Unprecedented advances in biomaterials, cell biology, 3D printing and medical imaging have attracted the attention of the clinical community across Australia. Projects with tangible outcomes are emerging that have prompted the establishment of entities to manufacture customised 3D printers for specific applications. There are also commercial opportunities for formulations and manufacture, opening new job opportunities for technicians working alongside researchers and surgeons.
In isolation none of these components delivers the clinical solution – it’s a package that must be tied together with rigorously tested surgical protocols to ensure delivery of real benefits to our communities. Productive collaboration is needed between researchers, suppliers, printer manufacturers, clinicians, surgical teams, regulators and patients.
We must address ethical issues in parallel with technological advances. We need to ask who will have access to these advances. What protections or support will they need? Are our regulatory mechanisms up to the task of assessing whether the new treatments are safe, effective and reliable? This kind of approach is needed to ensure potential risks and benefits are fully assessed for the individual and for broader society, that patients receive all the information they require to make informed decisions before undertaking treatment, that any improvement of materials, techniques or procedures are accessible to patients and that clinical follow-up is maintained.
Let’s look at an example of what these advances entail. The ARC Centre of Excellence for Electromaterials Science (ACES) has developed customised 3D printing systems to enable progress in medical technologies. These printers allow advanced materials to be combined with developments in cell biology to enable deployment in clinical environments. The convergence of advances in disparate fields means the rate of technological progress and the implementation of these are unprecedented.
Given the speed and scope of these applications for 3D printing, it’s important to ask whether the checks and balances that ensure safety, regulatory and policy issues are being developed and to ask whether there might be unexpected ethical concerns arising from this rapidly expanding area of research.
The development of material formulations containing cells, ‘bioinks’, for these customised printers enables the creation of 3D structures with cells strategically distributed throughout. The resulting structures are being used for cartilage regeneration in damaged knees, to fabricate missing ears for microtia patients, islet cell transplantation to treat diabetes and even to create 3D printed neuronal networks. These neural networks will provide new insights into neurological disorders such as epilepsy, schizophrenia and Alzheimer’s disease as well as providing a platform for testing potential treatments on the bench.
Given the speed and scope of these applications for 3D printing, it’s important to ask whether the checks and balances that ensure safety, regulatory and policy issues are being developed and to ask whether there might be unexpected ethical concerns arising from this rapidly expanding area of research.
Integrated into ACES is the Ethics, Policy and Public Engagement program. There you will find a group of researchers, philosophers, ethicists, political scientists and lawyers, who ask such questions daily.
To give a sense of how ACES is contributing to the technical and ethical regulatory aspects of 3D bioprinting, below are some current clinical applications in development and the ethical, regulatory or policy issues they raise.
Cartilage regeneration
In collaboration with Professor Peter Choong and his team at St Vincent’s Hospital Melbourne we developed a bioink containing adipose (fat) stem cells that can be used for cartilage regeneration. 3D structures containing the cells will be printed directly into the knee defect using a customised printer – the ‘biopen’- to ensure effective cartilage regeneration precisely where needed.
Once harvested the cells need to be further developed to ensure cell survival before, during and after the printing process.
Alongside the technical developments behind the biopen, there is a need to establish that cartilage regeneration treatment is safe and effective for patient use. For example, the biopen must be manufactured at the highest standard to ensure consistent hardware performance resulting in consistent delivery of the bioink. Identification of reliable and reproducible sources of the bioink components is critical. Surgical procedures need to be developed to enable patient cells to be harvested without impurities. Once harvested the cells need to be further developed to ensure cell survival before, during and after the printing process.
These developments must be optimised and tested in the lab, then in animal trials, before human clinical trials can begin.
Testing on humans is important. By using the patient’s own cells, the risk of rejection of the bioink and cartilage is much lower than if the cells were synthetic or from an animal or donor. It’s necessary to ensure that the surgery is safe and effective, the resulting cartilage growth occurs at the point of the damaged tissue without unwanted side effects and that it performs in a similar way to the patient’s natural cartilage.
Further research will also be needed to monitor long-term outcomes for patients, their mobility and overall health and the cartilage growth itself, to ensure it retains the same structural and functional properties of natural cartilage.
3D printed ears
Building on the above research, is the potential to develop 3D printed ears, a project developed in collaboration with Doctor Payal Mukherjee’s team at the Royal Prince Alfred Hospital, Sydney. To create a missing ear, cartilage must grow within a structure with a defined shape and the appropriate distribution of mechanical properties.
The 3D printed ears will be created for patients born with one ear, or a significant ear deformity (such as the condition microtia). The shape and fine features of the patient’s opposite ear are captured by a scanner to 3D print a mirror image structure. The distribution of stiffer and softer ear parts is achieved by appropriate arrangement of 3D struts, making up the more solid parts in the shape of the ear. The final printed component is a softer gel-like material capable of facilitating cartilage growth for the patient’s own stem cells. The implant is inserted under the patient’s skin giving the appearance of a matching ear.
It’s important to recognise the value to patients that could come from customised implanted treatment to address structural impairments, while ensuring safety and long-time stability.
In addition to the requirements for knee cartilage repair, printing ears requires development of an imaging and software package, as appearance is important. Patients with ear deformities often experience ostracism and possible hearing impairment. Some may view this treatment as primarily cosmetic however the impact on the self-esteem of children who have microtia can be significant. Printed ear structures implanted under the skin may provide treatment that enhances their capacity to engage socially and use everyday items such as hats or glasses without adjustment.
If this treatment proves successful there will be further opportunities to develop treatments for other cranio-facial impairments. It’s important to recognise the value to patients that could come from customised implanted treatment to address structural impairments, while ensuring safety and long-time stability. Previously people with significant impairments have been subjected to cosmetic implants that have been prone to infection or degradation over time.
For these treatments to achieve their potential, rigorous testing and quality control of the printer, stem cell harvesting and development processes, and long-term monitoring, are essential. Training of a new kind of clinician, who understands and can control the balance amongst aesthetics, function, comfort and patient safety, as well as mastering the techniques of scanning, printing and implantation, will also be required.
Structures for Islet Cell Transplantation
Transplantation of donor islet cells into type-1 diabetic patients is an approved treatment. In collaboration with Professor Toby Coates’s team at Royal Adelaide Hospital, we plan to improve this treatment by encapsulating donated islet cells in a 3D printed structure, to protect them during and after transplantation. ACES have developed bioinks that enable the printing of islet cells within 3D structures. This should result in patients having more effective and readily managed blood sugar control compared with using insulin injections.
Translation to the clinic will be dependent on high-end manufacturing to deliver customised printers to the clinic, appropriate sourcing of components for bioink formulations and development of protocols to ensure safe handling of living donor cells. A key challenge is for the printing process to consistently ensure high quality printing of viable islet cell bioinks.
If this treatment were low-cost, safe and effective, it would have a profound effect in reducing healthcare costs associated with managing diabetes.
Other challenges involve ensuring that donor cells are compatible to patients, risk of infection is reduced, developing safe surgical techniques and monitoring islet cell function to regulate blood sugars once transplanted. Ideally this research will allow type-1 diabetics to be treated once (or at long intervals) via a relatively minor surgical procedure, and for the cells to function to provide enduring treatment without the inconvenience and potential risks that comes from insulin dependence.
If this treatment were low-cost, safe and effective, it would have a profound effect in reducing healthcare costs associated with managing diabetes. Regulation of the treatment and long-term monitoring throughout patients’ lives will be required as there will need to be a realistic assessment of on-going costs, potential side-effects and management of patient expectations that the treatment is a cure-all.
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