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Sunday, September 30, 2018

Boehringer, Puma repurposing lung cancer drugs in leukemia


EGFR inhibitors, which block a key signaling pathway in solid tumor growth, are best known as treatments for lung cancer. But a new study led by scientists at the University of Liverpool found that some of them could potentially be used against blood cancers, too.
Their effectiveness in blood cancers is not related to the EGFR mechanism, they believe. Instead, it’s the drugs’ off-target effect on a pseudo-kinase known as TRIB2, which is part of a protein family called Tribbles, named after the small, fluffy fictional species from Star Trek. Just like tribbles in the sci-fi universe move slowly but reproduce rapidly, Tribbles in the real biology world are unable to catalyze chemical reactions. That’s why they are sometimes referred to as “zombie” enzymes. But they do promote cell survival and drug resistance in both solid tumors and blood cancers.
In their study, the researchers found that the unique disposition of cysteine residues in TRIB2 makes it vulnerable to destabilization by several seemingly unrelated FDA-approved EGFR inhibitors, including Boehringer Ingelheim’s Gilotrif, Puma Biotechnology’s Nerlynx and AstraZeneca’s Tagrisso. The researchers described their findings in the journal Science Signaling.
Using a human acute myeloid leukemia cell line, the team showed that Gilotrif and Nerlynx could successfully kill blood cancer cells in vitro. The drugs, which are actually dual EGFR/HER inhibitors, are 10- to 20-fold more effective at cell killing compared to two EGFR-specific inhibitors, Astellas and Genentech’s Tarceva and AstraZeneca’s Iressa.

EGFR mutation is associated with about 30% of non-small cell lung cancers. Gilotrif was first approved by the FDA in 2013, having been shown to delay tumor growth 4.2 months longer than what was seen in patients receiving chemotherapy. The drug has yielded share to new generations of EGFR inhibitors such as Tagrisso.
Repurposing could give drugs like Gilotrif a second life, the authors of the new study believe. “A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins. Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer,” said Patrick Eyers, the study’s senior author, in a statement.
Interestingly, not all dual EGFR/HER2 blockers examined by the team worked in the same way or showed the same level of potency. Novartis’ Tykerb and Takeda’s investigational TAK-285 actually stabilized TRIB2 in vitro rather than disrupting it.
The preliminary data opens the possibility of using EGFR inhibitors as TRIB2-degrading agents. For future studies, the researchers plan to better quantify the effects of these drugs on the TRIB2 protein by studying clinical samples from patients “as part of broader proteomics approaches to establish all the intracellular targets of such compounds,” they wrote in the study.

Bacteria’s hibernation, eating habits spur new ideas for tackling resistant infections


To effectively combat stubborn infections, drug developers need to better understand why bacteria are able to evade destruction with antibiotics. One team at the University of Copenhagen has discovered a surprising talent that some bacteria have that allows them to resist antibiotic attacks: hibernation. It’s one of two recent discoveries that could spark new ideas for developing medicines to treat resistant infections.
The University of Copenhagen researchers discovered that some pathogenic bacteria enter a dormant state, much like hibernation, in the presence of antibiotics. When the antibiotics are gone, the bugs wake up and return to business as usual. The team published the finding in the journal Science Signaling.
The researchers started by studying E. coli samples from urinary tract infections that had initially responded to antibiotics.
“In time, the bacteria re-awoke and began to spread once again,” said Kenn Gerdes, professor of biology at the University of Copenhagen, in a statement.
Gerdes’ team studied exactly what was happening in the cells that went dormant, and they found an enzyme that they believe put the bacteria in the hibernation-like state.
“The enzyme triggers a ‘survival program’ that almost all disease-causing bacteria deploy to survive in the wild and resist antibiotics in the body,” Gerdes said, adding that developing an antibiotic to target that mechanism could prove useful in fighting resistant infections.

Separately, a team led by the University of Washington School of Medicine and the University of Nebraska Medical Center figured out another quirk some bacteria have that might also be able to be applied to drug development. Pseudomonas aeruginosa, which causes infections in the urinary tract and other sites, can be tricked into absorbing gallium, because the bacteria mistake the metal for nutritious food. The gallium disrupts the ability of the bacteria to multiply, the researchers reportedin the journal Science Translational Medicine.
Gallium can fool bacteria because it looks much like iron, a nutrient that helps the bugs multiply and drive infection. “This and other essential processes require iron, and gallium is a monkey wrench that shuts the system down,” said co-author Bradley Britigan, professor of internal medicine at the University of Nebraska Medical Center, in a statement.
They went on to test a single dose of gallium in mice and found that it cured lung infections caused by Pseudomonas aeruginosa. Bacteria can slowly develop resistance to bacteria, but when the researchers combined the metal with existing antibiotics, they found the potency of the attack increased.
They went on to test gallium in 20 people with cystic fibrosis, a disease marked by hard-to-fight lung infections. They reported that the dose tested was safe and that they saw an improvement in the patients’ lung function.
Disrupting the process by which bacteria obtain and use nutrients is not a new idea, but developing treatments to accomplish that feat has proven challenging. The authors noted in their study that their preliminary findings would need to be confirmed in a larger, placebo-controlled study, but that they’re encouraged by the prospect of using gallium to fight infections.
“Our proof-of-principle work with P. aeruginosa and the fact that gallium has broad-spectrum activity against many extracellular and intracellular pathogens raise the possibility that gallium or other iron-disrupting strategies may be useful in infections caused by a range of resistant organisms,” they wrote.

Amazon primed to streamline healthcare supply chain


When supplies are running low, a Summit Pacific Medical Center employee presses an Amazon Web Services Dash Button or tells Alexa to order more.
The critical-access hospital in Elma, Wash., has a Dash Button in a bin large enough to store five computers. It also placed the internet-connected buttons in containers that hold gloves, paper, syringes, IV flushes and other items that aren’t necessarily checked daily. When there are two computers left, Matthew Palcich or one of his peers presses the button that is configured to order three more from a defined set of vendors via Amazon Business.
It shoots off an email to the corresponding manager who approves the purchase, and the shipment arrives two days later.
E-mail notificationWhen supplies are low, a staff member pushes a button to order more product, triggering a confirmation e-mail.
Fully integrating Amazon Business into Summit Pacific’s supply chain operations has taken the hassle and expense out of tedious procurement processes and freed up the center to focus on patient care, said Palcich, Summit Pacific’s manager of business analytics and logistics.
“At the end of the day Amazon lets us save a bunch of money, especially where we typically struggled with one-off marketing requests and custom orders,” he said. “The breadth of offerings is probably bigger than any other distributor that I have seen.”
Summit Pacific predominantly provides primary care in addition to acute-care and emergency services. Amazon Business is capable of supplying 90% of the hospital’s supply-chain needs, Palcich said, adding that it’s a helpful market research tool with customer service that is often more responsive than that of its vendors.
Like Summit Pacific, a growing number of providers are using Amazon Business to streamline their supply chain. While Amazon Business currently may not be suitable for larger systems yet, the industry disruptor is capable of scaling up, supply chain experts said. Also, the healthcare supply chain is just one of many areas where Amazon continues to explore and expand in the sector.

Cutting costs, Amazon style

Automating Summit Pacific’s procurement process through Amazon Business streamlined operations, reduced shipping costs and added visibility to its supply chain, ultimately reducing supply chain-related labor expenses by 80%.
It also trimmed its vendor portfolio and lowered expenses related to delays in lead time and upcharges on shipping thanks to Amazon Business Prime.
This allowed Summit Pacific nurses and clinicians to focus more on patients instead of sifting through supply-chain snafus, Palcich said. “We need to keep costs down to support patient care and not be all things for everyone and negotiate for every item. Negotiations are non-value-added unless the deal is good.” More time could be spent researching a product and placing an order than on what the product costs, Palcich added.
Supply chain accounts for healthcare providers’ second-biggest expense behind labor. It’s also been one of the first areas health system managers look to cut costs.
While the Amazon Business platform isn’t outfitted for more specialized items like imaging equipment or implants yet, its scale and capital coupled with its efficiency and reliability would serve it well, industry observers said.
“In time Amazon can be a tremendous force,” said John Kupice, CEO of H-Source, a private marketplace where hospitals can buy, sell and transfer excess inventory supplies and capital equipment with each other. “In the short term, it would be much more effective in critical-access hospitals that don’t have as much infrastructure as medium or large hospitals. It brings them more sophisticated tools than they are able to acquire or implement.”

How it works

Each supply-chain employee at Summit Pacific is armed with an Amazon login, which is tied to their department with a corresponding approving manager who can peruse product pictures and compare prices. Shipping address and payment methods are pre-loaded.
Amazon packages indicate who they are intended for on the exterior label and Amazon drop-ships to Summit Pacific’s off-site locations. Tracking packages and charges is easier through the Amazon ID number, and Summit Pacific is building a list of items purchased to standardize procurement, Palcich said.
Summit Pacific can set up tolerances to allow for shopping variation. It also can negotiate prices with suppliers through Amazon and use the Dash Button or Alexa to place orders with agreed-upon prices. Hospital employees know they can order something and get it quickly, which cuts down on bulk orders and inventory waste, Palcich said.
Amazon Business customer gatewaySummit Pacific Medical Center employees say the Amazon Business platform allows users to easily compare products.
While fulfillment disputes are rare, Amazon resolves them quickly, he said. Training is also almost nonexistent since most employees are familiar with ordering through Amazon.
Amazon’s strategy is to understand the customer’s needs and work backward, said Chris Holt, Amazon’s leader of global healthcare.
In addition to medical supplies, Amazon has been flirting with pharmaceutical delivery, evidenced by its recent purchase of online pharmacy PillPack. It also aims to revamp employee benefits through its joint venture with 
JPMorgan Chase and Berkshire Hathaway.
“We are just trying to figure out what we learned in other industries and how we have architected our own infrastructure to figure out how we can help healthcare migrate to simpler solutions,” Holt said. “This is not a unique healthcare problem.”
Currently, “tail spend” is where Amazon has had the biggest impact in healthcare, Holt said. Typically, 80% of providers’ spend is with 20% of their suppliers and 20% of their spend is with 80% of their suppliers, the latter being tail spend.
“Amazon freed up a ton of time for us on our tail spend related to IT goods, medical supplies and marketing materials,” Palcich said. “Things are moving more and more to medical supplies. It could be a really good fit for nonstock sterile tools.”

Potential downsides

While Amazon’s medical-surgical supply prices are similar to some of Summit Pacific’s other distributors, and even cheaper if the order is only a few units, verifying vendors can be a challenge, Palcich said. That could change if Amazon develops a mechanism for setting a list of approved vendors tied to a customer account and specific item.
Handling high-margin items that require temperature-controlled storage and other unique conditions could also be a hurdle, experts said.
Still, Amazon has the ability to build the capacity, Palcich said.
“If Amazon is innovating that fast and taking the entire shipping decision out of the supply chain for Summit’s commodities, how do you think they will do with durable medical equipment?” he asked.
Relying on an Amazon-sourced supplier for recalls and alerts could pose problems, said Tim Hagler, director of supply-chain management for the SouthEast Alaska Regional Health Consortium.
“Amazon can be totally disruptive, in a good way, to many areas of the supply chain, until you need to depend on a supplier for recalls and alerts. So medical products are a concern,” he said. “But the healthcare value analysis and supply-chain practitioners will eventually engage with solutions, either through Amazon Business or someone else, that will let us move past that issue with confidence.”
The consortium, which helps source and deliver products for providers in rural Alaska, is preparing for a more formalized engagement with Amazon next year, although it may not include medical products in the first phase, Hagler added.

Broken supply chain

Providers have standardized purchases across their systems, contracted directly with manufacturers or even built their own distribution centers; more than 60 health systems in the U.S. have done so, according to a recent survey by supply-chain consultant Jamie Kowalski.
But supply chain issues still haunt health systems.
Eighty-three percent of 305 surgical staff and hospital supply-chain experts surveyed in November 2017 by distributor Cardinal Health said their organizations are manually counting inventory in some parts of the supply chain while only 15% have implemented radio-frequency identification automation. Inventory mix-ups can result in lost supplies and canceled procedures or jeopardize patient outcomes. Automation reduces costs, according to 39% of respondents, while 1 in 4 said automated systems free up time to focus on patients and produce better outcomes.
“We increased our productivity by setting up certain business areas to request and order through Amazon Business, which allowed our team to focus their efforts on more critical areas of need to ensure we have the right product at the right prices at the right time so we don’t impact patient care,” said James LeRoy, director of strategic sourcing and value analysis at Seattle Children’s Hospital.
Confluence Health, a two-hospital system based in Wenatchee, Wash., also uses Amazon Business, which makes sense given Amazon’s vast presence in the Pacific Northwest.
If Amazon can build on its demand-forecasting, that would go a long way toward improving efficiency, Kowalski said. Suppliers can scale accordingly while locking in a regular revenue stream and providers will only buy what they can use and secure better prices, he said.
“If every hospital could do that, that would be huge as to what we could accomplish as an industry,” Kowalski said.
Palcich said Amazon Business’ technology has made Summit Pacific’s relationship with Vizient—which handles its group purchasing and provides consulting—even better. Rather than rely on Vizient for everyday office supplies, it can focus more on accounts payable solutions and leverage its consulting services, which Vizient and other GPOs continue to expand as providers drill down on care coordination.
Vizient helps providers verify whether vendors can deliver on their GPO pricing, liability protections and ordering practices, and delivery needs before finalizing a deal, the company said.
“Working cross-functionally to build consensus and align supply-chain decisions with clinical operations is central to Vizient’s service model and an essential—and differentiating—part of the value we deliver,” according to a Vizient statement.
GPOs have adapted well and will continue to add value, H-Source’s Kupice said.
Still, Amazon could eventually threaten GPOs, Kowalski said. While it doesn’t currently, Amazon certainly has the scale and capital to broaden its healthcare offerings, he said.
“If GPOs continue to provide more value, they’ll have a place in this supply chain,” Kowalski said. “If they don’t, there are no guarantees.”
Summit Pacific will continue to experiment with Amazon Business as it looks to drive more costs out of the supply chain, Palcich said.
“I think there are some legacy things about stocking levels and liability that have caused healthcare providers to stick with tradition,” he said. “But this shows us how we can bring new tools to the supply chain to make it faster and better. And we’re just getting started.”

Google program invests in voice assistant startup Aiva Health


  • Los Angeles-based startup Aiva Health got a shot in the arm from the Google Assistant Investment Program to support development of its artificial intelligence-powered voice assistant.
  • Aiva uses Google Home, Amazon Echo and other smart speakers to engage patients and the elderly and connect them with their caregivers.
  • The funding will be used to speed development and commercialization of Aiva’s voice assistant platform.

Voice assistants are a key trend, and everyone is looking to capitalize on Amazon Alexa, Google Home and other voice-activated platforms. A few healthcare organizations have deployed voice control applications, but they have mostly been for a broad base of consumers.
Last September, Mayo Clinic launched a health-related voice control Alexa skill aimed at helping people with first aid advice. More recently, Cigna rolled out “Answers by Cigna,” an Alexa skill to educate consumers on 150 commonly asked healthcare questions.
Tapping into the home health market in a meaningful way could prove lucrative, particularly if the technology enables a growing senior population to remain longer in their homes.
The Google Assistant Investment Program was created earlier this year to support development of innovative voice technologies. The Aiva infusion is the program’s first healthcare investment.
“Voice is the new mobile for delivering better healthcare,” Aiva founder and CEO Sumeet Bhatia said in a statement. “We’re thrilled to be working with the Google Assistant investments team to help expand our offerings and improve care for people who need it the most.”
Aiva’s other investors include Act One Ventures, Mucker Capital, Techstars and the Cedars-Sinai Accelerator powered by Techstars.

Employer-based health insurance offerings increase for first time in decade


  • After nearly a decade of declining employer-based health insurance plans, the overall percentage of private-sector employers offering health benefits in 2017 increased for the first time since 2008, according to the Employee Benefit Research Institute.
  • In a webinar on the topic on Thursday, EBRI said the strong economy is mostly the reason for the increase, including low unemployment, fewer self-employed people, more employees moving to larger companies and more people transitioning from part-time work.
  • Despite improved numbers, the National Federation of Independent Business (NFIB) said costs associated with health benefits remain the No. 1 problem for small businesses.

Experts believed that many businesses would drop health insurance after the Affordable Care Act. The law makes it easier for people to get health insurance on their own, such as through the exchanges. With that in mind, more employers were expected to drop coverage and let employees get insurance themselves.
Also, the country was in a recession a decade ago with unemployment at about 10%. A weak labor market meant that businesses didn’t need to offer competitive health benefits to compete against other companies, said Paul Fronstin, director of health research at EBRI.
This combination was a recipe for employers, especially small businesses, to drop insurance. In the years after the ACA, more smaller companies dropped coverage. That’s changing, and the economy and shifting healthcare costs to consumers are the reasons.
EBRI found that since 2014, when the ACA exchanges went into effect, the number of private sector businesses offering health insurance has actually increased. After years of a decline, EBRI first saw the change in 2015. Mid-sized employers (100-999 employees) increased from 92.5% in 2014 to 95.1% in 2015 and eclipsed 96% over the past two years.
Another trend in 2017 is that more small businesses are offering health insurance compared to previous years. “It’s this increase that’s driving the overall number up. You have to remember most employers in the U.S. are small,” Fronstin said.
Despite more businesses offering insurance, the costs associated with health benefits remain a major problem for small businesses, Holly Wade, director of research and policy analysis at NFIB, said. Small businesses have listed the cost of health insurance as their No. 1 problem and priority since 1986, she said.
In 2016, a survey of small businesses found that 52% of respondents believed health insurance costs were the most critical problem ahead of “unreasonable” government regulations and federal taxes on business income. Only 8% of respondents said healthcare costs were not a problem.
Though slightly more than half consider health costs their No. 1 problem, health insurance costs aren’t as much of an issue for small businesses as they were 14 years ago when 66% of small businesses said it was a critical issue.
One reason for the reduced concern is that benefit design changes have created high-deductible health plans and shifted more costs onto employees.​ NFIB found in a 2015 survey that 36% of small companies provide higher deductibles as a way to control healthcare costs, 30% increase copays, 20% reduce benefits and 18% offer restricted networks.
All of these actions have helped cut costs for businesses. A recent Mercer’s survey found that employer-sponsored health insurance costs have increased about 3% annually since 2012. A decade ago, annual cost growth was more than double that percentage.
Despite those improved numbers, many small businesses still face annual double-digit cost increases. Mercer said about one-third of smaller employers saw health insurance cost increases of more than 10% in 2017.
A strong economy is benefiting employer-based health insurance numbers now, but employer-based coverage will be tested in the next economic downturn. When that happens, it will be the first time the country faces a recession with the ACA providing an alternative for employer-based coverage, Fronstin said.
He suggested that higher unemployment could lead businesses to drop coverage with the belief that their employees can get individual coverage through the exchanges. “That’s when our traditional employer-based system gets put to the test,” Fronstin said.

Facebook, Instagram’s Anti-Weed Stance Frustrates Cannabis Entrepreneurs


Facebook And Instagram's Anti-Weed Stance Frustrates Cannabis Entrepreneurs
Advertising is crucial in the success of any business — and this holds true for cannabis as well. When U.S. states started to legalize cannabis, dozens of new companies flocked to the largest social media platforms in the world, including Facebook Inc (NASDAQ: FB) and Instagram.
They soon hit a snag. Facebook and its subsidiary Instagram weren’t keen on letting cannabis businesses promote their products on the platforms.
Although some businesses have managed to develop strategies that allow them to use social media as a tool to reach out to customers, Facebook’s anti-marijuana position extends beyond ads.

Blocking Cannabis Searches

A search on Facebook shows no results for “cannabis” or “marijuana.” Interestingly, searches for “hash,” “hashish,” “weed” and “pot” will show marijuana-related pages. In a way, Facebook’s anti-weed position only affects the official names of the plant.
It’s an unusual approach, as blocking searches for “cannabis” and “marijuana” not only affects legally operating businesses, but also filters out government agencies that are involved in the industry, such as the California Bureau of Cannabis Control.
When contacted by Benzinga for comment on this story, a Facebook spokeswoman referred to the company’s regulated goods policy.
“In our Community Standards, which are the guidelines outlining what is and is not allowed on Facebook, our regulated goods policy explains that we prohibit attempts by individuals, manufacturers, and retailers to purchase, sell or trade non-medical drugs, pharmaceutical drugs and marijuana,” the spokeswoman said in an email.
“We also further explain that while some of these items are not regulated everywhere, because of the borderless nature of our community, we try to enforce our policies as consistently as possible,”
It’s unclear how censoring marijuana and cannabis searches affects businesses, but there is unquestionably an impact. According to a study conducted by G/O Digital in 2014, 30 percent of those surveyed said that they checked a local business’ Facebook page several times a day before deciding to take their business there.
Some businesses found a way around the verbiage.
Jamie Cooper, the CEO and founder of Cannabiz Connection, an online platform that connects cannabis entrepreneurs, said she noticed that the search for “cannabis” on Facebook is blocked.
Cooper’s company was unaffected because of the “z” in its name, she said.

Selectivity With Marijuana Ads

Facebook’s advertising policy is based on its Community Standards, but is “more stringent” and prohibits the sale or use of illegal, prescription or recreational drugs, according to the social media platform.
While cannabis remains federally illegal, Facebook’s anti-drug policy also affects businesses that service the cannabis industry but do not interact with the plant itself.
Facebook seems to be selective with cannabis-related ads.
“Every time you submit an ad, it is reviewed by one of their team members for approval, and a lot of times it’s rejected no matter what and then sometimes it isn’t,” said Cannabiz Connection’s Cooper.
“The fact that they don’t adhere to their own policy and reject ads that comply with their rules is ridiculous. I can’t even begin to tell you the amount of time I have spent arguing with Facebook. It’s all dependent on who reviews your ad and their personal stance on cannabis.”

Censorship Goes Beyond Search, Ads

In addition to blocking searches and aads related to cannabis businesses, Facebook can also shut down business pages altogether.
In 2016, Facebook deleted or suspended dozens of pages operated by marijuana businesses. It created a backlash, as most of the businesses had operated their pages for years.
Two years later, things haven’t changed much.
The policies affect not only Facebook, but Instagram as well. A number of industry participants complain that their Instagram accounts were deleted while other businesses continued to operate theirs.
“As an edible reviewer, I spent years using Instagram as a way to connect with the cannabis community. I gained a following of 14,000 people only to be deleted by Instagram in 2016. The deletion was devastating and made me rethink the way I connect with the community,” said Alice Moon, a cannabis lifestyle entrepreneur.
Instead of focusing on Instagram, I spent 2017 going to events to build in-person connections, because you can’t delete those. I want to share more on Instagram but my concern is: will I be deleted again?”
Moon saidthat while her account was deleted, others, such as dispensary operator Medmen Enterprises Inc (OTC: MMNFF)’s account, are allowed to create sponsored posts. In another example, cannabis brand Beboe’s account is verified.
The same issue was pointed out by cannabis photographer Bess Byers.
“For being such a progressive, community-oriented platform, it is disappointing to see Instagram get conservative on cannabis. We ask Instagram to please update their draconian Terms of Service to reflect changing laws.”

3-D bioPen: A hydrogel injection to regenerate cartilage


Highly specialized cartilage is characteristically avascular and non-neural in composition with low cell numbers in an aliphatic environment. Despite its apparent simplicity, bioengineering regenerative hyaline cartilage in a form effective for implantation remains challenging in musculoskeletal tissue engineering. Existing surgical techniques including autologous chondrocyte implantation (ACI) and matrix-induced autologous chondrocyte implantation (MACI) are considered superior to self-repair induction techniques. However, both MACI and ACI are complex, multistage procedures that require a double operation; first for surgical excision of native cartilage, followed by expansion of adult chondrocytes in vitro prior to implantation by a second operation.
Regenerating robust articular hyaline-like  is a key priority in musculoskeletal tissue engineering to prevent cost-intensive degenerative osteoarthritis that limits the quality of life in global healthcare. Integrating mesenchymal stem cells and 3-D printing technologies has shown significant promise in bone tissue engineering– although the key challenge remains in transferring the bench-based technology to the operating room for real-time applications. To tackle this, a team of Australian orthopedic surgeons and bioengineers collaboratively proposed an in situ additive manufacturing technique for effective cartilage regeneration. The handheld engineered extrusion device known as the BioPen offers an advanced, co-axial extrusion strategy to deposit cells embedded in a hydrogel material within a surgical setting. The dynamics of material distribution to facilitate cell survival, and the maintenance of mechanical properties for cartilage tissue engineering of BioPen are now published in Biofabrication, IOP Science.
In the recent study, Claudia Di Bella and co-workers conducted neocartilage biofabrication as a requisite step in the path toward clinical translation of the BioPen device, preceded by an in vivo proof-of-principle pilot animal study performed in a sheep model. The authors used human adipose-derived  (hADSCs) laden in gelatin methacrylate (GelMa) and hyaluronic acid methacrylate (HAMa) hydrogels, extruded via the BioPen to generate bioscaffolds that formed hyaline-like cartilage. The authors replicated the previously established protocol to synthesize the GelMa/HAMa hydrogel. The surgical device showed capacity to biofabricate a regenerative stem cell niche in situ with future potential to change the existing clinical approaches in surgical practice for organ and tissue regeneration.
3D BioPen: a hydrogel injection to regenerate cartilage - developmental path towards clinical treatment
The bench to clinic framework of materials development for clinical translation of the BioPen device. The flow chart lists the steps achieved (green) and the steps projected (purple). The present stage is neocartilage biofabrication (red …more
Human stem cells were harvested from the infrapatellar fat pad (IPFP) of patients undergoing total knee replacement. To control the size and shape of the scaffolds extruded by the BioPen, the authors used polydimethylsiloxane (PDMS) cylindrical molds to create a desired shape with regulated cell numbers, providing reproducible structural organization with 3-D geometry for mechanical testing. Immediately after extrusion, samples were irradiated with UV light for photopolymerization. Materials were characterized with mechanical loading tests for compression and atomic force microscopy (AFM) to determine surface topology.
The capacity to produce hyaline-like neocartilage was analyzed using the cellular response to the chondrogenic stimuli via histology, gene and protein expression analysis. The building of new tissue was defined by protein localization and organization of the main components of hyaline cartilage. The neocartilage function was determined via mechanical properties with time.
The study demonstrated the capacity of the BioPen to produce human hyaline-like cartilage by coaxial extrusion of hADSC-laden in GelMa/HAMa hydrogel. A handheld device for surgical extrusion can also overcome clinical graft-site mismatch limitations. The previously established core/shell distribution of the scaffold geometry protected the survival and proliferative potential of the hADSCs. Genes expressed during hyaline-like cartilage formation were quantified with qRT-PCR, the expression of SOX9 – the master regulator of chondrogenesis reflected the chondrogenic potential of the source. Cells similarly expressed COL2A1 (type II collagen found in cartilage) and ACAN (that forms proteoglycan protein) to demonstrate differentiation. Bioscaffolds were further tested using non-linear two-photon microscopy and second-harmonic generation (SHG) to detect mature fibrillary collagen after eight weeks of chondrogenesis.
3D BioPen: a hydrogel injection to regenerate cartilage - developmental path towards clinical treatment
Extruding gel with UV light for photopolymerization. Credit: Melbourne Medical School, Biofabrication, doi: 10.1088/1758-5090/aad8d
The possibility of delivering osteogenic and chondrogenic growth factors within the hydrogel will be considered in the future. Additional studies will also aim to achieve biomechanical properties for the chondrogenic bioscaffolds comparable to native articular cartilage. Studies hereon will evaluate de novo cartilage formation to understand the interplay between stem cells and 3-D architectured hydrogels with different mechanical and biodegradation properties.
More information: Carmine Onofrillo et al. Biofabrication of human articular cartilage: a path towards the development of a clinical treatment, Biofabrication (2018). DOI: 10.1088/1758-5090/aad8d9
Serena Duchi et al. Handheld Co-Axial Bioprinting: Application to in situ surgical cartilage repair, Scientific Reports (2017). DOI: 10.1038/s41598-017-05699-x
Cathal D O’Connell et al. Development of the Biopen: a handheld device for surgical printing of adipose stem cells at a chondral wound site, Biofabrication (2016). DOI: 10.1088/1758-5090/8/1/015019