3D Printing of Human Organs — Future Perspective & IP Scenario
Published on 25 May, 2016
Thousands of patients are waiting for a lifesaving transplant today.
Some of these are critical cases, and mortality in those patients is high due to a dearth of suitable donors.
3D-Printed organs may emerge as a life-saver for such patients.
A science writer and journalist, Jenny Morber, had shared a moving story in her blog about a three-year old boy’s ordeal to get a new heart. This was about eight years ago, when Troupe Trice was diagnosed with a rare and life-threatening condition where the heart is unable to relax between heartbeats. With no cure and very few treatments for restrictive cardiomyopathy, Troupe had to go for heart transplant. But that’s where his nightmare didn’t end.
The Trice family had to wait for two agonizing months to get a new heart. And, within a month, Troupe’s heart began malfunctioning, asking for emergency surgery for its replacement. Troupe survived with the second organ transplant. But by the time he celebrated his tenth birthday, his parents had to experience such harrowing time all over again with their younger child Henry suffering from the same disease. Thankfully, Henry also received his match quickly. Not every child is as lucky, though. The United Network for Organ Sharing (UNOS) states that an average wait for a child’s heart is about six months. And, the average wait time for a child of Henry’s size is about a year.
As per the UNOS, over 120,700 people are awaiting lifesaving organ transplants in the US, of which over 77,000 are active wait-list candidates. The mortality rate among such patients is quite high primarily due to non-availability of suitable donors. Morber’s blog quotes Howard Nathan, the president and CEO of an NGO called Gift of Life, stating that about 2.4 million people die in the United States every year. The problem of delay is pretty straightforward – currently only a human body can grow a complex human organ. Creating usable large complex organs within animals haven’t been as successful. This translates to one simple fact—many patients may never receive a match.
And those who successfully receive organs, along with their families, usually bear guilt and grief on benefiting from someone else’s pain. This makes the exercise more emotionally complex and taxing. Here, 3D printing in healthcare is fast appearing as a plausible option and quite a promising idea. 3D printing in the healthcare segment recorded robust sales in last couple of years, and is projected to expand at a CAGR of 19% to exceed $1.8 billion by 2020.
3D printing definitely has a potential to stem the rising metrics of unfulfilled demand for organs. But it may also fuel regulatory and patenting concerns in addition to several other challenges.
In this article, we’ll understand the development and current state of the 3D organ printing technology, and decipher the commercialization scenarios for the market segments, applications and materials to be used. We’d also talk about the major technology sub-segments, and discuss potential hurdles in safeguarding the 3D printing technology.
Development and Current State of 3D Printed Organ Technology
3D printing is the process of making three dimensional objects from digital files; it includes creating a virtual 3D model that’s transferred to a printing device which creates "image slices" by depositing successive layers of materials in order to create a desired structure.
3D printing has been used in various industries to create customized and on-demand components, healthcare being a rapidly growing application area.
3D printing of organs (also known as bio-printing) is a process of creating scaffolds, human tissue, and organs in controlled environments by layered deposition of materials. It also comprises of broader variations such as the functionalization of organs with living cells, grafting of tissue, and processes to create such systems.
Bio-printing is currently used for research, drug development & testing, and organ transplant purposes.
The overall principle of bio-printing is similar to generic 3D printing technology, except for modifications to the ink used and post-deposition functionalization of the 3D printed tissue.
Commercialization Scenario – Market & Technology Sub-segments
The technology required for bio-printing can be broadly classified as follows:
- Software Components
Used to scan a target object and convert it into a computer model, and ultimately, into a blueprint.
- 3D Printing Equipment
Which are mechanical/hardware components used to store and deposit ink on the printing platform through sequential layers in order to form a desired solid structure or scaffold. It further includes the equipment required for post-processing, such as solidification and incubation of organs.
Used as the ink to deposit and create your desired structure, it may or may not comprise of living cells at the time of printing.
Biomaterials can be further divided (based on printing approach) into:
- Scaffold-based structures
- Scaffold-free (direct) structures
Scaffold-based structures are functionalized with cells during post-processing steps, whereas in direct printing, live cells are deposited onto a platform to give desired functionality.
Similarly, the bio-printing market can be broadly classified as follows:
- Printing Methods: Such as magnetic levitation, inkjet, laser, and syringe based methods.
- Applications: Such as medical, dental, biosensors, consumer/personal product testing, and food and animal product bio-printing.
- Medical Sub Segments: Such as tissue and organ generation, medical pills, prosthetics and implants printing.
Geographic Market Share and Major Players
The global 3D printing market is expected to reach US$8.6 billion by 2020, whereas the healthcare segment is projected to reach US$1.2 billion with a CAGR of 19%.
The healthcare and aerospace sectors will be major proponents of this progress.
The US holds around 40% of the healthcare 3D market, followed by Europe.
Asia-Pacific’s (APAC’s) market is relatively small at this stage, but expected to grow at higher pace than the American market in the near future due to growing demand, lower costs, and government policies.
3D Systems and Stratasys are major market players in healthcare 3D printing.
Other market players include Digilab, EnvisionTEC, Invetech, MicroFab Technologies, nScrypt and TeVido BioDevices.
Healthcare product segments encompass implants (including dental), surgical guides, hearing aids, and tissue engineered 3D printed organs. However, implants occupy the largest share of the market currently, and tissue engineered application will grow at highest CAGR of 26% over forecast period.
Recently, researchers have successfully demonstrated the advantage and feasibility of 3D printed organs in clinical case studies to treat congenital cardiac and ear defects as well as in skin grafting for burn patients.
Over 120,700 people are registered for lifesaving transplants according to the United Network for Organ Sharing organization’s estimates. Mortality is high among those patients due to incompatibility with donors as a result of underlying elements. Bio-printed tissue and engineered organs may emerge as a promising option for such patients. Although this technology has the potential to address current needs, it may raise ethical and patenting issues along with other challenges.
Tissue and Organ Regeneration Applications
Research in this area has been growing, as evident from the following graph:
These include areas such as:
- Blood Vessel Regeneration
Lawrence Livermore National Lab has created functional 3D-printed blood vessels by combining biomaterial with living cells. These scaffolds help small blood vessels to develop on their own.
- Dental Implants and Artificial Enamel
Printed using ceramic materials with precursor amyloblastic cells.
- Pancreatic Tissue
The University of Virginia bioengineering lab has successfully printed artificial pancreatic tissue, which could help to find cures for chronic diabetic patients. Researchers also hope to fabricate muscle tissue that can be used to treat craniofacial defects such as cleft palates.
- Skeletal Reconstruction
EpiBone, a biomedical startup, has demonstrated the successful bio-printing of bone tissue, which can be used for skeletal reconstruction.
- Cartilage Fabrication
Scientists from Texas Technical University are currently developing a 3D printed cartilage tissue that could replace commonly torn or injured knee meniscus.
- Skin Imprinting
Organovo and L’Oreal have collaborated in the development of advanced cell technology for growing artificial skin. This is done under laboratory conditions using Organovo’s NovoGen bioprinter. A recent tie up between BASF and Poietis is focusing on a bioactive material called Mimeskin that’s used to test cosmetics and skin care applications.
- Neural Tissue Regeneration
University of Melbourne researchers have grown cortical tissue from stem cells to treat neural disease such as schizophrenia and autism.
- Liver Tissue Printing
Indian researchers and Organovo are working on a technology to produce artificial liver tissue in labs using a 3D printed matrix loaded with hydrogel comprising of glucose, proteins, and living cells.
Researchers from the University of Pennsylvania have experimented with small plastic chips that have defined microfluidic channels which act as scaffolds and stimulate human cell growth, aiming to construct artificial eyelids; this approach is termed as ‘Eye-on-a-chip’ technology.
Major Technologies Used in 3D Printing Living Tissue
- Selective laser sintering
- Electron beam melting
- Fused deposition modeling
- Laminated object manufacturing
Commonly Used Methods & Materials
Standard 3D printing equipment uses laser techniques such as selective laser sintering and its offshoots, electron beam melting, fused deposition modeling, laminated object manufacturing, and stereolithography processes to deposit the material on a printing platform in order to form solid structures. But when it comes to printing 3D human organs, techniques such as inkjet printing, pressure-assisted bio-printing, laser bio-printing, solenoid valve-based printing and acoustic-based printing techniques are used.
“Material” constitutes the ink portion of the bio-printing process. Materials used for printing are either powder type, gel-based biomaterials, or photocurable materials based on the organ requirement, which may or may not contain live cells. The commonly used materials for 3D printing of healthcare products are plastics, metals, ceramics, donor cells, bone cement, biomaterials, and so on.
Plastic materials are more commonly used due to their low cost and ease of manufacturing. Ceramics are a close second, but use of other cell-based materials ought to increase in the future.
IP Scenario in 3D Printing Human Organs
Major 3D Printing Technology Sub-segments
3D printing of human organs comprises the printing equipment, printing materials, design and modeling software, as well as services and/or processes to manufacture functional materials. Each component, needless to say, comes with its own unique IP perspectives and challenges.
3D Printing Software
3D organ printing involves complex steps to handle living materials — before they’re deposited on a printing platform, and beyond deposition — in order to stimulate the functioning of living cells in physiological manners.
These complex processes require stringent parametric control, which involves regulating factors such as temperature, pH, wetness as well as oxygenation and nutrient concentrations. Creation, storage and deposition require precision during processing as well, which chiefly involves condition-based algorithms. Such control algorithms are protectable by patents or copyrights.
Copyright protection covers source code from proprietary applications and programming, but provides competitors the freedom to develop equivalent software by using independently formulated coding techniques.
Patents on the other hand, protect the functionality of printing equipment and the sequential execution schema of working. It covers specific settings and working conditions that require specific chemical reaction parameters in order to perform the deposition steps in their broader sense.
Similarly, software for creating 3D models from scanned images can also be considered as protected IP. The current US patent regime affords protection to such software and computer programs, whereas a few jurisdictions allow such patents if the software in question meets certain innovation criteria.
Software algorithms used to create live tissue/cells required for 3D printing involve steps such as harvesting live cells, storage subject to specific parameters, and processing to accelerate their functionality as natural cells. Such recipes definitely have complex thought processes invested in them, and it includes non-obvious technical contributions and implementations to solve particular problems as well. This makes them patentable in most jurisdictions including the US and EP.
3D Printing Equipment
The functional components of a typical 3D printer include hardware and embedded software components that perform sequential tasks in order to deposit layers on a printing platform.
Hardware here comprises of scanners that scan the topographical details of a target organ, reservoirs to store the bio-ink material, and extruders that spray the printing material in precise patterns. These components have been patentable inventions for years, but new modifications in existing systems for cell printing require capabilities such as creation, storage, processing, and preservation of live cells before they are deposited.
The creation and operation of these hardware components require complex intellectual expertise, and ingenuity, which is patentable under current US and most international patent regimes.
3D Printing Materials
The materials used for 3D printing of organs differ for scaffold and direct print approach.
In the scaffold approach, a machine does not print live cells in order to create a human organ. It first creates a support structure for implanting functioning cells using the 3D printing process. Subsequently, live cultured cells are adsorbed on the surface of the scaffold using various proteins that render the organ functional once cells divide and form tissue, soon followed by the formative scaffold’s degradation.
Current provisions support patents for non-living material compositions for plastic, ceramic and metals without any cell components in it, non-living material deposition techniques, as well as methods for synthesizing those materials.
Living cells as they appear in their natural environment cannot be patented. Neither can arrangements of living cells, cultured natural cells, or incubated tissue materials. Man-made cellular materials or sub-components that require human intervention or alterations to produce however, can be patented.
Another approach for direct printing with live cells involves incubating naturally occurring cells in reservoirs and depositing them on a print surface in order to product functional tissue. This process cannot be patented however, as there’s nothing particularly inventive about it, and it doesn’t meet the basic criteria of novelty.
Possible Hurdles and Current School of Thought in Protecting 3D Printed Organ Technology
Patenting human organs is prohibited under section 101 of US patent law in order to prevent monopolization of something that occurs naturally.
While there are changes afoot due to the advent of tissue engineering that have added exceptions and limitations to current patent laws, the US patent court strictly prohibits any intellectual protection on natural human body parts.
Even the America Invents Act prohibits claims around the “human organism”, which basically restricts any patents towards naturally occurring tissue, organs, and the body. By this definition, bioengineered tissue and cells are still human organisms; they’ve originated from human stem cells and perform the same functions that naturally occurring cells would (e.g. bioengineered beta cells of pancreas will secrete insulin peptide similar to a naturally-occurring peptide). Further, similarity in the end product and functions may render them non-patentable.
There are others who view genetically engineered and human modified organisms and tissues as “man-made” and different from naturally occurring cells, and therefore, they can be patented.
Tissue engineered cells that are modified — and discernibly different from natural cells — can be patented under this assumption if they contain any human intellectual intervention, as established during the Diamond vs Chakraborty case.
In such a scenario, 3D printed organs are produced by harvesting stem cells and processing/growing them under specific conditions, and in addition, printing on a customized surface — activities that clearly require human/manual intervention —thus making 3D printed organs patentable.
Considering this aspect of bio-printing technology, current patent systems need to be more cohesive in order to address this ambiguity and prevent future issues.
Key Patent Assignees and Their IP Coverage
Patent protection for 3D printing technology has begun in early 1980s, but significant patent activity was witnessed during the late 80’s when 3D systems adopted aggressive strategy to cover stereolithographic techniques and 3D object construction using film layers.
Patent filing increased thereafter due to technological advancements and the entry of new players such as Materialise, Stratasys and Microtec, who explored medical model construction and deposition techniques.
The following graph indicates patent filing trends over the past three decades:
The key IP players in 3D printing technology are 3D Systems, Stratasys, Microtec and Materialise, which provide the required 3D modeling software and material extruding assemblies to print 3D models.
In addition to Materialise and Stratasys, Voxeljet, EnvisionTEC (among others) hold key IP in the bio-printing domain, as evident in the following graphs:
Its portfolio primarily comprises of the hardware components that make up 3D printing systems, along with materials and other accessories required in bio-printing. They include electrophotography based systems, polymer extrusion assembly, and liquefiers. Recent patent filings cover concepts in electrophotography-based additive manufacturing, selective sintering techniques, and cross-layer patterning methods.
Its portfolio primarily comprises of design and construction methods for 3D models. These include image acquisition, processing and 3D prototyping algorithms/software. The company’s focus has been primarily on rapid prototype printing techniques, in particular for prosthetic devices, and surgical equipment meant for orthopedic and dental applications.
Its portfolio primarily comprises of devices and methods for multi-step printing, binder materials, atomized material transfer to layered assemblies, and self-hardening materials.
The patent portfolio of niche players such as Organovo is predominantly focused on 3D construct printing. Luxexcel is focusing on printing optical structures, while MakerBot’s focus is on replicators, scanners, and printing accessories. Ingo Ederer, William Swanson, and Samuel Batchelder are key inventors in the bio-printing technology space.
Although North America is currently leading market for the bio-printed devices, Europe and the Asia-Pacific region are predicted to grow at higher CAGR in future.
Most companies have adopted a strategy to protect their IP in the US jurisdiction, considering its predominant market attraction and revenue share.
Contrary to that, IP protection in other jurisdictions is weaker due to the nascent stage of the technology, lower market shares, and a dilemma about the defensibility of IP in 3D printed organs.
The following graph depicts the jurisdictional coverage (in %) for INPADOC patent families:
Future Prospects, Conclusions, and Remarks
Organ failure mortality is among the most preventable causes of death, and it could be addressed using artificial organs printed using 3D printing technology. Current research has successfully demonstrated the benefits and feasibility of this technology in clinical settings on a long-term basis to treat cardiac, ear, and skin defects.
Bio-printing involves the process of creating the scaffold, then forming human tissue and organs through layer-by-layer deposition of living or non-living materials. Although this technology has the potential to address current needs, it may raise ethical and patenting issues along with other challenges.
The key components of a typical bio-printing machine include software, hardware, methods/processes, and the materials used in formulating the object’s layers. From an IP standpoint, the algorithms for creating 3D models from scanned bio images and creating live tissue/cells required for 3D printing will definitely require complex thought processes. It includes non-obvious technical contributions and implementations to solve specific problems, and hence, makes them patentable in most jurisdictions including the US and EP.
The hardware components required for depositing and the post-processing of scaffolds and solid organs require complex intellectual expertise to build and operate. It goes well beyond the mere arrangement of a naturally available subject (in this case, living cells) as it occurs. This makes them patentable not only in the US, but also among most international patent regimes.
Non-living material compositions as well as methods for their synthesis and deposition can be patented under current patent systems.
Living cells as they appear in their natural environment cannot be patented; neither can the mere arrangement of living cells, cultured natural cells, or incubated tissue materials.
Man-made cellular materials or subcomponents that require human intervention or alterations to produce however, can be patented.
Thus, if bio-printing of human organs involves human intervention and manual processes (such as harvesting stem cells, processing/culturing them under specific conditions, building human tissue/organs layer-by-layer) then they can, and will be, patented.