue graft and enamel matrix derivative (Emdogain): a case report. *Int J Periodontics Restorative Dent.* 2000; 20(3):269-275.

129. Sculean A, Windisch P, Keglevich T, Chiantella GC, Gera I, Donos N. Clinical and histologic evaluation of human intrabony defects treated with an enamel matrix protein derivative combined with a bovine-derived xenograft. *Int J Periodontics Restorative Dent.* 2003; 23(1):47-55.

130. Jones JR. Review of bioactive glass: from Hench to hybrids. *Acta Biomater.* 2013;9(1):4457-4486. doi:10.1016/j.actbio.2012.08.023

131. van Dijk LA, Barrere-de Groot F, Rosenberg A, et al. MagnetOs, Vitoss, and Novabone in a multi-endpoint study of posterolateral fusion: a true fusion or not? *Clin Spine Surg.* 2020;33(6):E276-E287. doi:10.1097/BSD.0000000000000920

132. Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. *Pharm Res.* 2006;23(12):2709-2728. doi:10.1007/s11095-006-9104-4

133. Dumortier G, El Kateb N, Sahli M, Kedjar S, Boulliat A, Chaumeil JC. Development of a thermogelling ophthalmic formulation of cysteine. *Drug Dev Ind Pharm.* 2006;32(1):63-72. doi:10.1080/036390405 00390934

134. Kirschner HJ, Obermayr F, Schaefer J, Lieber J. Treatment of benign bone defects in children with silicate-substituted calcium phosphate (SiCaP). *Eur J Pediatr Surg.* 2012;22(2):143-147. doi:10.1055/s- 0032-1308699

135. Gruskin E, Doll BA, Futrell FW, Schmitz JP, Hollinger JO. Demineralized bone matrix in bone repair: history and use. *Adv Drug Deliv Rev.* 2012;64(12):1063-1077. doi:10.1016/j.addr.2012.06.008

136. Haugen HJ, Lyngstadaas SP, Rossi F, Perale G. Bone grafts: which is the ideal biomaterial? *J Clin Periodontol.* 2019;46(Suppl 21):92-102. doi:10.1111/jcpe.13058

137. Martin BI, Mirza SK, Spina N, Spiker WR, Lawrence B, Brodke DS. Trends in lumbar fusion procedure rates and associated hospital costs for degenerative spinal diseases in the United States, 2004 to 2015. *Spine (Phila Pa 1976).* 2019;44(5):369-376. doi:10.1097/ BRS.00000000000002822

138. Teraguchi M, Yoshimura N, Hashizume H, et al. Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. *Osteoarthr Cartil.* 2014;22(1):104-110. doi:10.1016/j. joca.2013.10.019

139. Mobbs RJ, Sivabalan P, Li J. Minimally invasive surgery compared to open spinal fusion for the treatment of degenerative lumbar spine pathologies. *J Clin Neurosci.* 2012;19(6):829-835. doi:10.1016/j. jocn.2011.10.004

140. Rajaee SS, Kanim LE, Bae HW. National trends in revision spinal fusion in the USA: patient characteristics and complications. *Bone Joint J.* 2014;96-B(6):807-816. doi:10.1302/0301-620X.96B6.31149

141. Bohner M, Miron RJ. A proposed mechanism for material-induced heterotopic ossification. *Mater Today.* 2019;22:132-141.

142. Maazouz Y, Chizzola G, Dobelin N, Bohner M. Cell-free, quantitative mineralization measurements as a proxy to identify osteoinductive bone graft substitutes. *Biomaterials.* 2021;275:120912. doi: 10.1016/j.biomaterials.2021.120912

143. Epstein NE. Pros, cons, and costs of INFUSE in spinal surgery. *Surg Neurol Int.* 2011;2:10. doi:10.4103/2152-7806.76147

144. Putz C, Wiedenhöfer B, Gerner HJ, Hüttinger K, Fürstenberg CH. Spinal fusion of an unstable atlantoaxial fracture in a completely tetraplegic patient using silicate-substituted calcium phosphate. *Eur J Trauma Emerg Surg.* 2010;36(2):169-175.

145. Licina P, Coughlan M, Johnston E, Pearcy M. Comparison of silicate-substituted calcium phosphate (Actifuse) with recombinant human bone morphogenetic Protein-2 (Infuse) in posterolateral instrumented lumbar fusion. *Global Spine J.* 2015;5(6):471-478. doi:10.1055/s-0035- 1566230

146. Newell N, Little JP, Christou A, Adams MA, Adam CJ, Masouros SD. Biomechanics of the human intervertebral disc: a review of testing techniques and results. *J Mech Behav Biomed Mater.* 2017;69:420- 434. doi:10.1016/j.jmbbm.2017.01.037

147. Chen YC, Su WY, Yang SH, Gefen A, Lin FH. In situ forming hydrogels composed of oxidized high molecular weight hyaluronic acid and gelatin for nucleus pulposus regeneration. *Acta Biomater.* 2013; 9(2):5181-5193. doi:10.1016/j.actbio.2012.09.039

148. Tavana S, Masouros SD, Baxan N, Freedman BA, Hansen UN, Newell N. The effect of degeneration on internal strains and the mechanism of failure in human intervertebral discs analyzed using digital volume correlation (DVC) and ultra-high field MRI. *Front Bio- eng Biotechnol.* 2021;8:610907.

149. Durdag E, Ayden O, Albayrak S, Atci IB, Armagan E. Fragmentation to epidural space: first documented complication of Gelsix(TM.). *Turk Neurosurg.* 2014;24(4):602-605. doi:10.5137/1019-5149. JTN.9328-13.1

150. Thier S, Baumann F, Weiss C, Fickert S. Feasibility of arthroscopic autologous chondrocyte implantation in the hip using an injectable hydrogel. *Hip Int.* 2018;28(4):442-449. doi:10.5301/hipint.5000580

151. Blanke F, Oehler N, Haenle M, Lenz R, Vogt S, Tischer T. All- arthroscopic hydrogel-based autologous chondrocyte transplanta- tion in the knee joint: good clinical and magnetic resonance imaging outcome after 24 months. *Art Ther.* 2021;37(6):1892-1899.e1. doi: 10.1016/j.arthro.2021.01.038

152. Tschugg A, Diepers M, Simone S, et al. A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of phase I—a short report. *Neu- rosurg Rev.* 2017;40(1):155-162. doi:10.1007/s10143-016-0781-0

153. Tschugg A, Michnacs F, Strowitzki M, Meisel HJ, Thome C. A prospective multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disc plus autologous disc chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disc to avoid secondary disease: study protocol for a
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**How to cite this article:** Øvrebø Ø, Perale G, Wojciechowski JP, et al. Design and clinical application of injectable hydrogels for musculoskeletal therapy. *Bioeng Transl Med*. 2022;7(2):e10295. doi:10.1002/btm2.10295
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163. Faris O, Shuren J. An FDA viewpoint on unique considerations for medical-device clinical trials. *N Engl J Med*. 2017;376(14):1350-1357. doi:10.1056/NEJMra1512592

164. Medtech Europe. The European Medical Technology Industry in Figures 2021. 2021.

165. Zhu H, Jostein Haugen H, Perale G, et al. Tailoring resorption rates and osteogenic response in xeno-hybrid bone grafts: the effect of added gelatins. *Engineering*. 2021. (In Press). doi:10.1016/j.eng.2021.01.010

166. Perale G, Monjo M, Ramis JM, et al. Biomimetic biomolecules in next generation xeno-hybrid bone graft material show enhanced in vitro bone cells response. *J Clin Med*. 2019;8:2159. doi:10.3390/jcm8122159

167. Rahmati M, Stötzel S, El Khassawna T, et al. Intrinsically disordered peptides enhance regenerative capacities of bone composite xenografts. *Mater Today*. 2021. (In Press). doi:10.1016/j.mattod.2021.12.001

168. Zhu H, Blahnova VH, Perale G, et al. Xeno-hybrid bone graft releasing biomimetic proteins promotes osteogenic differentiation of hMSCs. *Front Cell Dev Biol*. 2020;8:619111. doi:10.3389/fcell.2020.619111

169. Zhu H, Gomez M, Xiao J, et al. Xenohybrid bone graft containing intrinsically disordered proteins shows enhanced in vitro bone formation. *ACS Appl Bio Mater*. 2020;3(4):2263-2274. doi:10.1021/acsabm.0c00064

170. Pajarinen J, Lin T, Gibon E, et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. *Biomaterials*. 2019;196:80-89. doi:10.1016/j.biomaterials.2017.12.025

171. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Reconstituting organ-level lung functions on a chip. *Science*. 2010;328(5986):1662-1668. doi:10.1126/science.1188302

172. Zhang YS, Arneri A, Bersini S, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. *Biomaterials*. 2016;110:45-59. doi:10.1016/j.biomaterials.2016.09.003

173. Zaatreh S, Haffner D, Strauss M, et al. Thin magnesium layer confirmed as an antibacterial and biocompatible implant coating in a coculture model. *Mol Med Rep*. 2017;15(4):1624-1630. doi: 10.3892/mmr.2017.6218

174. Friedemann MC, Mehta NA, Jessen SL, et al. Introduction to currently applied device pathology. *Toxicol Pathol*. 2019;47(3):221-234. doi:10.1177/0192623319826585

175. Ray S, Thormann U, Eichelroth M, et al. Strontium and bisphosphonate coated iron foam scaffolds for osteoporotic fracture defect healing. *Biomaterials*. 2018;157:1-16. doi:10.1016/j.biomaterials.2017.11.049

176. Daghma DES, Malhan D, Simon P, et al. Computational segmentation of collagen fibers in bone matrix indicates bone quality in ovariectomized rat spine. *J Bone Miner Metab*. 2018;36(3):297-306. doi: 10.1007/s00774-017-0844-5

177. Schlundt C, El Khassawna T, Serra A, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. *Bone*. 2018;106:78-89. doi:10.1016/j.bone.2015.10.019

178. Zeller-Plumhoff B, Malich C, Kruger D, et al. Analysis of the bone ultrastructure around biodegradable Mg-xGd implants using small angle X-ray scattering and X-ray diffraction. *Acta Biomater*. 2020; 101:637-645. doi:10.1016/j.actbio.2019.11.030

How to cite this article: Øvrebø Ø, Perale G, Wojciechowski JP, et al. Design and clinical application of injectable hydrogels for musculoskeletal therapy. *Bioeng Transl Med*. 2022;7(2):e10295. doi:10.1002/btm2.10295