✕
☰

The future of 3D bioprinting in precision health

by

Paul Goodwin, science director, GE Healthcare Life Sciences, discusses how 3D bioprinting could advance precision health in the future.

In the US alone, there are over 120,000 people awaiting organ transplants annually and fewer than 15,000 donors. What if we could manufacture organs from cells and essentially solve this shortage without any donor necessary? Perhaps ambitious. But perhaps possible.

While 3D bioprinting may seem like a pipe dream, it could have major positive implications on the healthcare system. But of course, as my mentor in graduate school liked to say, “if it was easy it would have already been done.” These three hurdles --  Materials, Vascularisation, and Regulatory Approval—will be the biggest challenges to overcome before 3D bioprinting becomes a reality.

The Evolution of Biotherapy & Precision Medicines

The first biotherapies were recombinant proteins that served to provide man-made alternatives for patients who lacked the ability to make sufficient quantities naturally. In 1982, Genentech transformed the treatment of patients with Type 1 and Type 2 diabetes when they delivered the first human insulin to the market. A host of biotechnology companies followed suit with new therapies, and today, seven of the ten best-selling drugs are recombinant proteins used to treat a host of diseases from rheumatoid arthritis to diabetes to cancers.

In 1986, the first antibody-based therapeutic was created using a mouse monoclonal antibody against human CD3 to prevent kidney transplant rejection (muromonab-CD3). However, the use of this therapeutic was limited to acute cases because long-term use caused a myriad of problems due to human-mouse antibody interactions. Over the years, a number of improvements have been made to genetically engineer therapeutic antibodies to be more human-like and today, five of those seven top-selling protein therapeutics are antibodies with over 100 currently on the market and hundreds of others in development.

Following the success of mAbs, the industry brought us another step towards truly precise medicine: using cells as therapeutic agents. In the most common scenario, immune cells are removed from the patient and genetically modified to recognise cancer cells within the patient. The modified immune cells are then multiplied outside of the patient and then re-introduced to the patient where they now recognise a patient’s cancer and mount a response. This technology, called T cell therapy, is the basis of recently approved therapies to treat blood-based cancers (lymphomas and leukemias) that are resistant to conventional therapies. With recent approvals of the first two T cell therapies, the biotech industry is just beginning to harness the clinical potential of these incredibly personalised medicines.

However, T cell therapy is only the beginning in our journey towards precision health. If all we accomplish with these types of treatments is T Cell therapies we will have made a huge patient impact, but we will have missed out on the lion’s share of the opportunity in healthcare.  

Might Future Precision Medicines actually be 3D printed organs?  

The number of people awaiting organ transplants is growing three times as fast as the number of donors. Patients that do not receive transplants within six months of diagnosis are unlikely to ever receive one and will likely die as a result of organ failure. Even those patients that receive donated organs most often face a lifetime of immunosuppressant therapy and associated iatrogenic diseases. This pressing need represents a tremendous burden on the healthcare system as the patients awaiting organs consume a disproportionally large portion of healthcare dollars (dialysis, chronic heart failure, etc.). In addition to the large vital organs, there is a need for less “sexy” tissues and organs in orthopaedics (knee and spine cartilage), urology (ureters and bladders), reconstructive surgery (cranial defects, mandibular repair, etc.), obstetrics and gynaecology (ovary reconstructions), and other areas that contribute to significant pain, suffering, and billions of dollars in economic loss.

Whenever there is such a difference between supply and demand, new technologies and business models have been introduced to meet the demand. Hence, comes the idea of additive manufacturing for regenerative medicine or simply 3D bioprinting (3DBP). Additive manufacturing of mechanical parts or entire pieces of equipment have made a tremendous impact on costs, resources, time, and waste reduction in traditional manufacturing industries. So we’re left with the question of whether we can swap resin for cells, and print organs to render the same effect for the healthcare industry. Marketing studies predict that the current market size for 3DBP is approximately $350M almost entirely for research and applied markets. By 2021 it is estimated that the market will expand to $1.8 with $1.2B of that being in clinical applications. [BE(H1]

Can the industry create an infrastructure to 3D print regulated tissues and organs to address the clinical needs in Regenerative Medicine? It will require knowledge of traditional additive manufacturing, a digital infrastructure to tie workflows together from sourcing to patient management to in-process quality control. And we’ll have to solve these three major challenges first.

Materials

In additive manufacturing it is important to control the physical properties of the part that is being manufactured. The shape, strength, flexibility, chemical resistance, surface finish, etc. must be tightly controlled. In printing mechanical parts, these properties are controlled by the choice of printing technology and printing materials. 3DBP is not so different. We can’t just start printing cells; those cells must be printed into a matrix of material that provides for the support, shape, and mechanical properties of the desired tissues and organs. And we can’t just focus on providing the physical properties; these materials must also be chemically compatible with the cells during printing and with the patient when implanted.

Even the ways in which we would deposit the materials--the printing technology--must be carefully selected. The materials in 3DBP are referred to as bioinks. One approach is to try to use a single bioink for everything that you might want to print, but biology has taught us that the space between the cells is critical to the biology of the cells. We need a vast range of materials to properly support, maintain, and regulate the cells within tissues and organs. Think of it as the equivalent of comparing a pencil drawing by M. C. Escher to the elaborately and intricately coloured paintings of Jean-Claude Monet. Biology prefers Monet. For over a year now we have been working with Dr. Ramille Shah at Northwestern University. Ramille has developed over 300 different “colours” of bioinks and PAINTS for constructing biological tissues. One of material of great interest is hyperelastic bone. This PAINT is more than 90% hydroxyapatite (the mineral in bones) with the remainder being binders, elastomers, and agents that help make the PAINT printable. Once printed, most of the added materials evaporate or can be washed away leaving a bone-like material that can be made as flexible as tissue paper or as rigid as a solid bone.

Vascularisation

It is not enough to create a physical and chemical environment for the cells. You must also create a biological environment that will support the cells. One of the most significant challenges in this regard is creating a blood supply to nourish the cells, supply oxygen, and carry away waste. In the body, any cell that is more than the width of a hair away from a blood supply will suffer. Moreover, the natural vasculature does an amazing job of providing uniform perfusions (equal supply of nutrition and oxygen across space) as well maintaining low resistance to flow. Most human attempts to recreate a viable vascular bed fail to deliver both perfusion and low flow resistance. If we look at native tissues we see that the vasculature is not neatly engineered but rather resembles a semi-chaotic network of vessels. We have been working with Jay Hoying at Advanced Solutions Life Sciences (ASLS) who stumbled across a way to create these more native-like vasculatures. Years ago, Jay was working as a young investigator studying microvasculature. For his experimental model, he was using abdominal fat from mice. By luck he discovered that torn up small pieces of microvasculature will spontaneously grow new vessels (angiogenesis) and that these new vessels will self-assemble into a vascular bed that recreates the semi-chaotic native structure. When he placed these beds with different tissues (heart, liver, kidney, neural) they would spontaneously create vascular beds similar to what you would find on those tissues in the body. We are now working with ASLS to use cellular imaging instruments to create a fully automated agile work station for printing, verifying (physical, chemical, and biological), and maturing vascularised tissues.

Regulatory Approval

One of the biggest challenges around 3DBP has been regulatory approval. The FDA normally regulates products and devices where the same design is used to treat many people. In the case of a biologic, one manufacturing batch can treat thousands to millions of people. The regulatory process assures that the product is safe and effective and that each of them are exactly alike. As with other ‘precision medicines’ like T cell therapies, the major advantage of 3DP is that each product is tailored to the patient including using cells from the patient to create the tissue or organ. The downside, of course, is this poses a significant challenge for regulators because the cells are ideally suited to each individual patient but it also means that each treatment is unique. The FDA has been faced with the need to create new ways of regulating the process and not just the product. In the case of autologous T-cell therapies, recent approvals have opened the way for regulators to create guidelines for the manufacturing of bespoke and autologous tissues and organs. The FDA works closely with industry partners, including some leaders at GEHC, to create guidances for bespoke devices created using additive manufacturing, for printed biocompatible devices, and for living tissues and organs. This has provided a path to regulatory approval, though we haven’t quite mastered it yet.

There is an important role for in-process quality control, verification, and validation that spans the entire workflow starting with patient imaging and ending in the creation of a custom 3D model for each patient. As each layer of a tissue or organ is printed, it will be necessary to verify that it is physically, chemically, and biologically per design. Prior to implanting the device into a patient, the clinician will help validate that the final mature part is working, viable, and mechanically fits into the individual patient. This vision will likely create a scenario where the entire process is placed close to the clinician and the patient!

Start with the Low-hanging Fruit: Bringing 3D Bioprinting to Life

Regenerative Medicine is not new. Bioengineers and clinicians have been working in this field for decades but we are at a nexus: for the first time in human history we can harness the convergence of biology, 3D printing, digital analytics, and, perhaps most importantly of all, a regulatory environment that is poised to consider personalised, per-patient, therapies. There are significant efforts taking place in academia, biopharma, and medical device companies. Some companies are focusing on very near-term needs in Research and Applied Markets and foregoing the Clinical market at least for now.

We are indeed still years before we can deliver a fully functional major organ system in a clinical setting. Kidneys, livers, lungs, hearts, and neurological systems will have to wait for more development. I would argue that there are a number of “easier” tissues that are more near-term and that there is much that we can learn by starting now. After all, if we wait until we can deliver fully functional organs we will will have to stop to work out the business models, supply chain, regulatory affairs, and a host of other challenges that will have to be addressed before therapeutic delivery.

For instance:

It might be a decade or so before we can print clinically viable replacement vital organs like kidneys but, with concerted effort, we can get there by letting near-term tissues to pave the way.

[BE(H1]

BCC Research

Back to topbutton