Tag Archives: 3D printing

Nanocellulosic 3D-printed ears

It’s been a while since I’ve had a story abut cellulose nanocrystals (CNC) and this one comes from Switzerland’s Empa (Swiss Federal Laboratories for Materials Science and Technology) in a January 15, 2019 news item on Nanowerk (Note: A link has been removed),

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing (ACS Nano, “Dynamics of Cellulose Nanocrystal Alignment during 3D Printing”).

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains: “In viscous state cellulose nanocrystals can easily be shaped together with nother biopolymers into complex 3-dimensional structures using a 3D printer, such as the Bioplotter.”

Once cross-linked, the structures remain stable despite their soft mechanical properties. Hausmann is currently investigating the characteristics of the nanocellulose composite hydrogels in order to further optimize their stability as well as the printing process. The researcher already used X-ray analysis to determine how cellulose is distributed and organized within the printed structures.

At this point in time the printed ear is entirely and solely made of cellulose nanocrystals and a biopolymer. However, the objective is to incorporate both human cells and therapeutics into the base structure in order to produce biomedical implants.

Here’s one of the researchers (Michael Hausmann) showing off their ‘ear’,

A 3D-printed ear: Empa researcher Michael Hausmann uses nanocellulose as the basis for novel implants (Image: Empa)

Doesn’t look like much does, eh? It’s scaffolding or, you could say, a kind of skeleton and a January 15, 2019 Empa press release, which originated the news item, describes it and explains how it will house new cells,

A new project is currently underway, looking into how chondrocytes (cartilage cells) can be integrated into the scaffold to yield artificial cartilage tissue. As soon as the colonization of the hydrogel with cells is established, nanocellulose based composites in the shape of an ear could serve as an implant for children with an inherited auricular malformation as for instance, in microtia, where the external ears are only incompletely developed. A reconstruction of the auricle can esthetically and medically correct the malformation; otherwise the hearing ability can be severely impaired. In the further course of the project, cellulose nanocrystals containing hydrogels will also be used for the replacement of articular cartilage (e.g. knee) in cases of joint wear due to, for example, chronic arthritis.

Once the artificial tissue has been implanted in the body, the biodegradable polymer material is expected to degrade over time. The cellulose itself is not degradable in the body, but biocompatible. However, it is not only its biocompatibility that makes nanocellulose the perfect material for implant scaffolds. “It is also the mechanical performance of cellulose nanocrystals that make them such promising candidates because the tiny but highly stable fibers can extremely well reinforce the produced implant,” said Hausmann.

Moreover, nanocellulose allows the incorporation of various functions by chemical modifications into the viscous hydrogel. Thus, the structure, the mechanical properties and the interactions of the nanocellulose with its environment can be specifically tailored to the desired end product. “For instance, we can incorporate active substances that promote the growth of chondrocytes or that sooth joint inflammation into the hydrogel,” says the Empa researcher.

And last but not least, as raw material cellulose is the most abundant natural polymer on earth. Therefore, the use of cellulose nanocrystals not only benefits from the mere elegance of the novel process but also from the availability of the raw material.

The white nanocellulose ear lies glossy on the glass carrier. Just out of the Bioplotter, it is already robust and dimensionally stable. Hausmann can give the go-ahead for the next steps. 

Here’s a link to and a citation for the paper,

Dynamics of Cellulose Nanocrystal Alignment during 3D Printing by Michael K. Hausmann, Patrick A. Rühs, Gilberto Siqueira, Jörg Läuger, Rafael Libanori, Tanja Zimmermann, and André R. Studart. ACS Nano, 2018, 12 (7), pp 6926–6937 DOI: 10.1021/acsnano.8b02366 Publication Date (Web): July 5, 2018

Copyright © 2018 American Chemical Society

This paper is behind a paywall.

Gene editing and personalized medicine: Canada

Back in the fall of 2018 I came across one of those overexcited pieces about personalized medicine and gene editing tha are out there. This one came from an unexpected source, an author who is a “PhD Scientist in Medical Science (Blood and Vasculature” (from Rick Gierczak’s LinkedIn profile).

It starts our promisingly enough although I’m beginning to dread the use of the word ‘precise’  where medicine is concerned, (from a September 17, 2018 posting on the Science Borealis blog by Rick Gierczak (Note: Links have been removed),

CRISPR-Cas9 technology was accidentally discovered in the 1980s when scientists were researching how bacteria defend themselves against viral infection. While studying bacterial DNA called clustered regularly interspaced short palindromic repeats (CRISPR), they identified additional CRISPR-associated (Cas) protein molecules. Together, CRISPR and one of those protein molecules, termed Cas9, can locate and cut precise regions of bacterial DNA. By 2012, researchers understood that the technology could be modified and used more generally to edit the DNA of any plant or animal. In 2015, the American Association for the Advancement of Science chose CRISPR-Cas9 as science’s “Breakthrough of the Year”.

Today, CRISPR-Cas9 is a powerful and precise gene-editing tool [emphasis mine] made of two molecules: a protein that cuts DNA (Cas9) and a custom-made length of RNA that works like a GPS for locating the exact spot that needs to be edited (CRISPR). Once inside the target cell nucleus, these two molecules begin editing the DNA. After the desired changes are made, they use a repair mechanism to stitch the new DNA into place. Cas9 never changes, but the CRISPR molecule must be tailored for each new target — a relatively easy process in the lab. However, it’s not perfect, and occasionally the wrong DNA is altered [emphasis mine].

Note that Gierczak makes a point of mentioning that CRISPR/Cas9 is “not perfect.” And then, he gets excited (Note: Links have been removed),

CRISPR-Cas9 has the potential to treat serious human diseases, many of which are caused by a single “letter” mutation in the genetic code (A, C, T, or G) that could be corrected by precise editing. [emphasis mine] Some companies are taking notice of the technology. A case in point is CRISPR Therapeutics, which recently developed a treatment for sickle cell disease, a blood disorder that causes a decrease in oxygen transport in the body. The therapy targets a special gene called fetal hemoglobin that’s switched off a few months after birth. Treatment involves removing stem cells from the patient’s bone marrow and editing the gene to turn it back on using CRISPR-Cas9. These new stem cells are returned to the patient ready to produce normal red blood cells. In this case, the risk of error is eliminated because the new cells are screened for the correct edit before use.

The breakthroughs shown by companies like CRISPR Therapeutics are evidence that personalized medicine has arrived. [emphasis mine] However, these discoveries will require government regulatory approval from the countries where the treatment is going to be used. In the US, the Food and Drug Administration (FDA) has developed new regulations allowing somatic (i.e., non-germ) cell editing and clinical trials to proceed. [emphasis mine]

The potential treatment for sickle cell disease is exciting but Gierczak offers no evidence that this treatment or any unnamed others constitute proof that “personalized medicine has arrived.” In fact, Goldman Sachs, a US-based investment bank, makes the case that it never will .

Cost/benefit analysis

Edward Abrahams, president of the Personalized Medicine Coalition (US-based), advocates for personalized medicine while noting in passing, market forces as represented by Goldman Sachs in his May 23, 2018 piece for statnews.com (Note: A link has been removed),

One of every four new drugs approved by the Food and Drug Administration over the last four years was designed to become a personalized (or “targeted”) therapy that zeros in on the subset of patients likely to respond positively to it. That’s a sea change from the way drugs were developed and marketed 10 years ago.

Some of these new treatments have extraordinarily high list prices. But focusing solely on the cost of these therapies rather than on the value they provide threatens the future of personalized medicine.

… most policymakers are not asking the right questions about the benefits of these treatments for patients and society. Influenced by cost concerns, they assume that prices for personalized tests and treatments cannot be justified even if they make the health system more efficient and effective by delivering superior, longer-lasting clinical outcomes and increasing the percentage of patients who benefit from prescribed treatments.

Goldman Sachs, for example, issued a report titled “The Genome Revolution.” It argues that while “genome medicine” offers “tremendous value for patients and society,” curing patients may not be “a sustainable business model.” [emphasis mine] The analysis underlines that the health system is not set up to reap the benefits of new scientific discoveries and technologies. Just as we are on the precipice of an era in which gene therapies, gene-editing, and immunotherapies promise to address the root causes of disease, Goldman Sachs says that these therapies have a “very different outlook with regard to recurring revenue versus chronic therapies.”

Let’s just chew on this one (contemplate)  for a minute”curing patients may not be ‘sustainable business model’!”

Coming down to earth: policy

While I find Gierczak to be over-enthused, he, like Abrahams, emphasizes the importance of new policy, in his case, the focus is Canadian policy. From Gierczak’s September 17, 2018 posting (Note: Links have been removed),

In Canada, companies need approval from Health Canada. But a 2004 law called the Assisted Human Reproduction Act (AHR Act) states that it’s a criminal offence “to alter the genome of a human cell, or in vitroembryo, that is capable of being transmitted to descendants”. The Actis so broadly written that Canadian scientists are prohibited from using the CRISPR-Cas9 technology on even somatic cells. Today, Canada is one of the few countries in the world where treating a disease with CRISPR-Cas9 is a crime.

On the other hand, some countries provide little regulatory oversight for editing either germ or somatic cells. In China, a company often only needs to satisfy the requirements of the local hospital where the treatment is being performed. And, if germ-cell editing goes wrong, there is little recourse for the future generations affected.

The AHR Act was introduced to regulate the use of reproductive technologies like in vitrofertilization and research related to cloning human embryos during the 1980s and 1990s. Today, we live in a time when medical science, and its role in Canadian society, is rapidly changing. CRISPR-Cas9 is a powerful tool, and there are aspects of the technology that aren’t well understood and could potentially put patients at risk if we move ahead too quickly. But the potential benefits are significant. Updated legislation that acknowledges both the risks and current realities of genomic engineering [emphasis mine] would relieve the current obstacles and support a path toward the introduction of safe new therapies.

Criminal ban on human gene-editing of inheritable cells (in Canada)

I had no idea there was a criminal ban on the practice until reading this January 2017 editorial by Bartha Maria Knoppers, Rosario Isasi, Timothy Caulfield, Erika Kleiderman, Patrick Bedford, Judy Illes, Ubaka Ogbogu, Vardit Ravitsky, & Michael Rudnicki for (Nature) npj Regenerative Medicine (Note: Links have been removed),

Driven by the rapid evolution of gene editing technologies, international policy is examining which regulatory models can address the ensuing scientific, socio-ethical and legal challenges for regenerative and personalised medicine.1 Emerging gene editing technologies, including the CRISPR/Cas9 2015 scientific breakthrough,2 are powerful, relatively inexpensive, accurate, and broadly accessible research tools.3 Moreover, they are being utilised throughout the world in a wide range of research initiatives with a clear eye on potential clinical applications. Considering the implications of human gene editing for selection, modification and enhancement, it is time to re-examine policy in Canada relevant to these important advances in the history of medicine and science, and the legislative and regulatory frameworks that govern them. Given the potential human reproductive applications of these technologies, careful consideration of these possibilities, as well as ethical and regulatory scrutiny must be a priority.4

With the advent of human embryonic stem cell research in 1978, the birth of Dolly (the cloned sheep) in 1996 and the Raelian cloning hoax in 2003, the environment surrounding the enactment of Canada’s 2004 Assisted Human Reproduction Act (AHRA) was the result of a decade of polarised debate,5 fuelled by dystopian and utopian visions for future applications. Rightly or not, this led to the AHRA prohibition on a wide range of activities, including the creation of embryos (s. 5(1)(b)) or chimeras (s. 5(1)(i)) for research and in vitro and in vivo germ line alterations (s. 5(1)(f)). Sanctions range from a fine (up to $500,000) to imprisonment (up to 10 years) (s. 60 AHRA).

In Canada, the criminal ban on gene editing appears clear, the Act states that “No person shall knowingly […] alter the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants;” [emphases mine] (s. 5(1)(f) AHRA). This approach is not shared worldwide as other countries such as the United Kingdom, take a more regulatory approach to gene editing research.1 Indeed, as noted by the Law Reform Commission of Canada in 1982, criminal law should be ‘an instrument of last resort’ used solely for “conduct which is culpable, seriously harmful, and generally conceived of as deserving of punishment”.6 A criminal ban is a suboptimal policy tool for science as it is inflexible, stifles public debate, and hinders responsiveness to the evolving nature of science and societal attitudes.7 In contrast, a moratorium such as the self-imposed research moratorium on human germ line editing called for by scientists in December 20158 can at least allow for a time limited pause. But like bans, they may offer the illusion of finality and safety while halting research required to move forward and validate innovation.

On October 1st, 2016, Health Canada issued a Notice of Intent to develop regulations under the AHRA but this effort is limited to safety and payment issues (i.e. gamete donation). Today, there is a need for Canada to revisit the laws and policies that address the ethical, legal and social implications of human gene editing. The goal of such a critical move in Canada’s scientific and legal history would be a discussion of the right of Canadians to benefit from the advancement of science and its applications as promulgated in article 27 of the Universal Declaration of Human Rights9 and article 15(b) of the International Covenant on Economic, Social and Cultural Rights,10 which Canada has signed and ratified. Such an approach would further ensure the freedom of scientific endeavour both as a principle of a liberal democracy and as a social good, while allowing Canada to be engaged with the international scientific community.

Even though it’s a bit old, I still recommend reading the open access editorial in full, if you have the time.

One last thing abut the paper, the acknowledgements,

Sponsored by Canada’s Stem Cell Network, the Centre of Genomics and Policy of McGill University convened a ‘think tank’ on the future of human gene editing in Canada with legal and ethics experts as well as representatives and observers from government in Ottawa (August 31, 2016). The experts were Patrick Bedford, Janetta Bijl, Timothy Caulfield, Judy Illes, Rosario Isasi, Jonathan Kimmelman, Erika Kleiderman, Bartha Maria Knoppers, Eric Meslin, Cate Murray, Ubaka Ogbogu, Vardit Ravitsky, Michael Rudnicki, Stephen Strauss, Philip Welford, and Susan Zimmerman. The observers were Geneviève Dubois-Flynn, Danika Goosney, Peter Monette, Kyle Norrie, and Anthony Ridgway.

Competing interests

The authors declare no competing interests.

Both McGill and the Stem Cell Network pop up again. A November 8, 2017 article about the need for new Canadian gene-editing policies by Tom Blackwell for the National Post features some familiar names (Did someone have a budget for public relations and promotion?),

It’s one of the most exciting, and controversial, areas of health science today: new technology that can alter the genetic content of cells, potentially preventing inherited disease — or creating genetically enhanced humans.

But Canada is among the few countries in the world where working with the CRISPR gene-editing system on cells whose DNA can be passed down to future generations is a criminal offence, with penalties of up to 10 years in jail.

This week, one major science group announced it wants that changed, calling on the federal government to lift the prohibition and allow researchers to alter the genome of inheritable “germ” cells and embryos.

The potential of the technology is huge and the theoretical risks like eugenics or cloning are overplayed, argued a panel of the Stem Cell Network.

The step would be a “game-changer,” said Bartha Knoppers, a health-policy expert at McGill University, in a presentation to the annual Till & McCulloch Meetings of stem-cell and regenerative-medicine researchers [These meetings were originally known as the Stem Cell Network’s Annual General Meeting {AGM}]. [emphases mine]

“I’m completely against any modification of the human genome,” said the unidentified meeting attendee. “If you open this door, you won’t ever be able to close it again.”

If the ban is kept in place, however, Canadian scientists will fall further behind colleagues in other countries, say the experts behind the statement say; they argue possible abuses can be prevented with good ethical oversight.

“It’s a human-reproduction law, it was never meant to ban and slow down and restrict research,” said Vardit Ravitsky, a University of Montreal bioethicist who was part of the panel. “It’s a sort of historical accident … and now our hands are tied.”

There are fears, as well, that CRISPR could be used to create improved humans who are genetically programmed to have certain facial or other features, or that the editing could have harmful side effects. Regardless, none of it is happening in Canada, good or bad.

In fact, the Stem Cell Network panel is arguably skirting around the most contentious applications of the technology. It says it is asking the government merely to legalize research for its own sake on embryos and germ cells — those in eggs and sperm — not genetic editing of embryos used to actually get women pregnant.

The highlighted portions in the last two paragraphs of the excerpt were written one year prior to the claims by a Chinese scientist that he had run a clinical trial resulting in gene-edited twins, Lulu and Nana. (See my my November 28, 2018 posting for a comprehensive overview of the original furor). I have yet to publish a followup posting featuring the news that the CRISPR twins may have been ‘improved’ more extensively than originally realized. The initial reports about the twins focused on an illness-related reason (making them HIV ‘immune’) but made no mention of enhanced cognitive skills a side effect of eliminating the gene that would make them HIV ‘immune’. To date, the researcher has not made the bulk of his data available for an in-depth analysis to support his claim that he successfully gene-edited the twins. As well, there were apparently seven other pregnancies coming to term as part of the researcher’s clinical trial and there has been no news about those births.

Risk analysis innovation

Before moving onto the innovation of risk analysis, I want to focus a little more on at least one of the risks that gene-editing might present. Gierczak noted that CRISPR/Cas9 is “not perfect,” which acknowledges the truth but doesn’t convey all that much information.

While the terms ‘precision’ and ‘scissors’ are used frequently when describing the CRISPR technique, scientists actually mean that the technique is significantly ‘more precise’ than other techniques but they are not referencing an engineering level of precision. As for the ‘scissors’, it’s an analogy scientists like to use but in fact CRISPR is not as efficient and precise as a pair of scissors.

Michael Le Page in a July 16, 2018 article for New Scientist lays out some of the issues (Note: A link has been removed),

A study of CRIPSR suggests we shouldn’t rush into trying out CRISPR genome editing inside people’s bodies just yet. The technique can cause big deletions or rearrangements of DNA [emphasis mine], says Allan Bradley of the Wellcome Sanger Institute in the UK, meaning some therapies based on CRISPR may not be quite as safe as we thought.

The CRISPR genome editing technique is revolutionising biology, enabling us to create new varieties of plants and animals and develop treatments for a wide range of diseases.

The CRISPR Cas9 protein works by cutting the DNA of a cell in a specific place. When the cell repairs the damage, a few DNA letters get changed at this spot – an effect that can be exploited to disable genes.

At least, that’s how it is supposed to work. But in studies of mice and human cells, Bradley’s team has found that in around a fifth of cells, CRISPR causes deletions or rearrangements more than 100 DNA letters long. These surprising changes are sometimes thousands of letters long.

“I do believe the findings are robust,” says Gaetan Burgio of the Australian National University, an expert on CRISPR who has debunked previous studies questioning the method’s safety. “This is a well-performed study and fairly significant.”

I covered the Bradley paper and the concerns in a July 17, 2018 posting ‘The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle‘. (The ‘kerfufle’ was in reference to a report that the CRISPR market was affected by the publication of Bradley’s paper.)

Despite Health Canada not moving swiftly enough for some researchers, they have nonetheless managed to release an ‘outcome’ report about a consultation/analysis started in October 2016. Before getting to the consultation’s outcome, it’s interesting to look at how the consultation’s call for response was described (from Health Canada’s Toward a strengthened Assisted Human Reproduction Act ; A Consultation with Canadians on Key Policy Proposals webpage),

In October 2016, recognizing the need to strengthen the regulatory framework governing assisted human reproduction in Canada, Health Canada announced its intention to bring into force the dormant sections of the Assisted Human Reproduction Act  and to develop the necessary supporting regulations.

This consultation document provides an overview of the key policy proposals that will help inform the development of regulations to support bringing into force Section 10, Section 12 and Sections 45-58 of the Act. Specifically, the policy proposals describe the Department’s position on the following:

Section 10: Safety of Donor Sperm and Ova

  • Scope and application
  • Regulated parties and their regulatory obligations
  • Processing requirements, including donor suitability assessment
  • Record-keeping and traceability

Section 12: Reimbursement

  • Expenditures that may be reimbursed
  • Process for reimbursement
  • Creation and maintenance of records

Sections 45-58: Administration and Enforcement

  • Scope of the administration and enforcement framework
  • Role of inspectors designated under the Act

The purpose of the document is to provide Canadians with an opportunity to review the policy proposals and to provide feedback [emphasis mine] prior to the Department finalizing policy decisions and developing the regulations. In addition to requesting stakeholders’ general feedback on the policy proposals, the Department is also seeking input on specific questions, which are included throughout the document.

It took me a while to find the relevant section (in particular, take note of ‘Federal Regulatory Oversight’),

3.2. AHR in Canada Today

Today, an increasing number of Canadians are turning to AHR technologies to grow or build their families. A 2012 Canadian studyFootnote 1 found that infertility is on the rise in Canada, with roughly 16% of heterosexual couples experiencing infertility. In addition to rising infertility, the trend of delaying marriage and parenthood, scientific advances in cryopreserving ova, and the increasing use of AHR by LGBTQ2 couples and single parents to build a family are all contributing to an increase in the use of AHR technologies.

The growing use of reproductive technologies by Canadians to help build their families underscores the need to strengthen the AHR Act. While the approach to regulating AHR varies from country to country, Health Canada has considered international best practices and the need for regulatory alignment when developing the proposed policies set out in this document. …

3.2.1 Federal Regulatory Oversight

Although the scope of the AHR Act was significantly reduced in 2012 and some of the remaining sections have not yet been brought into force, there are many important sections of the Act that are currently administered and enforced by Health Canada, as summarized generally below:

Section 5: Prohibited Scientific and Research Procedures
Section 5 prohibits certain types of scientific research and clinical procedures that are deemed unacceptable, including: human cloning, the creation of an embryo for non-reproductive purposes, maintaining an embryo outside the human body beyond the fourteenth day, sex selection for non-medical reasons, altering the genome in a way that could be transmitted to descendants, and creating a chimera or a hybrid. [emphasis mine]

….

It almost seems as if the they were hiding the section that broached the human gene-editing question. It doesn’t seem to have worked as it appears, there are some very motivated parties determined to reframe the discussion. Health Canada’s ‘outocme’ report, published March 2019, What we heard: A summary of scanning and consultations on what’s next for health product regulation reflects the success of those efforts,

1.0 Introduction and Context

Scientific and technological advances are accelerating the pace of innovation. These advances are increasingly leading to the development of health products that are better able to predict, define, treat, and even cure human diseases. Globally, many factors are driving regulators to think about how to enable health innovation. To this end, Health Canada has been expanding beyond existing partnerships and engaging both domestically and internationally. This expanding landscape of products and services comes with a range of new challenges and opportunities.

In keeping up to date with emerging technologies and working collaboratively through strategic partnerships, Health Canada seeks to position itself as a regulator at the forefront of health innovation. Following the targeted sectoral review of the Health and Biosciences Sector Regulatory Review consultation by the Treasury Board Secretariat, Health Canada held a number of targeted meetings with a broad range of stakeholders.

This report outlines the methodologies used to look ahead at the emerging health technology environment, [emphasis mine] the potential areas of focus that resulted, and the key findings from consultations.

… the Department identified the following key drivers that are expected to shape the future of health innovation:

  1. The use of “big data” to inform decision-making: Health systems are generating more data, and becoming reliant on this data. The increasing accuracy, types, and volume of data available in real time enable automation and machine learning that can forecast activity, behaviour, or trends to support decision-making.
  2. Greater demand for citizen agency: Canadians increasingly want and have access to more information, resources, options, and platforms to manage their own health (e.g., mobile apps, direct-to-consumer services, decentralization of care).
  3. Increased precision and personalization in health care delivery: Diagnostic tools and therapies are increasingly able to target individual patients with customized therapies (e.g., individual gene therapy).
  4. Increased product complexity: Increasingly complex products do not fit well within conventional product classifications and standards (e.g., 3D printing).
  5. Evolving methods for production and distribution: In some cases, manufacturers and supply chains are becoming more distributed, challenging the current framework governing production and distribution of health products.
  6. The ways in which evidence is collected and used are changing: The processes around new drug innovation, research and development, and designing clinical trials are evolving in ways that are more flexible and adaptive.

With these key drivers in mind, the Department selected the following six emerging technologies for further investigation to better understand how the health product space is evolving:

  1. Artificial intelligence, including activities such as machine learning, neural networks, natural language processing, and robotics.
  2. Advanced cell therapies, such as individualized cell therapies tailor-made to address specific patient needs.
  3. Big data, from sources such as sensors, genetic information, and social media that are increasingly used to inform patient and health care practitioner decisions.
  4. 3D printing of health products (e.g., implants, prosthetics, cells, tissues).
  5. New ways of delivering drugs that bring together different product lines and methods (e.g., nano-carriers, implantable devices).
  6. Gene editing, including individualized gene therapies that can assist in preventing and treating certain diseases.

Next, to test the drivers identified and further investigate emerging technologies, the Department consulted key organizations and thought leaders across the country with expertise in health innovation. To this end, Health Canada held seven workshops with over 140 representatives from industry associations, small-to-medium sized enterprises and start-ups, larger multinational companies, investors, researchers, and clinicians in Ottawa, Toronto, Montreal, and Vancouver. [emphases mine]

The ‘outocme’ report, ‘What we heard …’, is well worth reading in its entirety; it’s about 9 pp.

I have one comment, ‘stakeholders’ don’t seem to include anyone who isn’t “from industry associations, small-to-medium sized enterprises and start-ups, larger multinational companies, investors, researchers, and clinician” or from “Ottawa, Toronto, Montreal, and Vancouver.” Aren’t the rest of us stakeholders?

Innovating risk analysis

This line in the report caught my eye (from Health Canada’s Toward a strengthened Assisted Human Reproduction Act ; A Consultation with Canadians on Key Policy Proposals webpage),

There is increasing need to enable innovation in a flexible, risk-based way, with appropriate oversight to ensure safety, quality, and efficacy. [emphases mine]

It reminded me of the 2019 federal budget (from my March 22, 2019 posting). One comment before proceeding, regulation and risk are tightly linked and, so, by innovating regulation they are by exttension alos innovating risk analysis,

… Budget 2019 introduces the first three “Regulatory Roadmaps” to specifically address stakeholder issues and irritants in these sectors, informed by over 140 responses [emphasis mine] from businesses and Canadians across the country, as well as recommendations from the Economic Strategy Tables.

Introducing Regulatory Roadmaps

These Roadmaps lay out the Government’s plans to modernize regulatory frameworks, without compromising our strong health, safety, and environmental protections. They contain proposals for legislative and regulatory amendments as well as novel regulatory approaches to accommodate emerging technologies, including the use of regulatory sandboxes and pilot projects—better aligning our regulatory frameworks with industry realities.

Budget 2019 proposes the necessary funding and legislative revisions so that regulatory departments and agencies can move forward on the Roadmaps, including providing the Canadian Food Inspection Agency, Health Canada and Transport Canada with up to $219.1 million over five years, starting in 2019–20, (with $0.5 million in remaining amortization), and $3.1 million per year on an ongoing basis.

In the coming weeks, the Government will be releasing the full Regulatory Roadmaps for each of the reviews, as well as timelines for enacting specific initiatives, which can be grouped in the following three main areas:

What Is a Regulatory Sandbox? Regulatory sandboxes are controlled “safe spaces” in which innovative products, services, business models and delivery mechanisms can be tested without immediately being subject to all of the regulatory requirements.
– European Banking Authority, 2017

Establishing a regulatory sandbox for new and innovative medical products
The regulatory approval system has not kept up with new medical technologies and processes. Health Canada proposes to modernize regulations to put in place a regulatory sandbox for new and innovative products, such as tissues developed through 3D printing, artificial intelligence, and gene therapies targeted to specific individuals. [emphasis mine]

Modernizing the regulation of clinical trials
Industry and academics have expressed concerns that regulations related to clinical trials are overly prescriptive and inconsistent. Health Canada proposes to implement a risk-based approach [emphasis mine] to clinical trials to reduce costs to industry and academics by removing unnecessary requirements for low-risk drugs and trials. The regulations will also provide the agri-food industry with the ability to carry out clinical trials within Canada on products such as food for special dietary use and novel foods.

Does the government always get 140 responses from a consultation process? Moving on, I agree with finding new approaches to regulatory processes and oversight and, by extension, new approaches to risk analysis.

Earlier in this post, I asked if someone had a budget for public relations/promotion. I wasn’t joking. My March 22, 2019 posting also included these line items in the proposed 2019 budget,

Budget 2019 proposes to make additional investments in support of the following organizations:
Stem Cell Network: Stem cell research—pioneered by two Canadians in the 1960s [James Till and Ernest McCulloch]—holds great promise for new therapies and medical treatments for respiratory and heart diseases, spinal cord injury, cancer, and many other diseases and disorders. The Stem Cell Network is a national not-for-profit organization that helps translate stem cell research into clinical applications and commercial products. To support this important work and foster Canada’s leadership in stem cell research, Budget 2019 proposes to provide the Stem Cell Network with renewed funding of $18 million over three years, starting in 2019–20.

Genome Canada: The insights derived from genomics—the study of the entire genetic information of living things encoded in their DNA and related molecules and proteins—hold the potential for breakthroughs that can improve the lives of Canadians and drive innovation and economic growth. Genome Canada is a not-for-profit organization dedicated to advancing genomics science and technology in order to create economic and social benefits for Canadians. To support Genome Canada’s operations, Budget 2019 proposes to provide Genome Canada with $100.5 million over five years, starting in 2020–21. This investment will also enable Genome Canada to launch new large-scale research competitions and projects, in collaboration with external partners, ensuring that Canada’s research community continues to have access to the resources needed to make transformative scientific breakthroughs and translate these discoveries into real-world applications.

Years ago, I managed to find a webpage with all of the proposals various organizations were submitting to a government budget committee. It was eye-opening. You can tell which organizations were able to hire someone who knew the current government buzzwords and the things that a government bureaucrat would want to hear and the organizations that didn’t.

Of course, if the government of the day is adamantly against or uninterested, no amount of persusasion will work to get your organization more money in the budget.

Finally

Reluctantly, I am inclined to explore the topic of emerging technologies such as gene-editing not only in the field of agriculture (for gene-editing of plants, fish, and animals see my November 28, 2018 posting) but also with humans. At the very least, it needs to be discussed whether we choose to participate or not.

If you are interested in the arguments against changing Canada’s prohibition against gene-editing of humans, there’s an Ocotber 2, 2017 posting on Impact Ethics by Françoise Baylis, Professor and Canada Research Chair in Bioethics and Philosophy at Dalhousie University, and Alana Cattapan, Johnson Shoyama Graduate School of Public Policy at the University of Saskatchewan, which makes some compelling arguments. Of course, it was written before the CRISPR twins (my November 28, 2018 posting).

Recaliing CRISPR Therapeutics (mentioned by Gierczak), the company received permission to run clinical trials in the US in October 2018 after the FDA (US Food and Drug Administration) lifted an earlier ban on their trials according to an Oct. 10, 2018 article by Frank Vinhuan for exome,

The partners also noted that their therapy is making progress outside of the U.S. They announced that they have received regulatory clearance in “multiple countries” to begin tests of the experimental treatment in both sickle cell disease and beta thalassemia, …

It seems to me that the quotes around “multiple countries” are meant to suggest doubt of some kind. Generally speaking, company representatives make those kinds of generalizations when they’re trying to pump up their copy. E.g., 50% increase in attendance  but no whole numbers to tell you what that means. It could mean two people attended the first year and then brought a friend the next year or 100 people attended and the next year there were 150.

Despite attempts to declare personalized medicine as having arrived, I think everything is still in flux with no preordained outcome. The future has yet to be determined but it will be and I , for one, would like to have some say in the matter.

Structural colo(u)r from transparent 3D printed nanostructures

Caption: Light hits the 3-D printed nanostructures from below. After it is transmitted through, the viewer sees only green light — the remaining colors are redirected. Credit: Thomas Auzinger [downloaded from http://visualcomputing.ist.ac.at/publications/2018/StructCol/]

An August 17, 2018 news item on ScienceDaily announces the work illustrated by the image above,

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and certain color effects are impossible to achieve. The natural world, however, also exhibits structural coloration, where the microstructure of an object causes various colors to appear. Peacock feathers, for instance, are pigmented brown, but — because of long hollows within the feathers — reflect the gorgeous, iridescent blues and greens we see and admire. Recent advances in technology have made it practical to fabricate the kind of nanostructures that result in structural coloration, and computer scientists from the Institute of Science and Technology Austria (IST Austria) and the King Abdullah University of Science and Technology (KAUST) have now created a computational tool that automatically creates 3D-print templates for nanostructures that correspond to user-defined colors. Their work demonstrates the great potential for structural coloring in industry, and opens up possibilities for non-experts to create their own designs. This project will be presented at this year’s top computer graphics conference, SIGGRAPH 2018, by first author and IST Austria postdoc Thomas Auzinger. This is one of five IST Austria presentations at the conference this year.

SIGGRAPH 2018, now ended, was mentioned in my Aug. 9, 2018 posting.but since this presentation is accompanied by a paper, it rates its own posting. For one more excuse, there’s my fascination with structural colour.

An August 17, 2018 Institute of Science and Technology Austria press release (also on EurekAlert), which originated the news item, delves into the work,

The changing colors of a chameleon and the iridescent blues and greens of the morpho butterfly, among many others in nature, are the result of structural coloration, where nanostructures cause interference effects in light, resulting in a variety of colors when viewed macroscopically. Structural coloration has certain advantages over coloring with pigments (where particular wavelengths are absorbed), but until recently, the limits of technology meant fabricating such nanostructures required highly specialized methods. New “direct laser writing” set-ups, however, cost about as much as a high-quality industrial 3D printer, and allow for printing at the scale of hundreds of nanometers (hundred to thousand time thinner than a human hair), opening up possibilities for scientists to experiment with structural coloration.

So far, scientists have primarily experimented with nanostructures that they had observed in nature, or with simple, regular nanostructural designs (e.g. row after row of pillars). Thomas Auzinger and Bernd Bickel of IST Austria, together with Wolfgang Heidrich of KAUST, however, took an innovative new approach that differs in several key ways. First, they solve the inverse design task: the user enters the color they want to replicate, and then the computer creates a nanostructure pattern that gives that color, rather than attempting to reproduce structures found in nature. Moreover, “our design tool is completely automatic,” says Thomas Auzinger. “No extra effort is required on the part of the user.”

Second, the nanostructures in the template do not follow a particular pattern or have a regular structure; they appear to be randomly composed—a radical break from previous methods, but one with many advantages. “When looking at the template produced by the computer I cannot tell by the structure alone, if I see a pattern for blue or red or green,” explains Auzinger. “But that means the computer is finding solutions that we, as humans, could not. This free-form structure is extremely powerful: it allows for greater flexibility and opens up possibilities for additional coloring effects.” For instance, their design tool can be used to print a square that appears red from one angle, and blue from another (known as directional coloring).

Finally, previous efforts have also stumbled when it came to actual fabrication: the designs were often impossible to print. The new design tool, however, guarantees that the user will end up with a printable template, which makes it extremely useful for the future development of structural coloration in industry. “The design tool can be used to prototype new colors and other tools, as well as to find interesting structures that could be produced industrially,” adds Auzinger. Initial tests of the design tool have already yielded successful results. “It’s amazing to see something composed entirely of clear materials appear colored, simply because of structures invisible to the human eye,” says Bernd Bickel, professor at IST Austria, “we’re eager to experiment with additional materials, to expand the range of effects we can achieve.”

“It’s particularly exciting to witness the growing role of computational tools in fabrication,” concludes Auzinger, “and even more exciting to see the expansion of ‘computer graphics’ to encompass physical as well as virtual images.”

Here’s a link to and a citation for the paper,

Computational Design of Nanostructural Color for Additive Manufacturing by Thomas Auzinger, Wolfgang Heidrich, and Bernd Bickel. ACM Trans. Graph. 37, 4, Article 159 (August 2018). 16 pages. doi.org/10.1145/3197517.3201376

This appears to be open access.

There is also a project page bearing the same title as the paper, Computational Design of Nanostructural Color for Additive Manufacturing.

3D printed all liquid electronics

Even after watching the video, I still don’t quite believe it. A March 28, 2018 news item on ScienceDaily announces the work,

Scientists from the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab [or LBNL]) have developed a way to print 3-D structures composed entirely of liquids. Using a modified 3-D printer, they injected threads of water into silicone oil — sculpting tubes made of one liquid within another liquid.

They envision their all-liquid material could be used to construct liquid electronics that power flexible, stretchable devices. The scientists also foresee chemically tuning the tubes and flowing molecules through them, leading to new ways to separate molecules or precisely deliver nanoscale building blocks to under-construction compounds.

A March 28, 2018 Berkeley Lab March 26, 2018 news release (also on EurekAlert), which originated the news item, describe the work in more detail,

The researchers have printed threads of water between 10 microns and 1 millimeter in diameter, and in a variety of spiraling and branching shapes up to several meters in length. What’s more, the material can conform to its surroundings and repeatedly change shape.

“It’s a new class of material that can reconfigure itself, and it has the potential to be customized into liquid reaction vessels for many uses, from chemical synthesis to ion transport to catalysis,” said Tom Russell, a visiting faculty scientist in Berkeley Lab’s Materials Sciences Division. He developed the material with Joe Forth, a postdoctoral researcher in the Materials Sciences Division, as well as other scientists from Berkeley Lab and several other institutions. They report their research March 24 [2018] in the journal Advanced Materials.

The material owes its origins to two advances: learning how to create liquid tubes inside another liquid, and then automating the process.

For the first step, the scientists developed a way to sheathe tubes of water in a special nanoparticle-derived surfactant that locks the water in place. The surfactant, essentially soap, prevents the tubes from breaking up into droplets. Their surfactant is so good at its job, the scientists call it a nanoparticle supersoap.

The supersoap was achieved by dispersing gold nanoparticles into water and polymer ligands into oil. The gold nanoparticles and polymer ligands want to attach to each other, but they also want to remain in their respective water and oil mediums. The ligands were developed with help from Brett Helms at the Molecular Foundry, a DOE Office of Science User Facility located at Berkeley Lab.

In practice, soon after the water is injected into the oil, dozens of ligands in the oil attach to individual nanoparticles in the water, forming a nanoparticle supersoap. These supersoaps jam together and vitrify, like glass, which stabilizes the interface between oil and water and locks the liquid structures in position.

This stability means we can stretch water into a tube, and it remains a tube. Or we can shape water into an ellipsoid, and it remains an ellipsoid,” said Russell. “We’ve used these nanoparticle supersoaps to print tubes of water that last for several months.”

Next came automation. Forth modified an off-the-shelf 3-D printer by removing the components designed to print plastic and replacing them with a syringe pump and needle that extrudes liquid. He then programmed the printer to insert the needle into the oil substrate and inject water in a predetermined pattern.

“We can squeeze liquid from a needle, and place threads of water anywhere we want in three dimensions,” said Forth. “We can also ping the material with an external force, which momentarily breaks the supersoap’s stability and changes the shape of the water threads. The structures are endlessly reconfigurable.”

This image illustrates how the water is printed,

These schematics show the printing of water in oil using a nanoparticle supersoap. Gold nanoparticles in the water combine with polymer ligands in the oil to form an elastic film (nanoparticle supersoap) at the interface, locking the structure in place. (Credit: Berkeley Lab)

Here’s a link to and a citation for the paper,

Reconfigurable Printed Liquids by Joe Forth, Xubo Liu, Jaffar Hasnain, Anju Toor, Karol Miszta, Shaowei Shi, Phillip L. Geissler, Todd Emrick, Brett A. Helms, Thomas P. Russell. Advanced Materials https://doi.org/10.1002/adma.201707603 First published: 24 March 2018

This paper is behind a paywall.

A 3D printed eye cornea and a 3D printed copy of your brain (also: a Brad Pitt connection)

Sometimes it’s hard to keep up with 3D tissue printing news. I have two news bits, one concerning eyes and another concerning brains.

3D printed human corneas

A May 29, 2018 news item on ScienceDaily trumpets the news,

The first human corneas have been 3D printed by scientists at Newcastle University, UK.

It means the technique could be used in the future to ensure an unlimited supply of corneas.

As the outermost layer of the human eye, the cornea has an important role in focusing vision.

Yet there is a significant shortage of corneas available to transplant, with 10 million people worldwide requiring surgery to prevent corneal blindness as a result of diseases such as trachoma, an infectious eye disorder.

In addition, almost 5 million people suffer total blindness due to corneal scarring caused by burns, lacerations, abrasion or disease.

The proof-of-concept research, published today [May 29, 2018] in Experimental Eye Research, reports how stem cells (human corneal stromal cells) from a healthy donor cornea were mixed together with alginate and collagen to create a solution that could be printed, a ‘bio-ink’.

Here are the proud researchers with their cornea,

Caption: Dr. Steve Swioklo and Professor Che Connon with a dyed cornea. Credit: Newcastle University, UK

A May 30,2018 Newcastle University press release (also on EurekAlert but published on May 29, 2018), which originated the news item, adds more details,

Using a simple low-cost 3D bio-printer, the bio-ink was successfully extruded in concentric circles to form the shape of a human cornea. It took less than 10 minutes to print.

The stem cells were then shown to culture – or grow.

Che Connon, Professor of Tissue Engineering at Newcastle University, who led the work, said: “Many teams across the world have been chasing the ideal bio-ink to make this process feasible.

“Our unique gel – a combination of alginate and collagen – keeps the stem cells alive whilst producing a material which is stiff enough to hold its shape but soft enough to be squeezed out the nozzle of a 3D printer.

“This builds upon our previous work in which we kept cells alive for weeks at room temperature within a similar hydrogel. Now we have a ready to use bio-ink containing stem cells allowing users to start printing tissues without having to worry about growing the cells separately.”

The scientists, including first author and PhD student Ms Abigail Isaacson from the Institute of Genetic Medicine, Newcastle University, also demonstrated that they could build a cornea to match a patient’s unique specifications.

The dimensions of the printed tissue were originally taken from an actual cornea. By scanning a patient’s eye, they could use the data to rapidly print a cornea which matched the size and shape.

Professor Connon added: “Our 3D printed corneas will now have to undergo further testing and it will be several years before we could be in the position where we are using them for transplants.

“However, what we have shown is that it is feasible to print corneas using coordinates taken from a patient eye and that this approach has potential to combat the world-wide shortage.”

Here’s a link to and a citation for the paper,

3D bioprinting of a corneal stroma equivalent by Abigail Isaacson, Stephen Swioklo, Che J. Connon. Experimental Eye Research Volume 173, August 2018, Pages 188–193 and 2018 May 14 pii: S0014-4835(18)30212-4. doi: 10.1016/j.exer.2018.05.010. [Epub ahead of print]

This paper is behind a paywall.

A 3D printed copy of your brain

I love the title for this May 30, 2018 Wyss Institute for Biologically Inspired Engineering news release: Creating piece of mind by Lindsay Brownell (also on EurekAlert),

What if you could hold a physical model of your own brain in your hands, accurate down to its every unique fold? That’s just a normal part of life for Steven Keating, Ph.D., who had a baseball-sized tumor removed from his brain at age 26 while he was a graduate student in the MIT Media Lab’s Mediated Matter group. Curious to see what his brain actually looked like before the tumor was removed, and with the goal of better understanding his diagnosis and treatment options, Keating collected his medical data and began 3D printing his MRI [magnetic resonance imaging] and CT [computed tomography] scans, but was frustrated that existing methods were prohibitively time-intensive, cumbersome, and failed to accurately reveal important features of interest. Keating reached out to some of his group’s collaborators, including members of the Wyss Institute at Harvard University, who were exploring a new method for 3D printing biological samples.

“It never occurred to us to use this approach for human anatomy until Steve came to us and said, ‘Guys, here’s my data, what can we do?” says Ahmed Hosny, who was a Research Fellow with at the Wyss Institute at the time and is now a machine learning engineer at the Dana-Farber Cancer Institute. The result of that impromptu collaboration – which grew to involve James Weaver, Ph.D., Senior Research Scientist at the Wyss Institute; Neri Oxman, [emphasis mine] Ph.D., Director of the MIT Media Lab’s Mediated Matter group and Associate Professor of Media Arts and Sciences; and a team of researchers and physicians at several other academic and medical centers in the US and Germany – is a new technique that allows images from MRI, CT, and other medical scans to be easily and quickly converted into physical models with unprecedented detail. The research is reported in 3D Printing and Additive Manufacturing.

“I nearly jumped out of my chair when I saw what this technology is able to do,” says Beth Ripley, M.D. Ph.D., an Assistant Professor of Radiology at the University of Washington and clinical radiologist at the Seattle VA, and co-author of the paper. “It creates exquisitely detailed 3D-printed medical models with a fraction of the manual labor currently required, making 3D printing more accessible to the medical field as a tool for research and diagnosis.”

Imaging technologies like MRI and CT scans produce high-resolution images as a series of “slices” that reveal the details of structures inside the human body, making them an invaluable resource for evaluating and diagnosing medical conditions. Most 3D printers build physical models in a layer-by-layer process, so feeding them layers of medical images to create a solid structure is an obvious synergy between the two technologies.

However, there is a problem: MRI and CT scans produce images with so much detail that the object(s) of interest need to be isolated from surrounding tissue and converted into surface meshes in order to be printed. This is achieved via either a very time-intensive process called “segmentation” where a radiologist manually traces the desired object on every single image slice (sometimes hundreds of images for a single sample), or an automatic “thresholding” process in which a computer program quickly converts areas that contain grayscale pixels into either solid black or solid white pixels, based on a shade of gray that is chosen to be the threshold between black and white. However, medical imaging data sets often contain objects that are irregularly shaped and lack clear, well-defined borders; as a result, auto-thresholding (or even manual segmentation) often over- or under-exaggerates the size of a feature of interest and washes out critical detail.

The new method described by the paper’s authors gives medical professionals the best of both worlds, offering a fast and highly accurate method for converting complex images into a format that can be easily 3D printed. The key lies in printing with dithered bitmaps, a digital file format in which each pixel of a grayscale image is converted into a series of black and white pixels, and the density of the black pixels is what defines the different shades of gray rather than the pixels themselves varying in color.

Similar to the way images in black-and-white newsprint use varying sizes of black ink dots to convey shading, the more black pixels that are present in a given area, the darker it appears. By simplifying all pixels from various shades of gray into a mixture of black or white pixels, dithered bitmaps allow a 3D printer to print complex medical images using two different materials that preserve all the subtle variations of the original data with much greater accuracy and speed.

The team of researchers used bitmap-based 3D printing to create models of Keating’s brain and tumor that faithfully preserved all of the gradations of detail present in the raw MRI data down to a resolution that is on par with what the human eye can distinguish from about 9-10 inches away. Using this same approach, they were also able to print a variable stiffness model of a human heart valve using different materials for the valve tissue versus the mineral plaques that had formed within the valve, resulting in a model that exhibited mechanical property gradients and provided new insights into the actual effects of the plaques on valve function.

“Our approach not only allows for high levels of detail to be preserved and printed into medical models, but it also saves a tremendous amount of time and money,” says Weaver, who is the corresponding author of the paper. “Manually segmenting a CT scan of a healthy human foot, with all its internal bone structure, bone marrow, tendons, muscles, soft tissue, and skin, for example, can take more than 30 hours, even by a trained professional – we were able to do it in less than an hour.”

The researchers hope that their method will help make 3D printing a more viable tool for routine exams and diagnoses, patient education, and understanding the human body. “Right now, it’s just too expensive for hospitals to employ a team of specialists to go in and hand-segment image data sets for 3D printing, except in extremely high-risk or high-profile cases. We’re hoping to change that,” says Hosny.

In order for that to happen, some entrenched elements of the medical field need to change as well. Most patients’ data are compressed to save space on hospital servers, so it’s often difficult to get the raw MRI or CT scan files needed for high-resolution 3D printing. Additionally, the team’s research was facilitated through a joint collaboration with leading 3D printer manufacturer Stratasys, which allowed access to their 3D printer’s intrinsic bitmap printing capabilities. New software packages also still need to be developed to better leverage these capabilities and make them more accessible to medical professionals.

Despite these hurdles, the researchers are confident that their achievements present a significant value to the medical community. “I imagine that sometime within the next 5 years, the day could come when any patient that goes into a doctor’s office for a routine or non-routine CT or MRI scan will be able to get a 3D-printed model of their patient-specific data within a few days,” says Weaver.

Keating, who has become a passionate advocate of efforts to enable patients to access their own medical data, still 3D prints his MRI scans to see how his skull is healing post-surgery and check on his brain to make sure his tumor isn’t coming back. “The ability to understand what’s happening inside of you, to actually hold it in your hands and see the effects of treatment, is incredibly empowering,” he says.

“Curiosity is one of the biggest drivers of innovation and change for the greater good, especially when it involves exploring questions across disciplines and institutions. The Wyss Institute is proud to be a space where this kind of cross-field innovation can flourish,” says Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

Here’s an image illustrating the work,

Caption: This 3D-printed model of Steven Keating’s skull and brain clearly shows his brain tumor and other fine details thanks to the new data processing method pioneered by the study’s authors. Credit: Wyss Institute at Harvard University

Here’s a link to and a citation for the paper,

From Improved Diagnostics to Presurgical Planning: High-Resolution Functionally Graded Multimaterial 3D Printing of Biomedical Tomographic Data Sets by Ahmed Hosny , Steven J. Keating, Joshua D. Dilley, Beth Ripley, Tatiana Kelil, Steve Pieper, Dominik Kolb, Christoph Bader, Anne-Marie Pobloth, Molly Griffin, Reza Nezafat, Georg Duda, Ennio A. Chiocca, James R.. Stone, James S. Michaelson, Mason N. Dean, Neri Oxman, and James C. Weaver. 3D Printing and Additive Manufacturing http://doi.org/10.1089/3dp.2017.0140 Online Ahead of Print:May 29, 2018

This paper appears to be open access.

A tangential Brad Pitt connection

It’s a bit of Hollywood gossip. There was some speculation in April 2018 that Brad Pitt was dating Dr. Neri Oxman highlighted in the Wyss Institute news release. Here’s a sample of an April 13, 2018 posting on Laineygossip (Note: A link has been removed),

It took him a long time to date, but he is now,” the insider tells PEOPLE. “He likes women who challenge him in every way, especially in the intellect department. Brad has seen how happy and different Amal has made his friend (George Clooney). It has given him something to think about.”

While a Pitt source has maintained he and Oxman are “just friends,” they’ve met up a few times since the fall and the insider notes Pitt has been flying frequently to the East Coast. He dropped by one of Oxman’s classes last fall and was spotted at MIT again a few weeks ago.

Pitt and Oxman got to know each other through an architecture project at MIT, where she works as a professor of media arts and sciences at the school’s Media Lab. Pitt has always been interested in architecture and founded the Make It Right Foundation, which builds affordable and environmentally friendly homes in New Orleans for people in need.

“One of the things Brad has said all along is that he wants to do more architecture and design work,” another source says. “He loves this, has found the furniture design and New Orleans developing work fulfilling, and knows he has a talent for it.”

It’s only been a week since Page Six first broke the news that Brad and Dr Oxman have been spending time together.

I’m fascinated by Oxman’s (and her colleagues’) furniture. Rose Brook writes about one particular Oxman piece in her March 27, 2014 posting for TCT magazine (Note: Links have been removed),

MIT Professor and 3D printing forerunner Neri Oxman has unveiled her striking acoustic chaise longue, which was made using Stratasys 3D printing technology.

Oxman collaborated with Professor W Craig Carter and Composer and fellow MIT Professor Tod Machover to explore material properties and their spatial arrangement to form the acoustic piece.

Christened Gemini, the two-part chaise was produced using a Stratasys Objet500 Connex3 multi-colour, multi-material 3D printer as well as traditional furniture-making techniques and it will be on display at the Vocal Vibrations exhibition at Le Laboratoire in Paris from March 28th 2014.

An Architect, Designer and Professor of Media, Arts and Science at MIT, Oxman’s creation aims to convey the relationship of twins in the womb through material properties and their arrangement. It was made using both subtractive and additive manufacturing and is part of Oxman’s ongoing exploration of what Stratasys’ ground-breaking multi-colour, multi-material 3D printer can do.

Brook goes on to explain how the chaise was made and the inspiration that led to it. Finally, it’s interesting to note that Oxman was working with Stratasys in 2014 and that this 2018 brain project is being developed in a joint collaboration with Statasys.

That’s it for 3D printing today.

A cheaper way to make artificial organs

In the quest to develop artificial organs, the University of British Columbia (UBC) is the not the first research institution that comes to my mind. It seems I may need to reevaluate now that UBC (Okanagan) has announced some work on bio-inks and artificial organs in a Sept. 12, 2017 news  release (also on EurekAlert) by Patty Wellborn,,

A new bio-ink that may support a more efficient and inexpensive fabrication of human tissues and organs has been created by researchers at UBC’s Okanagan campus.

Keekyoung Kim, an assistant professor at UBC Okanagan’s School of Engineering, says this development can accelerate advances in regenerative medicine.

Using techniques like 3D printing, scientists are creating bio-material products that function alongside living cells. These products are made using a number of biomaterials including gelatin methacrylate (GelMA), a hydrogel that can serve as a building block in bio-printing. This type of bio-material—called bio-ink—are made of living cells, but can be printed and molded into specific organ or tissue shapes.

The UBC team analyzed the physical and biological properties of three different GelMA hydrogels—porcine skin, cold-water fish skin and cold-soluble gelatin. They found that hydrogel made from cold-soluble gelatin (gelatin which dissolves without heat) was by far the best performer and a strong candidate for future 3D organ printing.

“A big drawback of conventional hydrogel is its thermal instability. Even small changes in temperature cause significant changes in its viscosity or thickness,” says Kim. “This makes it problematic for many room temperature bio-fabrication systems, which are compatible with only a narrow range of hydrogel viscosities and which must generate products that are as uniform as possible if they are to function properly.”

Kim’s team created two new hydrogels—one from fish skin, and one from cold-soluble gelatin—and compared their properties to those of porcine skin GelMA. Although fish skin GelMA had some benefits, cold-soluble GelMA was the top overall performer. Not only could it form healthy tissue scaffolds, allowing cells to successfully grow and adhere to it, but it was also thermally stable at room temperature.

The UBC team also demonstrated that cold-soluble GelMA produces consistently uniform droplets at temperatures, thus making it an excellent choice for use in 3D bio-printing.

“We hope this new bio-ink will help researchers create improved artificial organs and lead to the development of better drugs, tissue engineering and regenerative therapies,” Kim says. “The next step is to investigate whether or not cold-soluble GelMA-based tissue scaffolds are can be used long-term both in the laboratory and in real-world transplants.”

Three times cheaper than porcine skin gelatin, cold-soluble gelatin is used primarily in culinary applications.

Here’s a link to and a citation for the paper,

Comparative study of gelatin methacrylate hydrogels from different sources for biofabrication applications by Zongjie Wang, Zhenlin Tian, Fredric Menard, and Keekyoung Kim. Biofabrication, Volume 9, Number 4 Special issue on Bioinks https://doi.org/10.1088/1758-5090/aa83cf Published 21 August 2017

© 2017 IOP Publishing Ltd

This paper is behind a paywall.

4D printing, what is that?

According to an April 12, 2017 news item on ScienceDaily, shapeshifting in response to environmental stimuli is the fourth dimension (I have a link to a posting about 4D printing with another fourth dimension),

A team of researchers from Georgia Institute of Technology and two other institutions has developed a new 3-D printing method to create objects that can permanently transform into a range of different shapes in response to heat.

The team, which included researchers from the Singapore University of Technology and Design (SUTD) and Xi’an Jiaotong University in China, created the objects by printing layers of shape memory polymers with each layer designed to respond differently when exposed to heat.

“This new approach significantly simplifies and increases the potential of 4-D printing by incorporating the mechanical programming post-processing step directly into the 3-D printing process,” said Jerry Qi, a professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech. “This allows high-resolution 3-D printed components to be designed by computer simulation, 3-D printed, and then directly and rapidly transformed into new permanent configurations by simply heating.”

The research was reported April 12 [2017] in the journal Science Advances, a publication of the American Association for the Advancement of Science. The work is funded by the U.S. Air Force Office of Scientific Research, the U.S. National Science Foundation and the Singapore National Research Foundation through the SUTD DManD Centre.

An April 12, 2017 Singapore University of Technology and Design (SUTD) press release on EurekAlert provides more detail,

4D printing is an emerging technology that allows a 3D-printed component to transform its structure by exposing it to heat, light, humidity, or other environmental stimuli. This technology extends the shape creation process beyond 3D printing, resulting in additional design flexibility that can lead to new types of products which can adjust its functionality in response to the environment, in a pre-programmed manner. However, 4D printing generally involves complex and time-consuming post-processing steps to mechanically programme the component. Furthermore, the materials are often limited to soft polymers, which limit their applicability in structural scenarios.

A group of researchers from the SUTD, Georgia Institute of Technology, Xi’an Jiaotong University and Zhejiang University has introduced an approach that significantly simplifies and increases the potential of 4D printing by incorporating the mechanical programming post-processing step directly into the 3D printing process. This allows high-resolution 3D-printed components to be designed by computer simulation, 3D printed, and then directly and rapidly transformed into new permanent configurations by using heat. This approach can help save printing time and materials used by up to 90%, while completely eliminating the time-consuming mechanical programming process from the design and manufacturing workflow.

“Our approach involves printing composite materials where at room temperature one material is soft but can be programmed to contain internal stress, and the other material is stiff,” said Dr. Zhen Ding of SUTD. “We use computational simulations to design composite components where the stiff material has a shape and size that prevents the release of the programmed internal stress from the soft material after 3D printing. Upon heating, the stiff material softens and allows the soft material to release its stress. This results in a change – often dramatic – in the product shape.” This new shape is fixed when the product is cooled, with good mechanical stiffness. The research demonstrated many interesting shape changing parts, including a lattice that can expand by almost 8 times when heated.

This new shape becomes permanent and the composite material will not return to its original 3D-printed shape, upon further heating or cooling. “This is because of the shape memory effect,” said Prof. H. Jerry Qi of Georgia Tech. “In the two-material composite design, the stiff material exhibits shape memory, which helps lock the transformed shape into a permanent one. Additionally, the printed structure also exhibits the shape memory effect, i.e. it can then be programmed into further arbitrary shapes that can always be recovered to its new permanent shape, but not its 3D-printed shape.”

Said SUTD’s Prof. Martin Dunn, “The key advance of this work, is a 4D printing method that is dramatically simplified and allows the creation of high-resolution complex 3D reprogrammable products; it promises to enable myriad applications across biomedical devices, 3D electronics, and consumer products. It even opens the door to a new paradigm in product design, where components are designed from the onset to inhabit multiple configurations during service.”

Here’s a video,


Uploaded on Apr 17, 2017

A research team led by the Singapore University of Technology and Design’s (SUTD) Associate Provost of Research, Professor Martin Dunn, has come up with a new and simplified 4D printing method that uses a 3D printer to rapidly create 3D objects, which can permanently transform into a range of different shapes in response to heat.

Here’s a link to and a citation for the paper,

Direct 4D printing via active composite materials by Zhen Ding, Chao Yuan, Xirui Peng, Tiejun Wang, H. Jerry Qi, and Martin L. Dunn. Science Advances  12 Apr 2017: Vol. 3, no. 4, e1602890 DOI: 10.1126/sciadv.1602890

This paper is open access.

Here is a link to a post about another 4th dimension, time,

4D printing: a hydrogel orchid (Jan. 28, 2016)

Hollywood and neurosurgery

Usually a story about Hollywood and science (in this case, neurosurgery) is focused on how scientifically accurate the portrayal is. This time the situation has been reversed and science has borrowed from Hollywood. From an April 25, 2017 Johns Hopkins University School of Medicine news release (also on EurekAlert), Note: A link has been removed,

A team of computer engineers and neurosurgeons, with an assist from Hollywood special effects experts, reports successful early tests of a novel, lifelike 3D simulator designed to teach surgeons to perform a delicate, minimally invasive brain operation.

A report on the simulator that guides trainees through an endoscopic third ventriculostomy (ETV) was published in the Journal of Neurosurgery: Pediatrics on April 25 [2017]. The procedure uses endoscopes, which are small, computer-guided tubes and instruments, to treat certain forms of hydrocephalus, a condition marked by an excessive accumulation of cerebrospinal fluid and pressure on the brain. ETV is a minimally invasive procedure that short-circuits the fluid back into normal channels in the brain, eliminating the need for implantation of a shunt, a lifelong device with the associated complications of a foreign body.

“For surgeons, the ability to practice a procedure is essential for accurate and safe performance of the procedure. Surgical simulation is akin to a golfer taking a practice swing,” says Alan R. Cohen, M.D., professor of neurosurgery at the Johns Hopkins University School of Medicine and a senior author of the report. “With surgical simulation, we can practice the operation before performing it live.”

While cadavers are the traditional choice for such surgical training, Cohen says they are scarce, expensive, nonreusable, and most importantly, unable to precisely simulate the experience of operating on the problem at hand, which Cohen says requires a special type of hand-eye coordination he dubs “Nintendo Neurosurgery.”

In an effort to create a more reliable, realistic and cost-effective way for surgeons to practice ETV, the research team worked with 3D printing and special effects professionals to create a lifelike, anatomically correct, full-size head and brain with the touch and feel of human skull and brain tissue.

The fusion of 3D printing and special effects resulted in a full-scale reproduction of a 14-year-old child’s head, modeled after a real patient with hydrocephalus, one of the most common problems seen in the field of pediatric neurosurgery. Special features include an electronic pump to reproduce flowing cerebrospinal fluid and brain pulsations. One version of the simulator is so realistic that it has facial features, hair, eyelashes and eyebrows.

To test the model, Cohen and his team randomly paired four neurosurgery fellows and 13 medical residents to perform ETV on either the ultra-realistic simulator or a lower-resolution simulator, which had no hair, lashes or brows.

After completing the simulation, fellows and residents each rated the simulator using a five-point scale. On average, both the surgical fellows and the residents rated the simulator more highly (4.88 out of 5) on its effectiveness for ETV training than on its aesthetic features (4.69). The procedures performed by the trainees were also recorded and later watched and graded by two fully trained neurosurgeons in a way that they could not identify who the trainees were or at what stage they were in their training.

The neurosurgeons assessed the trainees’ performance using criteria such as “flow of operation,” “instrument handling” and “time and motion.”

Neurosurgeons consistently rated the fellows higher than residents on all criteria measured, which accurately reflected their advanced training and knowledge, and demonstrated the simulator’s ability to distinguish between novice and expert surgeons.

Cohen says that further tests are needed to determine whether the simulator will actually improve performance in the operating room. “With this unique assortment of investigators, we were able to develop a high-fidelity simulator for minimally invasive neurosurgery that is realistic, reliable, reusable and cost-effective. The models can be designed to be patient-specific, enabling the surgeon to practice the operation before going into the operating room,” says Cohen.

Other authors on this paper include Roberta Rehder from the Johns Hopkins School of Medicine, and Peter Weinstock, Sanjay P. Parbhu, Peter W. Forbes and Christopher Roussin from Boston Children’s Hospital.

Funding for the study was provided by a grant from the Boston Investment Conference. The research team acknowledges the contribution of FracturedFX, an Emmy Award-winning special effects group from Hollywood, California, in the development of the surgical models.

The investigators report no financial stake or interests in the success of the simulator.

Here’s what the model looks like,

Caption: A. Low-fidelity simulated surgical model for ETV. B. High-fidelity model with hair, eyelashes and eyebrows. Credit: Copyright AANS. Used with permission.

An April 25, 2017 Journal of Neurosurgery news release on EurekAlert details the refinements applied to this replica (Note: There is some repetitive material),

….

A neurosurgery residency training program generally lasts seven years–longer than any other medical specialty. Trainees log countless hours observing surgeries performed by experienced neurosurgeons and developing operative skills in practice labs before touching patients. It is challenging to create a realistic surgical experience outside an operating room. Cadaveric specimens and virtual reality programs have been used, but they are costly and do not provide as realistic an experience as desired.

The new training simulation model described in this paper is a full-scale reproduction of the head of an adolescent patient with hydrocephalus. The external appearance of the head is uncannily accurate, as is the internal neuroanatomy.

One failing of 3D models is the stiffness of most sculpting material. This problem was overcome by addition of special-effects materials that reproduce the textures of external skin and internal brain structures. In addition, the operative environment in this training model is amazingly alive, with pulsations of a simulated basilar artery and ventricles as well as movement of cerebrospinal fluid. These advances provide visual and tactile feedback to the trainee that closely resembles that of the surgical experience.

The procedure selected to test the new training model was endoscopic third ventriculostomy (ETV), a minimally invasive surgical procedure increasingly used to treat hydrocephalus. The goal of ETV is to create a hole in the floor of the third ventricle. This provides a new pathway by which excess cerebrospinal fluid can circulate.

During ETV, the surgeon drills a small hole in the skull of the patient and inserts an endoscope into the ventricular system. The endoscope accommodates a lighted miniature video camera to visualize the operative site and specialized surgical instruments suited to perform operative tasks through the endoscope. The video camera sends a direct feed to external monitors in the operating room so that surgeons can clearly see what they are doing.

To evaluate the usefulness of the training simulation model of ETV, the researchers solicited feedback from users (neurosurgical residents and fellows) and their teachers. Trainees were asked to respond to a 14-item questionnaire focused on the external and internal appearances of the model and its tactile feel during simulated surgery (face validity) as well as on how closely the simulated procedure reproduced an actual ETV (content validity). The usefulness of the model in assessing trainees’ performances was then evaluated by two attending neurosurgeons blinded to the identity and training status (post-graduate year of training) of the residents and fellows (construct validity).

The neurosurgical residents and fellows gave high scores to the training model for both face and content validity (mean scores of 4.69 and 4.88, respectively; 5 would be a perfect score). The performance scores given to individual trainees by the attending neurosurgeons clearly distinguished novice surgeons from more experienced surgeons, accurately reflecting the trainees’ post-graduate years of training.

The training model described in this paper is not limited to hydrocephalus or treatment with ETV. The simulated head accommodates replaceable plug-and-play components to provide a fresh operative field for each training session. A variety of diseased or injured brain scenarios could be tested using different plug-and-play components. In addition, the ability to pop in new components between practice sessions greatly reduces training costs compared to other models.

When asked about the paper, the senior author, Alan R. Cohen, MD, at Johns Hopkins Hospital, said, “This unique collaboration of interdisciplinary experts resulted in the creation of an ultra-realistic 3D surgical training model. Simulation has become increasingly important for training in minimally invasive neurosurgery. It also has the potential to revolutionize training for all surgical procedures.

Here’s a link to and a citation for the paper,

Creation of a novel simulator for minimally invasive neurosurgery: fusion of 3D printing and special effects by Peter Weinstock, Roberta Rehder, Sanjay P. Parbhu, Peter W. Forbes, Christopher J. Roussin, and Alan R. Cohen. Journal of Neurosurgery: Pediatrics, published online, ahead of print, April 25, 2017; DOI: 10.3171/2017.1.PEDS16568

This paper appears to be open access.

Saving modern art with 3D-printed artwork

I first wrote about the NanoRestART project in an April 4. 2016 post highlighting work which focuses on a problem unique to modern and contemporary art, the rapid deterioration of the plastics and synthetic materials used to create the art and the lack of conservation techniques for preserving those materials. A Dec. 22, 2016 news item on phys.org provides an update on the project,

Many contemporary artworks are endangered due to their extremely fast degradation processes. NANORESTART—a project developing nanomaterials to protect and restore this cultural heritage—has created a 3-D printed artwork with a view to testing restoration methods.

The 3D printed sculpture was designed by engineer-artist Tom Lomax – a UK-based sculptor and painter specialised in 3D-printed colour sculpture. Drawing inspiration from the aesthetic of early 20th century artworks, the sculpture was made using state-of-the-art 3D printing processes and can be downloaded for free. [I believe the downloadable files are available at the end of the paper in Heritage Science in the section titled: Additional files, just prior to the References {see below for citation and link to the paper}

Fig. 1
Images of the RP artwork “Out of the Cauldron” designed by Tom Lomax produced with the most common RP Technologies: (1) stereolithography (SLA®) (2) polyjet (3) 3D printing (3DP) (4) selective laser sintering (SLS). Before (above) and after (below) photodegradation
Courtesy: Heritage Science

A Dec. 21, 2016 Cordis press release, which originated the news item, provides more information about the artist and his 3D printed sculpture,

‘As an artist I previously had little idea of the conservation threat facing contemporary art – preferring to leave these issues for conservators and focus on the creative process. But while working on this project with UCL [University College of London] I began to realise that artists themselves have a crucial role to play,’ Lomax explains.

The structure has been printed using the most common rapid prototyping (RP) technologies, which are gaining popularity among designers and artists. It will be a key tool for the project team to test how these structures degrade and come up with solutions to better preserve them.

As Caroline Coon, researcher at the UCL Institute for Sustainable Heritage, notes, ‘Art is being transformed by fast-changing new technologies and it is therefore vital to preempt conservation issues, rather than react to them, if we are to preserve our best contemporary works for future generations. This research project will benefit both artists and academics alike – but ultimately it is in the best interests of the public that art and science combine to preserve works.’

The NANORESTART team subjected the artwork to accelerated testing, discovering that many 3D-printing technologies use materials that degrade particularly rapidly. It is particularly true for polymers, whose only-recently achieved cultural heritage status also means that conservation experience is almost inexistent.

Preserving or not: an intricate question for artists

The experiments were part of a UCL paper entitled ‘Preserving Rapid Prototypes: A Review’, published in late November in Heritage Science. In this review, Caroline Coon and her team have critically assessed the most commonly used technologies used to tackle the degradation of materials, noting that ‘to conserve RP artworks it is necessary to have an understanding of the process of creation, the different technologies involved, the materials used as well as their chemical and mechanical properties.’

Besides technical concerns, the paper also voices those of artists, in particular the importance of the original artefact and the debate around the appropriateness of preventing the degradation process of artworks. Whilst digital conservation of these artworks would prevent degradation and allow designs to be printed on-demand, some artists argue that the original artefact is actually the one with artistic value as it references a specific time and place. On the other hand, some artists actually embrace and accept the natural degradation of their art as part of its charm.

With two more years to go before its completion, NANORESTART will undoubtedly bring valuable results, resources and reflexions to both conservators and artists. The nanomaterials it aims to develop will bring the EU at the forefront of a conservation market estimated at some EUR 5 billion per year.

Here`s a link to and a citation for the paper,

Preserving rapid prototypes: a review by Carolien Coon, Boris Pretzel, Tom Lomax, and Matija Strlič. Heritage Science 2016 4:40 DOI: 10.1186/s40494-016-0097-y Published: 22 November 2016

©  The Author(s) 2016

This paper is open access.