Diseases and Abnormalities at or Before Birth

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Neoplasms

Musculoskeletal Diseases

Mouth and Tooth Diseases

Congenital Abnormalities

Mandibular Neoplasms

Dentofacial Deformities

Maxillary Neoplasms

Maxillofacial Abnormalities

Craniofacial Abnormalities

Musculoskeletal Abnormalities

Stomatognathic System Abnormalities

Stomatognathic Diseases

Jaw Neoplasms

Skull Neoplasms

Bone Neoplasms

Bone Diseases

Jaw Diseases

Maxillary Diseases

Mandibular Diseases

3D-printed patient-specific plate will be used for reconstruction in this patient group

conventional commercial plates will be used for reconstruction in this patient group

We adopt an in-house approach for designing by surgeons. All patient-specific devices are designed in 3-matic 13.0 (Materialise). Both cutting and transferring guides are then additively manufactured by Fused Deposition Manufacturing (FDM) using ULTEM 1010, or by Stereolithography using MED610 resin (Stratasys Ltd, Eden Prairie, MN, USA). Both ULTEM 1010 and MED610 are FDA cleared biocompatible materials applicable to high-temperature autoclaving.

Patient-specific surgical plates are designed by delineating a plate path on bone surface, then followed by the placement of screw holes. Surgical plates are generated by the built-in command in 3-matic. After that, surgical plates are fabricated by SLM using grade 2 titanium powder.

3D-printed patient-specific plate

Bone segments will be stabilized using commercial titanium surgical plates (DePuy Synthes, United States), which are bent manually before fastening the screws.\[

Conventional commercial reconstruction plate

Yuxiong Su, Dr.

Objectives: The aim of this randomised controlled clinical trial is to evaluate surgical accuracy and efficiency of computer-assisted jaw reconstruction using 3D-printed patient-specific titanium surgical plates versus conventional plates.

Hypothesis to be tested: The investigators hypothesize that compared to conventional surgical plates, 3D-printed patient-specific surgical plates improve surgical accuracy and efficiency of computer assisted jaw reconstruction.

Design and subjects: This is an open-label, prospective, double-arm, and single-centre randomised controlled clinical trial. Patients with maxillary or mandibular neoplastic, inflammatory and congenital diseases who require immediate or secondary reconstructive surgery will be invited to participate in the study.

Study instruments: 3D-printed patient-specific titanium surgical plates and conventional plates.

Main Outcome Measures: The primary endpoint is the accuracy of reconstruction. The secondary endpoints include the accuracy of osteotomy, reconstruction time, total operative time, intraoperative blood loss, length of post-operative hospital stay, and postoperative adverse events.

Data analysis: The accuracy parameters, reconstruction time, total operative time, intraoperative blood loss, length of post-operative hospital stay will be presented as mean values with standard deviations. The post-operative adverse events will be calculated and presented as frequency with standard deviation.

Expected results: This randomised control trial will prove improved accuracy and efficiency of reconstruction using 3D printed patient-specific titanium surgical plates. This study is expected to provide high-level evidence to push forward the popularity of using 3D medical printing technology in surgical field.

This randomised controlled clinical trial was based on our previous clinical trial "Three-Dimensional Printing of Patient-Specific Titanium Plates in Jaw Surgery: A Pilot Study" (HKU/HA HKW IRB, No. UW 16-315; registered in ClinicalTrials.gov with a No. of NCT03057223; supported by HMRF Project no.: 05161626).

Over the past few decades, autologous vascularized bone flaps have become the preferred choice for head and neck reconstruction. The anastomosed blood supply endows vascularized bone flaps with improved survival rate and inherent anti-infection performance. Along with the development of microvascular surgery, surgeons are seeking more accurate reconstruction to enhance better aesthetic and functional outcomes. However, a main disadvantage of autologous bone flaps is the mismatch in the shape of donor bone, which need to be cut and trimmed to fit the defects and better restore the natural appearance. Much efforts have been devoted to facilitate bone manipulations, and then the computer-assisted surgery (CAS) emerged in the 21st century as a viable option. In CAS, surgeons do virtual plans in computer, which then guide the precise harvest and arrangement of bone segments for repairing defects in the operating theatre. Bone segments can be fine-navigated to best restore the original skeleton. In previous researches, various devices have been developed to navigate bone segments according to virtual plans, including cutting templates, skull models, and surgical navigation system.

However, the missing link between bone navigation and accurate reconstruction is the plate fixation procedure. In a conventional manner, bone segments are fixed using commercial off-the-shelf titanium plates, which should be manually bent and twisted to fit bone anatomy. The manual contouring process is often tedious and technique-demanding, and adversely affect the precise location of bone segments. What's worse, repeated bending can even lead to poor fatigue performance. The disadvantages of conventional surgical plates make it necessary to develop patient-specific surgical plates. Compared to conventional plates, patient-specific surgical plates are designed and manufactured in 3D structures aligned with individual bone contours. Instead of contouring plates based on anatomical structure of bones in conventional plates, patient-specific surgical plates navigate the folding and precise location of bone segments, and hopefully improve the accuracy of reconstruction. Meanwhile, since no plate bending is required, patient-specific surgical plates can be used to optimize bone reconstruction in a more efficient and standardized manner.

In recent years, with the rapid development of additive manufacturing (3D printing), it is now feasible to manufacture patient-specific metal implants with topologically optimized structures. Many efforts have been made to develop porous bone scaffolds for regenerative medicine, which are endowed with customized porosity to achieve optimal biomechanical properties. However, although additively manufactured bone scaffolds demonstrate excellent performance in some complicated cases, they still cannot replace the dominant role of autologous vascularized bone flaps in head and neck reconstruction. Therefore, it is of crucial importance to explore the application of additive manufactured (3D printed) patient-specific surgical plates, albeit not much research has been done in this direction.

In our previous study (HKU/HA HKW IRB, No. UW 16-315) supported by Health and Medical Research Fund (Project no.: 05161626), the investigators have successfully manufactured patient-specific titanium plates with high precision through selective laser melting (SLM) technology, which is a high-tech 3D printing technology that fully melts titanium powders into complete entities in the layer by layer manner. SLM enables the fabrication of patient-specific titanium surgical plates with tailored structures and outstanding biomechanical properties. Our results showed promising clinical outcomes in the application of 3D printed patient-specific titanium plates in head and neck reconstruction. Furthermore, the investigators did a retrospective study comparing the patients who had undergone jaw reconstructive surgery using 3D printed patient-specific surgical plates versus conventional titanium plates and the result showed superior accuracy of reconstruction outcomes in the study group with the use of 3D printed patient-specific surgical plates. However, there were significant limitations in our study. First, as a retrospective study, the innate flaw of study design was unavoidable, such as selection bias. Second, there was significantly difference in follow-up periods between the study group and control group. The imaging data used for accuracy analysis were obtained during different post-operative periods, which compromised the final outcomes. Finally, surgical efficiency endpoints, such as operation time, blood loss, and post-operative hospital stay, which could be significantly affected by multiple confounding factors, are difficult to control by retrospective study design. Hence, there is still lack of high-level evidence concerning the advantages of 3D printed patient-specific surgical plates in head and neck reconstruction. Whether 3D printed patient-specific surgical plates improve surgical accuracy and efficiency compared to conventional plates in computer assisted jaw reconstruction should be further investigated before large-scale clinical application.

Therefore, the investigators aim to evaluate surgical accuracy and efficiency of computer-assisted jaw reconstruction using 3D-printed patient-specific titanium surgical plates versus conventional plates in a prospective randomised controlled clinical trial. Our study is expected to provide high-level evidence to push forward the popularity of using 3D medical printing new technology in the surgical field.

Methods

The methodology has already been set up and has been proved feasible in our earlier studies. The PI has been working on computer aided surgical simulation, virtual planning, and 3D printed surgical templates in the maxillofacial surgery for several years and has published a series of articles.

1. Computer-assisted Surgery

   The CAS techniques used in head and neck reconstruction are well established in our unit and have been described previously. Briefly, CAS is composed of three main phases: the pre-operative phase of the virtual surgery and 3D printing of patient-specific devices, intra-operative phase involving precision-enhanced surgery to install the patient-specific devices, and post-operative phase involving the accuracy analysis. The patient-specific devices can include cutting guides, positioning guides, and the patient-specific titanium plates. In our trial, the study group will use cutting guides and patient-specific titanium plates, whereas the control group will use cutting guides, positioning guides, and conventional plates.

   In the pre-operative phase, the virtual surgery will be performed by surgeons using the ProPlan CMF 2.0 software (Materialise, Leuven, Belgium). The patient's CT data is initially segmented to rebuild 3D virtual models of the maxilla or mandible using ProPlan's interactive interface. Next, bone resection is performed in the 3D models for en bloc removal of any tumours. Meanwhile, bone grafts are harvested from fibula or iliac crest to repair defects and restore the normal appearance. Finally, the virtually reconstructed maxilla or mandible is used to design patient-specific devices to navigate the bone segments.
2. Additive Manufacturing of Patient-specific Devices

   Compared to the conventional approach of designing patient-specific devices using engineering companies, we have adopt an in-house approach that allow the surgeons to design and manufacture the devices. All patient-specific devices are designed in 3-matic 13.0 (Materialise). Cutting guides, which guide and adapt to bone surface for accurate bone resection, are generated by wrapping to the bone surface.

   For the study group, patient-specific surgical plates are designed by delineating the plate path on the bone surface, followed by the placement of screw holes. Surgical plates are generated by a built-in command in 3-matic. Next, the surgical plates are fabricated by SLM using grade 2 titanium powder. For the control group, positioning guides will be designed for the bone segment alignment and inset.

   Both cutting and positioning guides will be additively manufactured by Fused Deposition Manufacturing (FDM) using ULTEM 1010, or by Stereolithography using MED610 resin (Stratasys Ltd, Eden Prairie, MN, USA). Both ULTEM 1010 and MED610 are FDA cleared biocompatible materials usable in high-temperature autoclaving.
3. Surgical Procedures

   In the present study, all patients in both groups will undergo CAS carried out by the same chief surgeon (PI). During the surgery, patient-specific cutting guides will enable precise jawbone resection and bone flap osteotomy.

   In the control group, the arrangement of bone segments will be manipulated according to the positioning guide. Bone segments will be stabilized using commercial titanium surgical plates (DePuy Synthes, United States), which are bent manually before fastening with screws. In the study group, patient-specific surgical plates will be designed and fabricated to custom-fit the bone contours of reconstructed maxilla or mandible. The screw holes embedded in cutting guides correspond to the 3D-printed patient-specific surgical plates, which will guide the position of surgical plates and bone segments, thereby facilitating folding, positioning, and fixation of bone segments in the real surgery. Standard peri-operative management will be similar in both groups. Post-operative follow-up will be conducted in a routine manner.
4. Data collection procedures

CT scan will be obtained at baseline (before surgery) and post-operatively (within 1 month after the surgery). The accuracy of reconstruction will be independently assessed by two assessors. Training will be provided using previous cases, and calibration between the two assessors will be done with the aim of achieving over 90% inter-assessor agreement in three consecutive training cases before starting the measurement of subject cases in this study. Other information such as reconstruction time, total operative time, intra-operative blood loss, length of post-operative hospital stay, and post-operative adverse events will be recorded.

Patients fulfilling the eligibility criteria and willing to participate will be randomised after baseline assessment (1:1 allocation ratio). A priori, an independent statistician will prepare a computer-generated randomisation schedule in a random-sized permuted blocks of four or six patients stratified by location of reconstruction (maxilla/mandible) and gender (F/M) to ensure that the numbers of participants receiving the two interventions are closely balanced within each stratum. The allocation numbers will be concealed in opaque sealed envelopes prepared by a central study coordinator, only opening them after informed consent and baseline measures have been obtained.

3D-Printed Patient-Specific Surgical Plates Versus Conventional Surgical Plates in Jaw Reconstruction

Computer-Assisted Jaw Reconstruction Using 3D-Printed Patient-Specific Surgical Plates Versus Conventional Surgical Plates: A Randomised Controlled Clinical Trial

The primary endpoint is accuracy of reconstruction, which is defined as the distance or angulation deviations of anatomical landmarks between the virtual plan and actual surgical outcome.

Deviation of actual osteotomy from the digital planning

time from the start of flap ischemia to the finish of anastomosis and internal fixation

The University of Hong Kong

Clinical Professor

Nervous System Diseases

Wounds and Injuries

Symptoms and General Pathology

Maxillofacial Injuries

Facies

Facial Injuries

Craniocerebral Trauma

Trauma, Nervous System

3D Jaw Plate will be used in internal fixation.

3D-printed patient-specific titanium plates will be used in patients.

3D-printed patient-specific titanium plates

Yuxiong SU, Dr.

Medical titanium plates are routinely used in fixing mobilized bone segments in jaw surgeries. Generally these plates are commercialized with standard construction specifications. Thus they should be repeatedly bended and arched to match the contour of anchored jaw bones before located in place and fastened by screws. To prevent stress fatigue induced by plate bending and improve structural design, we utilized the three-dimensional printing technique and developed a new production procedure in fabricating customized titanium plates according to each patient's specific skeletal contours and dimensions derived from medical imaging data. In general, the three-dimensional printing of customized implants are expected to facilitate surgical operation, reduce application duration and improve precise restoration.

Up until now, the application of three-dimensional printing of titanium fixation plates in jaw surgery has been available only at two centers globally. The published preliminary work have proved the prospect of customized titanium plates in promoting mandibular reconstruction surgery and upper maxilla orthognathic surgery though their printed titanium plates looked rather bulky and the sample sizes were small and there is still lack of qualified randomized controlled trials between the printed and the conventional titanium plates. To better benefit from the burgeoning use of three-dimensional printing in health care, it is imperative to conduct a feasibility study in exploring the application of three-dimensional printing of titanium fixation plates in jaw surgery based on our patients.

The aim of the study is to conduct a case series study focusing on the feasibility and safety of applying three-dimensional printed titanium plates in jaw reconstruction surgery and orthognathic surgery. The outcome measures include the success rate, potential adverse events and accuracy. A sample size of 48 subjects will be recruited prospectively. Considering the facts that titanium plates are widely used in jaw surgery and our unit is the largest oral and maxillofacial surgery center in Hong Kong, the well-designed customized titanium plate is therefore with great potential benefit for the patients in our population. Furthermore, the well-developed three-dimensional manufacturing protocol could also be applied in other relevant medical areas and push forward the personalized medicine era in the future.

Plate osteosynthesis is the basic philosophy in maintaining skeletal stabilization in jaw surgery. Numerous branded osteosynthesis systems are available and most of them are made from pure titanium or titanium alloys with standard construction specifications. Usually these titanium plates should be bended and arched to better match the three-dimensional contour of anchored jaw bones. However the optimal bending of the titanium plate sometimes is difficult and time-consuming especially for the inexperienced surgeons and in complicated cases. Excessive bending could also initiate residual stress and potentially worsen the mechanical properties of titanium plates(1).

The three-dimensional (3D) printing, or additive manufacturing, has been well developed in fabricating customized materials from the computer-generated digital files. In recent years, 3D printing of patient-specific medical implants has been evolving with the newly-emerged technology of powder bed fusion, which enabled the melting of metals and further shaping of devices(2). In September 2015, China's innovative 3D printed hip joint prosthesis was commercially certified by China's State Food and Drug Administration. In February 2016, the world's first 3D printed patient-specific titanium cranial/craniofacial plate implant got the U.S. Food and Drug Administration's approval. Beyond that, a number of other printed implants have showed excellent performance in clinical research. These printed medical implants are majorly from pure titanium or Ti6Al4V alloy, which exhibit good resistance to fatigue and corrosion and are considered the most biocompatible metal(3). Relying on individualized imaging data, the printed implants are patient-specific and adapt to the anatomical structures precisely. Since the additive manufacturing is ultimately different from the conventional multi-step production operations, it could reduce costs and lead times, especially in printing complex devices for individualized cases. While in clinical applications, 3D printing of customized implants are expected to facilitate surgical operation, reduce application duration and improve precise restoration(4). It is predicted the application of 3D printing technique in medical area may bring forward another major advance toward personalized medicine(5). Many more customized medical implants will be approved in the future across the world.

With the advent of metal additive manufacturing, the 3D-printed patient-specific titanium plates have been successfully fabricated. In 2012, Per Derand et al. reported the first application of 3D-printed titanium plates with the established workflow from imaging, via virtual design, to manufacturing of cutting guide and customized titanium reconstruction plates, and its utility in the fibula-based mandibular reconstruction surgery. The pre-printed plates did facilitate the operation and reduced the operation duration about half an hour though the postoperative accuracy of the grafted bone was modest compared with the virtual planning(6). Simultaneously, Leonardo Ciocca et al. reported the computer-aided designing and manufacturing in guiding secondary mandibular reconstruction of a discontinuity defect involving the employment of the surgical guide and printed titanium reconstruction plate in surgical transferring of virtual planning(7). In 2013, Simona Mazzoni and Leonardo Ciocca et al. applied the same surgical protocol in a study group of seven mandibular reconstruction patients and compared its advantages with the standard pre-plating technique on stereolithographic models in a control group. The results revealed the computer-aided surgical protocol was viable in reproducing the patients' anatomical contour, giving the surgeon better procedural control and reducing procedure time(8). In 2015, Simona Mazzoni et al. further developed the computer-aided designing and manufacturing technique in fabricating surgical cutting guides and titanium fixation plates in upper maxilla repositioning surgery without an occlusal wafer. The study result confirmed the high accuracy in transferring the virtual planning by using the surgical guides and fixation plates(9).

In reviewing the literature, the application of 3D printing of titanium fixation plates in jaw surgery are available only at two centers currently: the Maxillofacial Surgery Department of S Orsola Malpighi Hospital in Italy and the Oral and Maxillofacial Surgery Department of Lund University in Sweden(6,7). The published preliminary work have proved the prospect of 3D-printed titanium plates in promoting mandibular reconstruction surgery and upper maxilla orthognathic surgery though their printed titanium plates looked rather bulky and the sample sizes were small and there is still lack of qualified randomized controlled trials between the printed and the conventional titanium plates. To better benefit from the burgeoning use of 3D printing in health care, we will develop a new designing and manufacturing protocol in printing customized fixation plates, which will be designed in specific loading circumstances and will perfectly adapt to the anatomical structures of the jaw. It is imperative to conduct a feasibility study in exploring the application of 3D printing of titanium fixation plates in jaw surgery based on our patients.

This is an open-label, prospective, single-arm, and single-center interventional clinical study.

Three-Dimensional Printing of Patient-Specific Titanium Plates in Jaw Surgery: A Pilot Study

Three-Dimensional Printing of Patient-Specific Titanium Plates in Jaw Surgery: An Open-Label, Prospective Pilot Clinical Study

The accuracy of using the 3D-printed customized titanium plates in transferring the virtual surgical plan.

1) the uneventful application of the 3D-printed patient-specific titanium plate in jaw surgery without any minor revision; 2) the final restored outcome being optimal based on clinical parameters.

An adverse event is defined as any untoward medical occurrence in a patient administered the 3D-printed patient-specific titanium plate, which may or may not necessarily have a causal relationship with this new device.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
3D-Printed Patient-Specific Surgical Plates Versus Conventional Surgical Plates in Jaw Reconstruction	NCT04635865	Mandibular Neop... Maxillary Neopl... Dentofacial Def...	3D-printed pati... Conventional co...	18 Years -	The University of Hong Kong
Three-Dimensional Printing of Patient-Specific Titanium Plates in Jaw Surgery: A Pilot Study	NCT03057223	Mandibular Neop... Maxillary Neopl... Dentofacial Def... Maxillofacial I...	3D-printed pati...	18 Years -	The University of Hong Kong

Spots Global Cancer Trial Database for dentofacial deformities