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Large skull defects present a reconstructive challenge. Conventional cranioplasty options include autologous bone grafts, vascularized bone, metals, synthetic ceramics, and polymers. Autologous options are affected by resorption and residual contour deformities. Synthetic materials may be customized via digital planning and 3D printing, but they all carry a risk of implant exposure, failure, and infection, which increases when the defect is large. These complications can be a threat to life. Without reconstruction, patients with cranial defects may experience headaches and stigmatization. The protection of the brain necessitates lifelong helmet use, which is also stigmatizing.
Our clinical trial will formally study a hybridized technique's capacity to reconstruct large calvarial defects.
A hybridized technique that draws on the benefits of autologous and synthetic materials has been developed by the research team. This involves wrapping a biodegradable, ultrastructured, 3D-printed scaffold made of medical-grade polycaprolactone and tricalcium phosphate in a vascularized, autotransplanted periosteum to exploit the capacity of vascularized periostea to regenerate bone. In vitro, the scaffold system supports cell attachment, migration, and proliferation with slow but sustained degradation to permit host tissue regeneration and the replacement of the scaffold. The in vivo compatibility of this scaffold system is robust—the base material has been used clinically as a resorbable suture material for decades. The importance of scaffold vascularization, which is inextricably linked to bone regeneration, is underappreciated. A variety of methods have been described to address this, including scaffold prelamination and axial vascularization via arteriovenous loops and autotransplanted flaps. However, none of these directly promote bone regeneration.
We expect to have results before the end of 2023. As of December 2020, we have enrolled 3 participants for the study.
The regenerative matching axial vascularization technique may be an alternative method of reconstruction for large calvarial defects. It involves performing a vascularized free tissue transfer and using a bioresorbable, 3D-printed scaffold to promote and support bone regeneration (termed the
Australian New Zealand Clinical Trials Registry ACTRN12620001171909; https://tinyurl.com/4rakccb3
DERR1-10.2196/36111
Cranioplasty, as a procedure for reconstructing cranial defects, has been around for thousands of years. Despite significant advances in technology and extensive research into bone biology, the reconstruction of the calvarium still poses a significant challenge for surgeons [
These issues with autologous bone grafts have prompted research into suitable synthetic alternatives; metals, synthetic ceramics, and polymers are all advantageous in different ways but have significant fallbacks that relate to infection, malleability, and in situ inflammatory or exothermic reactions [
The success of these cellular impregnation techniques for promoting acceptable osteogenesis has been shown to be directly linked with the vascularity of the constructs used [
Throughout the literature, there is a clear consensus that an ideal cranioplasty graft should have the following: (1) long-term mechanical protection for the brain and meninges until the host bone regenerates, (2) acceptable cosmetic contouring, and (3) graft materials that promote bone growth through osteoconductive and osteoinductive mechanisms that are governed by degradation kinetics and biological interactions. Moreover, if the prosthesis remains, it should not cause undue complications or patient inconveniences.
The composite PCL-TCP scaffold acts as a synthetic analogue of two major bone constituents—hydroxyapatite and collagen. As cranioplasty materials, PCL-TCP fulfill the above criteria by retaining strength and promoting osteoconduction over extended remodeling periods via consistent degradation mechanics and with minimal adverse effects. As a consequence of advancements in tissue engineering, the demand for customizable implants is understandably intensifying. This case highlights the potential of harnessing emerging biomedical technologies and 3D tailoring to meet individual and specific clinical needs.
In a case report published by Yogishwarappa et al [
Osteoinduction and, as a consequence, osteogenesis are intricately linked to angiogenesis in normal fracture healing [
Investigations into periosteal flaps as sources of axial vascularization are well documented in animal models. Nau et al [
The research by our group at the Centre for Regenerative Medicine (Queensland University of Technology, Brisbane, Australia) has focused on the reconstruction of critical-sized bone defects for more than 1 decade [
Although osteoinductive scaffolds have been trialed clinically by a number of authors [
The regenerative capacity of vascularized corticoperiosteal tissue is well recognized [
Between 2016 and 2018, we undertook a preclinical study that evaluated the concept of RMAV by using a corticoperiosteal flap from a sheep’s hind limb and a 3D-printed mPCL-TCP scaffold to reconstruct 6- and 3-cm intercalary defects of the tibia [
Given these successes in preclinical research and our first-in-human case, we feel that the logical next step for the emerging RMAV technique should be a robust feasibility clinical trial examining the behavior of the mPCL-TCP implant and postimplantation bone healing. Once appropriate outcome measures are clearly defined, it may then be appropriate to proceed to a randomized clinical trial in which RMAV is compared to other clinical techniques for a given bone defect.
The use of an mPCL-TCP scaffold, in conjunction with a corticoperiosteal tissue transfer, is a safe and effective approach to reconstructing critical-sized bone defects in the calvarium.
The primary objectives of our trial are to (1) determine the feasibility and efficacy of using an mPCL-TCP scaffold, in conjunction with a vascularized corticoperiosteal tissue transfer, for the reconstruction of calvarial bone and (2) determine the clinically relevant functional outcomes that follow the reconstruction of an acquired calvarial defect by using an mPCL-TCP scaffold in conjunction with a vascularized corticoperiosteal tissue transfer.
The secondary objective is to collect data to allow for the later evaluation of the cost-effectiveness of this approach and a view of its applications across a broader range of clinical situations.
Our study will be a single-arm feasibility trial that evaluates the outcomes of using an mPCL-TCP scaffold, in conjunction with a vascularized corticoperiosteal tissue, in participants with acquired defects of the calvarial bones of the skull resulting from trauma, malignancy, or infection. The study will capture data that will be used to inform the design of future clinical trials in this area.
The mPCL-TCP scaffold that will be used in the study will be manufactured by the trial sponsor—Osteopore International Pte Ltd (Singapore). Osteopore products are made of a US Food and Drug Administration–approved polymer (K051093) called
The study will be an open-label, single-arm feasibility trial that will be jointly coordinated by the investigators at the Princess Alexandra Hospital (PAH) in Woolloongabba (Queensland, Australia), the Herston Biofabrication Institute, the Australian Centre for Complex Integrated Surgical Solutions at the Translational Research Institute (Queensland, Australia), and the Centre for Regenerative Medicine at the Institute of Health and Biomedical Innovation in Kelvin Grove (Queensland, Australia). With the aim of calvarial reconstruction, the study population will include any patient with a calvarial defect that is amenable to reconstructive approaches that involve using the Osteopore implant, following discussions by the multidisciplinary team (MDT) of investigators.
Our inclusion criteria are as follows:
Acquired defect of the calvarium that is suitable for reconstruction by using a PCL-TCP scaffold system and performing a corticoperiosteal tissue transfer
Patients aged >18 years and <55 years
Patients aged >55 years may still be eligible for the trial after an assessment by and at the discretion of the investigators, and documentation to this effect will be provided by the clinic for the trial documents pertaining to such patients
Patients who are willing and able to comply with the study requirements
Patients who are eligible for undergoing magnetic resonance imaging (MRI; ie, no implanted metal or metal devices and no history of severe claustrophobia)
Patients or their guardians are capable of providing valid informed consent
Our exclusion criteria are as follows:
Active infection at the time of study inclusion (in chronic infection cases, active infections may manifest as the result of a failed trial of being taken off antibiotics)
Patients or their guardians are unwilling or unable to provide fully informed consent
Patients with a known history of immunodeficiency, including a history of HIV, concomitant systemic corticosteroid therapy, chemotherapy, synchronous hematological malignancy, or other causes of a secondary or primary immunodeficiency
Patients with a known severe concurrent or intercurrent illness (eg, a cardiovascular, respiratory, or immunological illness; psychiatric disorders; alcohol or chemical dependence; or possible allergies [including allergy to polycaprolactone]) that would, in the opinion of the primary investigator, compromise their safety or compliance or interfere with the interpretation of study results
Women who are currently pregnant, are breastfeeding, or are planning to become pregnant within 2 years after the reconstruction surgery
Women of childbearing potential who are not using an appropriate contraceptive method
Patients who are ineligible for undergoing MRI
Patients with a life expectancy of <36 months.
Patients who are unable or unwilling to comply with the study requirements
This feasibility trial will recruit a total of 10 patients.
As a part of their clinical management, patients with acquired calvarial defects from the neurosurgery clinic or the skull base/head and neck clinic at the PAH will be reviewed as candidates for cranial reconstruction via the Osteopore implant by the MDT. Referrals to this process will be accepted from throughout Queensland via standard pathways, and national out-of-catchment referrals will be considered for special circumstances in which the PAH has unique expertise. The specific conditions assessed may include acute and subacute pathologies (major acute fractures with bone loss, bone malignancy, etc) or chronic pathologies (osteomyelitis, osteoradionecrosis, etc).
The relevant specialties that will be involved in the MDT review and decision-making process include infectious diseases, plastic and reconstructive surgery, neurosurgery, infectious diseases, and engineering. The MDT will determine the best treatment option for each patient. Should cranial reconstruction by using an Osteopore implant be recommended by the MDT, the patient’s treating specialist will discuss the case with the coordinating principal investigator, and the extent to which the potential participant satisfies the trial’s inclusion and exclusion criteria will be determined collaboratively. Written informed consent will be obtained following the MDT’s decision and prior to the conduct of the cranioplasty. Informed consent must be completed prior to any study-related activities.
Patients will be followed up for at least 24 months from the time of initial reconstruction. Given that the PAH collectively sees around 5 patients per year with significant bone defects, the recruitment phase will take place over 2 to 3 years to recruit a total of 10 patients for the feasibility analysis.
In addition to the prospective recruitment pathway detailed above, patients who have undergone cranioplasty via the Osteopore implant may also be recruited into the study at the discretion of the sponsor and coordinating principal investigator.
Prior to deciding on a treatment pathway, medical imaging will be conducted as a part of each patient’s standard clinical management, which may include CT and/or MRI scans of the head and neck, as well as white cell–labeled, whole-body bone scans. The imaging results will inform the clinical assessment performed by the neurosurgeon or the skull base/head and neck surgeon involved in the care of the patients and inform the MDT review. Clinical notes, including medical histories, will also be generated as a part of the clinical care process of patients during their clinical management. Imaging data and clinical notes that relate to the defects among patients and are collected prior to informed consent will be made available to the study participants as a part of the informed consent process.
A description of the patient journey is summarized in
Flowchart of patient journey. CT: computed tomography; MDT: multidisciplinary team; mPCL-TCP: medical-grade polycaprolactone and tricalcium phosphate; MRI: magnetic resonance imaging; WC: white cell. *see "Eligibility Criteria" section; **antibiotic therapy, as indicated by infectious disease physician consultation.
The trial-related interventions will focus on capturing defined functional outcomes and, consequently, will require the collection of data at specific time points. CT and/or MRI scans of the head and neck will be used to identify complications and establish clinical and radiological evidence of union at 1, 12, and 24 months after surgery. As performing 2 CT scans in the first year during the postoperative follow-up period is standard clinical practice, the amount of ionizing radiation to which the participants are exposed will not exceed the amount of radiation that patients typically receive during standard clinical care. Additional CT and MRI scans may be performed during the follow-up period in accordance with patients’ clinical needs.
The other research-related functional assessments will include the administration of the Quality of Life After Brain Injury (QOLIBRI) and 36-item Short Form Quality of Life (SF-36) questionnaires at prereconstruction and at 1, 12, and 24 months after surgery.
The key primary end points for evaluation in our single-arm study are the time to the formation of stable, regenerated bone that is sufficient for protecting the brain (ie, radiographic or clinical evidence of bony union) and patient-reported outcomes. These primary end points serve as surrogate markers for satisfactory bone healing but, more importantly, are clinically useful for and relevant to the study goal and overarching purpose of the intervention. Functional outcomes are more difficult to measure reliably and are therefore secondary outcomes, which will be measured with the QOLIBRI and the SF-36 questionnaires [
Schedule of assessments.
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Multidisciplinary team review | Enrollment | Reconstruction | Follow-up period | |||||||
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1-month review | 3-, 6-, 9-, 12-, 15-, 18-, 21-, and 24-month review | ||||||
Time pointa | −t2 | −t1 | 0 | T1 | T2-9 | ||||||
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Informed consent |
|
✓b |
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|||||
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Eligibility screen |
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✓ |
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|||||
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Demographics |
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✓ |
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|
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|||||
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Medical history and medical review | ✓ | ✓ |
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✓ | ✓ | |||||
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|||||||||||
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Infection management |
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✓ |
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|
|
|||||
|
Reconstruction |
|
|
✓ |
|
|
|||||
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|||||||||||
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Computed tomography of head | ✓ |
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✓ | ✓c | |||||
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Magnetic resonance imaging | ✓ |
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✓ | ✓ | |||||
|
White cell–labeled, whole-body bone scan | ✓ |
|
|
✓ | ✓ | |||||
|
Quality of Life After Brain Injury questionnaire |
|
✓ |
|
✓ | ✓c | |||||
|
36-item Short Form Quality of Life questionnaire |
|
✓ |
|
✓ | ✓c |
a“t” represents a time point prior to the intervention, and “T” represents a time point after the intervention.
bDenotes a clinical activity from which data may be utilized for the trial analysis.
cTrial-related assessment at 12 and 24 months only.
The statistical analysis of the data will be undertaken by the Queensland Facility of Advanced Bioinformatics (QFAB). QFAB personnel will use REDCap (Research Electronic Data Capture) software (Vanderbilt University) to design and validate an electronic data capture system for use in the trial. Deidentified data will be entered into the REDCap-based electronic data capture system by a member of the research team after the coordinating principal investigator or delegate has certified each case report form (CRF). The database will contain validation ranges for each variable to minimize the chance of data entry errors. An audit trail will be created to maintain a record of the initial entries and changes made, the reasons for changes, the times and dates of entries, and the usernames of the people who made the changes. Data queries will be raised, and missing data or suspected errors will be resolved prior to locking the database and performing the analysis.
All patients who are registered for the trial will be accounted for in the (intention-to-treat) analysis. For retrospectively recruited patients, all data points may not be available for all assessments, or data collection may have occurred outside of the trial-specific window (eg, CT data are available for the 9-month follow-up but are not available for the 12-month follow-up). In such cases, these subjects will not be evaluated for a particular analysis unless the number of data points required for the analysis is enough, or a trend can be extrapolated from the data that were collected outside of the trial-specified window.
A quantitative analysis that relates to the evaluation of the cost-effectiveness of this approach will not be undertaken as a part of this study, as the data set will most likely be too small to achieve statistical significance. Instead, the outcome measures that have an impact on the financial burden for treating patients will be combined with data from other similar trials that are conducted in the future, and the analysis of health economics data will be undertaken at that point.
Statistical analyses of descriptive statistics for the demographic, primary, and secondary outcomes at each time point will be conducted. A comparison analysis of the questionnaire results at each time point and a univariate Cox regression analysis of the time to weight-bearing for the affected limbs will be performed due to the small sample size. Statistical significance will be defined as
The study represents a high-quality clinical study in which bias will be kept to an absolute minimum. The study will be heavily controlled with the well-defined inclusion and exclusion criteria that will ensure that the number of patients with confounding features will be reduced, thereby effectively minimizing sources of selection bias and increasing the homogeneity of the cohort under investigation.
The follow-up period is 24 months. Generally, we would expect to see sufficient bone regeneration for most extensive defects by this time. Ongoing care will be provided in accordance with the recommendations of the treating surgeons and other members with relevant specialties, as appropriate.
The trial will be conducted in accordance with the principles of the Declaration of Helsinki, Notes for Guidance on Good Clinical Practice (CPMP/ICH/135/95), as adopted by the Australian Therapeutic Goods Administration in 2000, and in accordance with the National Health and Medical Research Council’s National Statement on Ethical Conduct in Research Involving Humans [
It is the responsibility of the investigator to obtain written informed consent from each individual who participates in the study after an adequate explanation (in lay terms) of the aims; methods; objectives; and potential discomforts, risks, and benefits of the study is given. The investigator must also explain to the subjects that they are completely free to refuse to enter the study or withdraw, without prejudice, from the study at any time. Before enrollment into the study, each prospective candidate will be given a full explanation of the study. Individuals who are eligible and wish to participate will be provided the trial’s participant information and consent form (PICF) prior to participation. The PICF details all of the relevant aspects of the trial procedures. Potential participants will be given time to read through the information and ask any questions. The formal consent process will be undertaken by the principal investigator or the associate investigator and will be documented by the trial coordinator. The PICF will be submitted for approval to the Human Research Ethics Committee of the PAH. Participants will be provided with a copy of their signed PICF.
As of December 2020, we have enrolled 3 participants for the study. We expect to have results before the end of 2023.
We aim to evaluate the potential of tissue engineering with a bioresorbable, 3D-printed scaffold and autologous vascularized tissue transfer in the reconstruction of acquired calvarial defects. It is essential to undertake a prospective feasibility trial that formally explores this technique to establish its safety and efficacy. This trial will offer critical baseline data against which current and future implants can be compared. Tissue regeneration could be enhanced via scaffold refinements, including additives such as growth factors, osteoprogenitor cells, and vascular networks [
The project, as a whole, has a number of benefits for both individuals and society at large. It is expected that the results of our open-label feasibility trial will provide additional evidence on the effectiveness of the RMAV treatment approach for patients with calvarial defects for which contemporary surgical management may have a greater risk of failure or complications [
The RMAV technique may be an alternative method of reconstruction for large calvarial defects. It involves performing a vascularized free tissue transfer and using a bioresorbable, 3D-printed scaffold to promote and support bone regeneration (termed the
computed tomography
case report form
multidisciplinary team
magnetic resonance imaging
medical-grade polycaprolactone and tricalcium phosphate
Princess Alexandra Hospital
polycaprolactone and tricalcium phosphate
participant information and consent form
Queensland Facility of Advanced Bioinformatics
Quality of Life After Brain Injury
Research Electronic Data Capture
recombinant human bone morphogenic protein-7
regenerative matching axial vascularization
36-item Short Form Quality of Life
MW and DWH conceived the study. IGM, MW, DWH, SO, and MR contributed to the development of the protocol, in conjunction with Osteopore Limited. Osteopore Limited approved the final protocol. The trial sponsor—Osteopore Limited—will provide funding to support the non–standard-of-care components of this trial, including the design, manufacturing, and transport of the scaffold device from Osteopore Limited (Singapore). The practical costs associated with organizing the treatment of patients and the coordination of their care (ie, costs for both routine clinical care and the care provided as a part of the trial protocol) will be the responsibility of the investigators and will therefore be funded in kind by Metro South Health. Similarly, the costs for conducting the cranioplasty procedure, including the costs for conducting clinical follow-ups, will be funded by Metro South Health. Part of this work was funded by the National Health and Medical Research Council (investigator grant 2008018).
The mPCL-TCP scaffold that will be used in the study is manufactured by Osteopore Limited (Singapore) and will be provided free of charge by the company during the trial investigative phase. A senior coinvestigator (DWH) was a cofounder of the company that will manufacture the scaffolds that will be used in the trial. DWH has since left the company, has no ongoing financial involvement with Osteopore Limited, and is not currently receiving any financial benefits or other benefits from Osteopore Limited. Otherwise, no other types of financial involvement are anticipated or are apparent at the time of writing this protocol, for any and all investigators involved, that would lead to a conflict of interest.