3D-printed patient-specific titanium implant for mandibular reconstruction with local drug release: Optimization, in vivo evaluation, and functional assessment

Abstract

Reconstruction of severe mandibular defects remains a significant clinical challenge due to high recurrence rates, inadequate anatomical restoration, and the limited efficacy of systemic chemotherapy. To address these limitations, a patient-specific, 3D-printed titanium mandibular implant was developed with an integrated refillable drug storage tank for localized cisplatin release. The tank surface geometry and the hydrogel formulation were optimized using the Taguchi method and incorporated into anatomically matched implants. In vivo evaluation in six porcine mandibular defect models demonstrated systemic safety over 12 weeks, with plasma platinum levels reduced by more than 60% compared to systemic administration. Hematological and biochemical indicators—including white blood cell count, liver enzymes, and renal function markers—remained within normal ranges throughout the observation period, confirming physiological stability and biocompatibility. No significant complications or implant loosening were observed. Functional validation was further performed on three representative human mandibular large-defect models. Finite element analysis revealed implant stresses well below the yield strength of Ti6Al4V (<40%), and four-point bending fatigue tests confirmed structural endurance beyond one million loading cycles. This study presents the first functional and biocompatible patient-specific mandibular implant with integrated, refillable drug delivery, offering a clinically translatable strategy for simultaneous reconstruction and localized chemotherapy in head and neck oncology.  

Keywords

3D printing / Drug release / Functional test / Patient-specific implant / Taguchi

Funding

This study was supported in part by the National Science and Technology Council project (project no.: 113-2327-B-A49-001), Taiwan.

Conflict of Interest

No potential conflict of interest was reported by the authors.

References

[1] Li CH, Wu CH, Lin CL. Design of a patient-specific mandible reconstruction implant with dental prosthesis for metal 3D printing using integrated weighted topology optimization and finite element analysis. J Mech Behav Biomed Mater. 2020;105:103700. doi: 10.1016/j.jmbbm.2020.103700

[2] Lee SW, Kim HG, Ham MJ, et al. Custom implant for reconstruction of mandibular continuity defect. J Oral Maxillofac Surg. 2018;76(6):1370-1376. doi: 10.1016/j.joms.2017.12.003

[3] Patel A, Harrison P, Cheng A, et al. Fibular reconstruction of the maxilla and mandible with immediate implant-supported prosthetic rehabilitation: jaw in a day. Oral Maxillofac Surg Clin North Am. 2019;31(3):369-386. doi: 10.1016/j.coms.2019.03.002

[4] Toure G, Gouet E. Use of a 3-dimensional custom-made porous titanium prosthesis for mandibular body reconstruction with prosthetic dental rehabilitation and lipofilling. J Oral Maxillofac Surg. 2019;77(6):1305-1313. doi: 10.1016/j.coms.2018.12.026

[5] Lin CL, Wang YT, Chang CM, et al. Design criteria for patient-specific mandibular continuity defect reconstructed implant with lightweight structure using weighted topology optimization and validated with biomechanical fatigue testing. Int J Bioprint. 2022;8(1):437. doi: 10.18063/ijb.v8i1.437

[6] Kumar BP, Venkatesh V, Kumar KA, et al. Mandibular reconstruction: overview. J Maxillofac Oral Surg. 2016;15(4):425-441. doi: 10.1007/s12663-015-0766-5

[7] Wang B, Zhang S, Yue K, et al. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin J Cancer. 2013;32(11):614-618. doi: 10.5732/cjc.012.10219

[8] Pinheiro M, Alves JL. The feasibility of a custom-made endoprosthesis in mandibular reconstruction: implant design and finite element analysis. J Craniomaxillofac Surg. 2015;43(10):2116-2128. doi: 10.1016/j.jcms.2015.10.004

[9] Stoor P, Suomalainen A, Mesimaki K, et al. Rapid prototyped patient specific guiding implants in critical mandibular reconstruction. J Craniomaxillofac Surg. 2017;45(1):63-70. doi: 10.1016/j.jcms.2016.10.021

[10] Yusa K, Yamanouchi H, Yoshida Y, et al. Evaluation of quality of life and masticatory function in patients treated with mandibular reconstruction followed by occlusal rehabilitation with dental implants: a preliminary report. J Oral Maxillofac Surg Med Pathol. 2017;29(6):499-503. doi: 10.1016/j.ajoms.2017.06.004

[11] Cheng K, Liu Y, Yao C, et al. A personalized mandibular implant with supporting and porous structures designed with topology optimization – a case study of canine. Rapid Prototyping J. 2019;25(2):417-426. doi: 10.1108/rpj-11-2017-0231

[12] Chen CF, Chen CM, Chen HS, et al. The use of customized three-dimensionally printed mandible prostheses with a pressure-reducing device: a finite element analysis in different chewing positions, biomechanical testing, and in vivo animal study using lanyu pigs. Biomed Res Int. 2022;2022:9880454. doi: 10.1155/2022/9880454

[13] Chen CF, Chen CM, Huang WC, et al. The use of customized 3D-printed mandibular prostheses with pressure-reducing device: a clinical trial. Head Neck. 2024;46(7):1614-1624. doi: 10.1002/hed.27660

[14] Domsta V, Seidlitz A. 3D-printing of drug-eluting implants: an overview of the current developments described in the literature. Molecules. 2021;26(13):4066. doi: 10.3390/molecules26134066

[15] Chen C, Chen J, Luo T, et al. Late toxicities, failure patterns, local tumor control, and survival of esophageal squamous cell carcinoma patients after chemoradiotherapy with a simultaneous integrated boost: a 5-year phase II study. Front Oncol. 2021;11:738936. doi: 10.3389/fonc.2021.738936

[16] Lang K, Held T, Meixner E, et al. Frequency of osteoradionecrosis of the lower jaw after radiotherapy of oral cancer patients correlated with dosimetric parameters and other risk factors. Head Face Med. 2022;18(1):7. doi: 10.1186/s13005-022-00311-8

[17] Muzumder S, Srikantia N, Udayashankar AH, et al. Late toxicities in locally advanced head and neck squamous cell carcinoma treated with intensity modulated radiation therapy. Radiat Oncol J. 2021;39(3):184-192. doi: 10.3857/roj.2020.00913

[18] Ma X, Gao Y, Zhao D, et al. Titanium implants and local drug delivery systems become mutual promoters in orthopedic clinics. Nanomaterials (Basel). 2021;12(1):47. doi: 10.3390/nano12010047

[19] Kong X, Feng M, Wu L, et al. Biodegradable gemcitabine-loaded microdevice with sustained local drug delivery and improved tumor recurrence inhibition abilities for postoperative pancreatic tumor treatment. Drug Deliv. 2022;29(1):1595-1607. doi: 10.1080/10717544.2022.2075984

[20] Yang N, Chen H, Han H, et al. 3D printing and coating to fabricate a hollow bullet-shaped implant with porous surface for controlled cytoxan release. Int J Pharm. 2018;552(1-2):91-98. doi: 10.1016/ijpharm.2018.09.042

[21] Yang G, Liu H, Li A, et al. Antibacterial structure design of porous Ti6Al4V by 3D printing and anodic oxidation. Materials (Basel). 2023;16(15):5206. doi: 10.3390/ma16155206

[22] Park YS, Cho JY, Lee SJ, et al. Modified titanium implant as a gateway to the human body: the implant mediated drug delivery system. Biomed Res Int. 2014;2014:801358. doi: 10.1155/2014/801358

[23] Fayazfar H, Salarian M, Rogalsky A, et al. A critical review of powder-based additive manufacturing of ferrous alloys: process parameters, microstructure and mechanical properties. Mater Design. 2018;144:98-128. doi: 10.1016/j.matdes.2018.02.018

[24] Fan D, Zhang C, Wang H, et al. Fabrication of a composite 3D-printed titanium alloy combined with controlled in situ drug release to prevent osteosarcoma recurrence. Mater Today Bio. 2023;20:100683. doi: 10.1016/j.mtbio.2023.100683

[25] Li R, Ting YH, Youssef SH, et al. Three-dimensional printing for cancer applications: research landscape and technologies. Pharmaceuticals (Basel). 2021;14(8):787. doi: 10.3390/ph14080787

[26] Belz JE, Kumar R, Baldwin P, et al. Sustained release talazoparib implants for localized treatment of BRCA1- deficient breast cancer. Theranostics. 2017;7(17):4340-4349. doi: 10.7150/thno.18563

[27] Adepu S, Ramakrishna S. Controlled drug delivery systems: current status and future directions. Molecules. 2021;26(19):302. doi: 10.3390/pharmaceutics11070302

[28] Lee WC, Zhang M. Design of monolimb using finite element modelling and statistics-based Taguchi method. Clin Biomech (Bristol). 2005;20(7):759-766. doi: 10.1016/j.clinbiomech.2005.03.015

[29] Huang S-F, Lo L-J, Lin C-L. Factorial analysis of variables influencing mechanical characteristics in Le Fort I osteotomy using FEA and statistics-based Taguchi method. J Med Biol Eng. 2016;36(4):495-505. doi: 10.1007/s40846-016-0157-5

[30] Maazinejad B, Mohammadnia O, Ali GAM, et al. Taguchi L9 (34) orthogonal array study based on methylene blue removal by single-walled carbon nanotubes-amine: adsorption optimization using the experimental design method, kinetics, equilibrium and thermodynamics. J Mol Liq. 2020;298:112001. doi: 10.1016/j.molliq.2019.112001

[31] Lin CL, Chang SH, Chang WJ, et al. Factorial analysis of variables influencing mechanical characteristics of a single tooth implant placed in the maxilla using finite element analysis and the statistics-based Taguchi method. Eur J Oral Sci. 2007;115(5):408-416. doi: 10.1111/j.1600-0722.2007.00473.x

[32] Zhuang B, Chen T, Xiao Z, et al. Drug-loaded implantable surgical cavity-adaptive hydrogels for prevention of local tumor recurrence. Int J Pharm. 2020;577:119048. doi: 10.1016/j.ijpharm.2020.119048

[33] Jing Z, Ni R, Wang J, et al. Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel. Bioact Mater. 2021;6(12):4542-4557. doi: 10.1016/j.bioactmat.2021.05.007

[34] Madhulaxmi M, Iyer K, Periasamy R, et al. Role of cisplatin in oral squamous cell carcinoma—a review. J Adv Pharm Educ Res. 2017;7:39–42.

[35] U. S. Food and Drug Administration. Orthopedic Non-Spinal Bone Plates, Screws, and Washers – Premarket Notification (510(k)) Submissions: Guidance for Industry and FDA Staff. Silver Spring (MD): FDA; 2024. Available from: https://www.fda.gov/media/177663/download

[36] Qin M, Liu Y, Wang L, et al. Design and optimization of the fixing plate for customized mandible implants. J Craniomaxillofac Surg. 2015;43(7):1296-1302. doi: 10.1016/j.jcms.2015.06.003

[37] Ono K, Sato K, Nakamura T, et al. Reproduction of the antitumor effect of cisplatin and cetuximab using a three-dimensional spheroid model in oral cancer. Int J Med Sci. 2022;19(8):1320-1333. doi: 10.7150/ijms.74109

[38] Meng F, Yin Z, Ren X. et al. Construction of local drug delivery system on titanium-based implants to improve osseointegration. Pharmaceutics. 2022;14(5):1069. doi: 10.3390/pharmaceutics14051069

[39] Mittal L, Kalra M, Mahajan A. Study of feasibility and acceptability of subcutaneous implantable ports (SIPs) in cancer patients. Indian J Pediatr. 2012;79(12):1601-1604. doi: 10.1007/s12098-012-0711-2

[40] Vogl TJ, Engelmann K, Mack MG, et al. CT-guided intratumoural administration of cisplatin/epinephrine gel for treatment of malignant liver tumours. Br J Cancer. 2002;86(4):524-529. doi: 10.1038/sj.bjc.6600116