{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T10:20:17Z","timestamp":1779013217217,"version":"3.51.4"},"reference-count":24,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"\n OBJECTIVE<\/jats:title>\n Cranial bone flap fixation is typically achieved by using titanium plates and screws (TPS), which are the standard of care. However, the use of hardware to achieve long-term bone fixation and healing across a kerf line poses challenges and potential complications, including infection, nonunion, loosening, cranial flap bone resorption, pain, cosmetic deformity, and CSF leakage. The use of a tetracalcium phosphate and phosphoserine (TTCP-PS) regenerative bone adhesive to fixate cranial flaps has been previously shown to be advantageous compared to TPS in an in vivo ovine model and a human cadaveric model. However, the potential impact of TTCP-PS on the underlying brain has not been previously studied. To investigate the local tissue effects of TTCP-PS bone adhesive compared to TPS, a clinically relevant sheep craniotomy model was developed.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n Twelve skeletally mature crossbred sheep were used in this study. All craniotomies and surgical procedures were performed by an experienced, US-trained, licensed, and practicing attending neurosurgeon. Bilateral parietal craniotomies were created using a Medtronic Midas Rex craniotome and perforator. Durotomy was performed and repaired in half of the subjects. Craniotomies were repaired with TPS or the TTCP-PS bone adhesive. CT scans were performed postoperatively and at 12 weeks. Histopathology was performed on the brain and cranial bone.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n All sheep reached the study endpoint. Histopathological changes in underlying cerebral cortical tissue were comparable in magnitude and incidence between groups (minimal superficial cortical deformation\/loss and\/or malacia\/loss). The magnitude of microgliosis and astrogliosis related to the cortical changes was comparable between groups (minimal\/mild and minimal, respectively). Histopathological findings were procedural in nature, associated with the craniotomy model, and unrelated to the bone flap fixation method. The histological changes did not result in clinically adverse effects.<\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS<\/jats:title>\n TTCP-PS was safe, producing no significant difference in adverse effects on local tissues compared to standard craniotomy with plate and screw fixation. This is the first study to quantify histological changes in the underlying cerebral cortex due to standard craniotomy technique.<\/jats:p>\n <\/jats:sec>","DOI":"10.3171\/2025.8.jns243158","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T12:00:20Z","timestamp":1769083220000},"page":"673-681","source":"Crossref","is-referenced-by-count":1,"title":["Demonstration of the safety of a regenerative bone adhesive for cranial flap fixation in a 12-week clinically relevant sheep model"],"prefix":"10.3171","volume":"144","author":[{"given":"Timothy R.","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Brigham and Women\u2019s Hospital, Boston, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John B.","family":"Lazor","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan R.","family":"Slotkin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Geisinger Medical Center, Danville, Pennsylvania;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric J.","family":"Woodard","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, New England Baptist Hospital, Boston, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sourabh","family":"Boruah","sequence":"additional","affiliation":[{"name":"RevBio, Inc., Lowell, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Bichara","sequence":"additional","affiliation":[{"name":"RevBio, Inc., Lowell, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Brown","sequence":"additional","affiliation":[{"name":"RevBio, Inc., Lowell, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian J.","family":"Hess","sequence":"additional","affiliation":[{"name":"RevBio, Inc., Lowell, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin T.","family":"Foley","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Semmes Murphey Clinic & University of Tennessee Health Science Center, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"issue":"3","key":"b1","series-title":"Neurosurgery","first-page":"417","article-title":"Adaptation of rigid fixation to cranial flap replacement","volume":"29","author":"Smith SC","year":"1991","unstructured":"Smith SC, Pelofsky S. Adaptation of rigid fixation to cranial flap replacement. Neurosurgery. 1991;29(3):417\u2013418."},{"issue":"6","key":"b2","series-title":"J Neurosurg Sci","first-page":"723","article-title":"Comparison between the different types of heterologous materials used in cranioplasty: a systematic review of the literature","volume":"63","author":"Morselli C","year":"2019","unstructured":"Morselli C, Zaed I, Tropeano MP, Comparison between the different types of heterologous materials used in cranioplasty: a systematic review of the literature. J Neurosurg Sci. 2019;63(6):723\u2013736."},{"issue":"10","key":"b3","series-title":"Acta Neurochir (Wien)","first-page":"1845","article-title":"Removal of symptomatic titanium fixation plates after craniotomy","volume":"158","author":"Gupta R","year":"2016","unstructured":"Gupta R, Adeeb N, Griessenauer CJ, Removal of symptomatic titanium fixation plates after craniotomy. Acta Neurochir (Wien). 2016;158(10):1845\u20131848."},{"key":"b4","series-title":"Eplasty","first-page":"e2","article-title":"Intracranial migration of hardware 16 years following craniosynostosis repair","volume":"18","author":"Ayyala HS","year":"2018","unstructured":"Ayyala HS, Hoppe IC, Rathmann AM, Ciminello FS. Intracranial migration of hardware 16 years following craniosynostosis repair. Eplasty. 2018;18:e2."},{"issue":"2","key":"b5","series-title":"J Neurosurg","first-page":"244","article-title":"Titanium miniplates or stainless steel wire for cranial fixation: a prospective randomized comparison","volume":"96","author":"Broaddus WC","year":"2002","unstructured":"Broaddus WC, Holloway KL, Winters CJ, Titanium miniplates or stainless steel wire for cranial fixation: a prospective randomized comparison. J Neurosurg. 2002;96(2):244\u2013247."},{"key":"b6","series-title":"Scand J Trauma Resusc Emerg Med","first-page":"75","article-title":"Cranioplasty complications and risk factors associated with bone flap resorption","volume":"23","author":"Brommeland T","year":"2015","unstructured":"Brommeland T, Rydning PN, Pripp AH, Helseth E. Cranioplasty complications and risk factors associated with bone flap resorption. Scand J Trauma Resusc Emerg Med. 2015;23:75."},{"issue":"1","key":"b7","series-title":"PLoS One","first-page":"e0228009","article-title":"Aseptic bone-flap resorption after cranioplasty - incidence and risk factors","volume":"15","author":"Rashidi A","year":"2020","unstructured":"Rashidi A, Sandalcioglu IE, Luchtmann M. Aseptic bone-flap resorption after cranioplasty - incidence and risk factors. PLoS One. 2020;15(1):e0228009."},{"issue":"3","key":"b8","series-title":"Neurosurg Rev","first-page":"1755","article-title":"Long-term complications and implant survival rates after cranioplastic surgery: a single-center study of 392 patients","volume":"44","author":"Giese H","year":"2021","unstructured":"Giese H, Meyer J, Unterberg A, Beynon C. Long-term complications and implant survival rates after cranioplastic surgery: a single-center study of 392 patients. Neurosurg Rev. 2021;44(3):1755\u20131763."},{"issue":"2","key":"b9","series-title":"J Neurosurg","first-page":"621","article-title":"Cranial flap fixation in sheep using a resorbable bone adhesive","volume":"134","author":"Foley KT","year":"2021","unstructured":"Foley KT, Woodard EJ, Slotkin JR, Cranial flap fixation in sheep using a resorbable bone adhesive. J Neurosurg. 2021;134(2):621\u2013629."},{"issue":"2","key":"b10","series-title":"J Neurosurg","first-page":"517","article-title":"Use of adhesive cranial bone flap fixation without hardware to improve mechanical strength, resist cerebrospinal fluid leakage, and maintain anatomical alignment: a laboratory study","volume":"139","author":"Smith TR","year":"2023","unstructured":"Smith TR, Foley KT, Boruah S, Use of adhesive cranial bone flap fixation without hardware to improve mechanical strength, resist cerebrospinal fluid leakage, and maintain anatomical alignment: a laboratory study. J Neurosurg. 2023;139(2):517\u2013527."},{"issue":"9","key":"b11","series-title":"Theranostics","first-page":"2583","article-title":"Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions","volume":"8","author":"Pelekanos M","year":"2018","unstructured":"Pelekanos M, Leinenga G, Odabaee M, Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions. Theranostics. 2018;8(9):2583\u20132602."},{"issue":"7","key":"b12","series-title":"Toxicol Pathol","first-page":"1028","article-title":"STP position paper: Recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies","volume":"41","author":"Bolon B","year":"2013","unstructured":"Bolon B, Garman RH, Pardo ID, STP position paper: Recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies. Toxicol Pathol. 2013;41(7):1028\u20131048."},{"issue":"3","key":"b1","series-title":"Neurosurgery","first-page":"417","article-title":"Adaptation of rigid fixation to cranial flap replacement","volume":"29","author":"Smith SC","year":"1991","unstructured":"Smith SC, Pelofsky S. Adaptation of rigid fixation to cranial flap replacement. Neurosurgery. 1991;29(3):417\u2013418."},{"issue":"6","key":"b2","series-title":"J Neurosurg Sci","first-page":"723","article-title":"Comparison between the different types of heterologous materials used in cranioplasty: a systematic review of the literature","volume":"63","author":"Morselli C","year":"2019","unstructured":"Morselli C, Zaed I, Tropeano MP, Comparison between the different types of heterologous materials used in cranioplasty: a systematic review of the literature. J Neurosurg Sci. 2019;63(6):723\u2013736."},{"issue":"10","key":"b3","series-title":"Acta Neurochir (Wien)","first-page":"1845","article-title":"Removal of symptomatic titanium fixation plates after craniotomy","volume":"158","author":"Gupta R","year":"2016","unstructured":"Gupta R, Adeeb N, Griessenauer CJ, Removal of symptomatic titanium fixation plates after craniotomy. Acta Neurochir (Wien). 2016;158(10):1845\u20131848."},{"key":"b4","series-title":"Eplasty","first-page":"e2","article-title":"Intracranial migration of hardware 16 years following craniosynostosis repair","volume":"18","author":"Ayyala HS","year":"2018","unstructured":"Ayyala HS, Hoppe IC, Rathmann AM, Ciminello FS. Intracranial migration of hardware 16 years following craniosynostosis repair. Eplasty. 2018;18:e2."},{"issue":"2","key":"b5","series-title":"J Neurosurg","first-page":"244","article-title":"Titanium miniplates or stainless steel wire for cranial fixation: a prospective randomized comparison","volume":"96","author":"Broaddus WC","year":"2002","unstructured":"Broaddus WC, Holloway KL, Winters CJ, Titanium miniplates or stainless steel wire for cranial fixation: a prospective randomized comparison. J Neurosurg. 2002;96(2):244\u2013247."},{"key":"b6","series-title":"Scand J Trauma Resusc Emerg Med","first-page":"75","article-title":"Cranioplasty complications and risk factors associated with bone flap resorption","volume":"23","author":"Brommeland T","year":"2015","unstructured":"Brommeland T, Rydning PN, Pripp AH, Helseth E. Cranioplasty complications and risk factors associated with bone flap resorption. Scand J Trauma Resusc Emerg Med. 2015;23:75."},{"issue":"1","key":"b7","series-title":"PLoS One","first-page":"e0228009","article-title":"Aseptic bone-flap resorption after cranioplasty - incidence and risk factors","volume":"15","author":"Rashidi A","year":"2020","unstructured":"Rashidi A, Sandalcioglu IE, Luchtmann M. Aseptic bone-flap resorption after cranioplasty - incidence and risk factors. PLoS One. 2020;15(1):e0228009."},{"issue":"3","key":"b8","series-title":"Neurosurg Rev","first-page":"1755","article-title":"Long-term complications and implant survival rates after cranioplastic surgery: a single-center study of 392 patients","volume":"44","author":"Giese H","year":"2021","unstructured":"Giese H, Meyer J, Unterberg A, Beynon C. Long-term complications and implant survival rates after cranioplastic surgery: a single-center study of 392 patients. Neurosurg Rev. 2021;44(3):1755\u20131763."},{"issue":"2","key":"b9","series-title":"J Neurosurg","first-page":"621","article-title":"Cranial flap fixation in sheep using a resorbable bone adhesive","volume":"134","author":"Foley KT","year":"2021","unstructured":"Foley KT, Woodard EJ, Slotkin JR, Cranial flap fixation in sheep using a resorbable bone adhesive. J Neurosurg. 2021;134(2):621\u2013629."},{"issue":"2","key":"b10","series-title":"J Neurosurg","first-page":"517","article-title":"Use of adhesive cranial bone flap fixation without hardware to improve mechanical strength, resist cerebrospinal fluid leakage, and maintain anatomical alignment: a laboratory study","volume":"139","author":"Smith TR","year":"2023","unstructured":"Smith TR, Foley KT, Boruah S, Use of adhesive cranial bone flap fixation without hardware to improve mechanical strength, resist cerebrospinal fluid leakage, and maintain anatomical alignment: a laboratory study. J Neurosurg. 2023;139(2):517\u2013527."},{"issue":"9","key":"b11","series-title":"Theranostics","first-page":"2583","article-title":"Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions","volume":"8","author":"Pelekanos M","year":"2018","unstructured":"Pelekanos M, Leinenga G, Odabaee M, Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions. Theranostics. 2018;8(9):2583\u20132602."},{"issue":"7","key":"b12","series-title":"Toxicol Pathol","first-page":"1028","article-title":"STP position paper: Recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies","volume":"41","author":"Bolon B","year":"2013","unstructured":"Bolon B, Garman RH, Pardo ID, STP position paper: Recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies. Toxicol Pathol. 2013;41(7):1028\u20131048."}],"container-title":["Journal of Neurosurgery"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/144\/3\/article-p673.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/144\/3\/article-p673.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/144\/3\/article-p673.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T15:27:14Z","timestamp":1776094034000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/144\/3\/article-p673.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,1]]},"references-count":24,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.3171\/2025.8.jns243158","relation":{},"ISSN":["0022-3085","1933-0693"],"issn-type":[{"value":"0022-3085","type":"print"},{"value":"1933-0693","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,1]]}}}