New 3D scaffold composites; Akron at ISCT 2016

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Improving biomaterial scaffolds for regenerative medicine starts from identifying the most suitable materials based on their mechanical and physicochemical properties. Traditionally, a number of materials have been used in various scaffold configurations (polymers such as PLA, PGA and PLGA have been commonly used in assembling 3D constructs), and ongoing research efforts are advancing the development of scaffolds based on these as well as new material composites.

Chitosan, collagen and hyaluronic acid are not newcomers to the field of regenerative medicine, with their use having been reported in various applications, particularly in regenerative medicine. With that in mind, new studies on their use as scaffold constructs are building on that knowledge and contributing to a better understanding of these materials for tissue regeneration.

A new composite biomaterial based on blends of chitosan, collagen and hyaluronic acid was described in a new study by the lab of Dr. Tomasz Drewa at the Department of Regenerative Medicine at Nicolaus Copernicus University in Torun, Poland.

Titled “3D composites based on the blends of chitosan and collagen with the addition of hyaluronic acid,” the manuscript is published in the August 2016 issue of the International Journal of Biological Macromolecules.

The authors blended chitosan and collagen, and then supplemented the blended polymers by the addition of 1%, 2% and 5% of hyaluronic acid. Biological activity of the novel biomaterial composite was analyzed via the proliferation rate of fibroblasts incubated with the biomaterial scaffolds using an MTT assay. The authors observed good cell proliferation with no cytotoxicity, and postulated that the addition of hylarunoic acid was a positive addition to the scaffolds. Other assays included swelling behavior and thermal stability. Though positive, these are preliminary findings and further studies are needed to assert the in vivo performance of these scaffold blends.

Hyaluronic acid, owing to its favorable biomaterial properties that include favorable degradation profile, has in other studies been shown to be a suitable biomaterial for constructing scaffolds (Collins and Birkinshaw, 2013).

You can read the paper here.

 

Akron Biotech at ISCT 2016

Next week, Singapore hosts the 2016 Annual Meeting of the International Society for Cellular Therapy, which takes place May 25 – 28, 2016 at the Suntec Convention and Exhibition Centre in Singapore. Like previous years, Akron will be there, this time represented through a number of talks.

Akron’s CEO, Dr. Claudia Zylberberg, will participate and speak during two sessions.

The first will be during Quality and operations track 1 – Raw Materials Sourcing scheduled for Thursday, May 26th at 13:45 in Room 330. Dr. Zylberberg will give a talk titled “Raw Materials Regulations” which focuses on various regulatory, standardization and harmonization efforts, as well as optimal criteria when selecting raw materials for use in cell therapy product development.

Dr. Zylberberg will also chair the session Strategies for commercialization Track 8 – Ancillary materials from the user and supplier perspectives: advances and new approaches to reduce cost of goods, decrease risk, and enhance quality, which takes place on Saturday, May 28th in Room 335-336 from 13:15 – 14:45 with speakers that include Brian Newsom (Thermo Fisher Scientific), Jiwen Zhang (GE Healthcare) and Lynn Csontos (STEMCELL Technologies).

For more information about the ISCT Annual Meeting, please visit the official meeting website.

Akron will also be available for private meetings. Should you wish you schedule a private meeting, please contact us.

 

 

Delivery of drugs by liposomes: Akron Publishes Paper in Drug Delivery

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Liposomes represent a mature, robust technology for the delivery of therapeutic drugs – small molecules, DNA, proteins – owing to their ability to mimic the physical and chemical characteristics of living cells. The ability to control their assembly enables biophysical control of the interaction between liposomes and encapsulated material.

Though liposomes have been approved by the FDA for clinical use, in recent years the emergence of new liposome-based systems that enable the delivery of target material to specific organelles, as well as allow for more efficient function such as skin penetration, has added attractive new knowledge to the field.

Liposome-based encapsulation is an active area of growing interest at Akron, and research and development efforts in that area are currently ongoing.

Last week, Akron’s Claudia Zylberberg and Sandro Matosevic published a review paper titled “Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape” in the journal Drug Delivery.

The paper focuses on new delivery systems that have emerged in the last few years – including ethosomes, transferosomes, pharmacosomes and more – as extensions of traditional liposomes, and discusses recent clinical efforts in the commercial approval for these technologies. This review represents a unique example of a recent peer-reviewed manuscript that focuses on new liposome-based delivery technologies which have emerged in recent years. A focus on recent FDA guidelines provides additional relevant information on the clinical relevance of these systems.

The paper is accessible here.

Target Product Profiles: What they are and how they can help your product’s approval

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This past week during the American Society of Gene and Cell Therapy’s Annual Meeting in Washington DC, Akron’s Claudia Zylberberg participated on an industry panel, alongside a host of other industry experts, on Target Product Profiles.

For those not familiar with the topic – what are Target Product Profiles?

It goes without saying that every commercial drug approved by the FDA comes with a label and directions for its use. What is communicated to the patient through these is the result of a long development process, throughout which the drug product has gone through multiple iterations – due to both developmental as well as regulatory constraints.

Requirements for a particular drug change throughout the development process. Communicating such specifications to the various development teams is important, yet can be difficult.

A document called the Target Product Profile (TPP) exists for that reason – to provide informations on the drug’s requirements and specifications for every stage of the process, from development, to pre-clinical, and clinical studies, through to the formulation and drug product characteristics.

It is an extremely useful document that provides information and focus to the research and development teams and can, if used correctly, prevent late-stage development failures. It has tangible endpoints. It is also used as a communication tool that reflects the development company’s, manufacturing and regulatory agencies’ requirements for a particular drug product, and can track changes throughout the drug’s development timeline.

Target Product Profiles are defined in FDA’s Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool, issued in 2007.

A full TPP can include up to 17 different sections. Typical sections for a therapeutic product include:

  • Indications and usage
  • Dosage and administration
  • Contraindications
  • Adverse reactions
  • Storage and handling
  • Clinical pharmacology
  • Non-clinical toxicology
  • Clinical studies
  • Warnings and precautions

The FDA encourages companies to submit TPPs as a part of their Briefing Documents during all steps of the drug development process.

A TPP should, ideally, be developed at the early stages of the drug development process and kept up to date throughout the entire process. It is a “living” document, one that changes as the drug moves through the various development stages.

A helpful webinar on TPPs given by the FDA can be found here.

For more questions on TPPs, contact us and we’ll be happy to talk.

How ECM proteins are helping understand – and eradicate – cancer

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The convergence of 3D assembly technologies such as 3D printing and electrospinning with cell therapy advancements is allowing researchers an unprecedented look into the mechanics of cellular behavior to study the development of diseases such as cancer.

By allowing the construction of three dimensional model systems, we are now able to look into the behavior of cells at the microscopic level by placing cells in synthetic environments that more closely resemble their native ones.

A key to constructing such 3D systems is the use of biological matrix proteins including fibronectin, vitronectin, laminin, collagen and elastin.

A new study by Dr. Wei Sun’s lab at Drexel University is further proof of this.

In the study, titled “Three-dimensional printing of Hela cells for cervical tumor model in vitro,” the authors 3D printed a tumor-like structure with gelatin, fibrous proteins including fibronectin, and cervical cancer cells layer by layer.

This generated a structure that resembled the fibrous proteins that make up the extracellular matrix of a tumor.

Cell proliferation was compared between the 3D model system and a regular 2D plate system. The results showed that Hela cells showed a higher proliferation rate in the 3D printed system where they formed cellular spheroids, but formed monolayer cell sheets in 2D culture. Moreover, a cell viability of over 90% was observed using the 3D printing process.

The study, published in Biofabrication, can be accessed here.

Another recent study, titled “Regulators of Metastasis Modulate the Migratory Response to Cell Contact under Spatial Confinement” and published by Dr. Anand Ashtagiri’s lab at Northeastern University focused on studying the migration and development of cancer cells.

To study this, they also used a model ECM system with fibronectin, which provided a substrate for cell migration.

The study highlights a characteristic fibrillar dimension at which effective sliding was achieved.

Both studies are examples of the critical role ECM proteins play in the development of model systems to study cell-based disease modeling.

Understanding how these ECM proteins work is the key to studying how they can be used in modeling cell migration and disease development. A supplier like Akron possesses a wide knowledge base of expertise that includes not only sourcing of these proteins, but also their mode of action and the ways in which they can be implemented in bioassays and 3D systems.

Options like viral inactivation – an Akron industry first – further enhance the clinical utility of these proteins. Contact us to discuss.

It beats: 3D Miniaturized Heart Created from Stem Cells

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A remarkable new step toward heart regeneration: a beating 3D micro heart from induced pluripotent stem cells.

This is what a new study by Dr. Bruce Conklin’s lab at the Gladstone Institute of Cardiovascular Disease and the University of California, San Francisco described in a new manuscript published in the journal Scientific Reports.

Engineering micro heart muscle from induced pluripotent stem cells has been challenging: obtaining aligned and unidirectionally contracting tissue without requiring unfeasibly high numbers of cells and requiring easily manufactured materials has been a traditional constraint that has limited progress in this area. Moreover, differentiating iPS cells into heart cells produces weak and immature heart cells, making working with these cells difficult.

 

The new study overcame these constraints by creating a system wherein the authors seeded a mixture of cardiomyocytes and fibroblasts derived from iPS cells into stencils containing – in the authors’ own words – “dogbone” through-holes comprised of a high-aspect ratio “shaft” flanked on either end by square “knobs.”

To clarify this design, see image in Panel A below.

 

Screen Shot 2016-04-24 at 9.27.47 AM

 

Such confinement of cardiomyocytes and fibroblasts into rectangular canals aligned in three dimensions and induced uniaxial beating within these canals.

Moreover, such alignment allowed the authors to work with significantly fewer cells than traditionally needed for engineered micro heart tissue systems.

This is a remarkably simple solution to a complex problem.

These cells were also cultured for a short time, during which they adopted an in vivo-like morphology, and exhibited some functional aspects of adult cardiac tissue. These paramters, however, require further investigation and experimentation.

The authors intend to follow this up with more advanced systems that allow parallelization and automation, to try and achieve a higher throughput screening system of artificial mini hearts.

See video below of the beating mini hearts in action.

 

 

 

And though more work is necessary to establish whether this iPS-CM-based micro heart system can accurately model adult heart tissue, it is an interesting example of how geometry and environment can regulate the behavior of cells and tissue towards fully functional organs.

Cancer Immunotherapy: Not all IL-2s are created equal, and why this matters

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On the heels of Akron Biotech’s acceptance of our Drug Master File for interleukin-2 by the FDA, it is appropriate to highlight what such an acceptance means and why one should be concerned with the quality of any interleukin-2 used in their immunotherapy projects.

As the first immunotherapy approved by the FDA for treatment of metastatic melanoma, interleukin-2 (IL-2) has come a long way from where it was two decades ago: the subjects of extensive research, it remains one of the most important cytokines used in the development of cancer-targeting immunotherapies. There is compelling data of immune activation leading to cancer regression after treatment with IL-2 activated T-cells, and such research continues.

But not all interleukin-2s are the same: the path to the clinic – and eventually, regulatory approval and commercialization – is paved with a number of checkpoints that are often overlooked.

Oftentimes, when it comes to sourcing raw materials – including interleukin-2 – one of the most important factors taken into consideration is cost. This is a reasonable selection criterion, but one that fails to address the complexity and severity of proper selection of IL-2.

No consideration of cost should come at the expense of quality – but what does quality mean, exactly?

Across the industry, there is widespread confusion about terms such as “GMP,” “research grade,” “injectable grade,” “clinical grade,” as well as the importance and use of batch records, drug master files, SOPs and quality documentation. Common questions one should be expected to know the answers to are: when are these documents needed? Who is responsible for writing them? What kind of data and information is needed for each of them?

If you were asked which of the above are required for pre-clinical development of an IL-2-based immunotherapy, would you know? What about clinical trials?

Moreover, if you are currently a user of interleukin-2 either as a raw material in a current immunotherapy development process or as a reseller to end users , are you aware of the type of documentation available for the IL-2 and how the needs for this documentation change as the development pipeline progresses? What is needed at the research and development phase is very different to what one needs when submitting documents to the FDA. Not being adequately prepared often causes scrambles down the road and, more worringly, regulatory denials.

This happens often and has caused regulatory issues that have costed companies significantly more than it would have cost them had they sourced their raw materials correctly.

It is very common to underestimate the need for such documentation as well as background data supporting these products, but most of all, misunderstand the need for continued support and updates to such documentation.

Unfortunately, many IL-2 suppliers also do not have a full understanding of the clinical development process and as such, do not translate this information adequately to customers thereby further promoting miseducation about this.

Just like not all immunotherapies are the same, not all IL-2s are the same either: ask yourself, what kind of IL-2 is your supplier providing? What kind of data – stability, functionality, pre-clinical and clinical – are they able to provide you?

Do not be surprised if most of this information is not available, or if you are not able to obtain answers to such questions.

Make sure that your supplier is able to provide a full portfolio of information, data, but most importantly, support to help guide the development process.

While this post should not come across as a direct promotion of Akron Biotech’s interleukin portfolio, we want to highlight the unique prospect of working with us on your immunotherapy products: not only is our interleukin-2 (and many other growth factors) manufactured as pharmaceutical grade, the product is supported by an extensive dossier of data – from stability, to functionality, all based on international standards – that allows us to provide the right product for the right stage of development.

More importantly, the flexibility of adjusting documentation as your process changes is possible and done easily and quickly.

Ask yourself: is your current interleukin-2 right for you?

 

US Government Highlights Future Support for Regenerative Medicine Manufacturing

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In an Advanced Manufacturing report for April 2016, A Snapshot of Priority Technology Areas Across the Federal Government, the US Federal Government’s Subcommittee for Advanced Manufacturing of the National Science and Technology Council highlighted areas of US manufacturing technology areas of emergeing priority.

Among them, regenerative medicine was highlighted as one of the areas of interest for continued future financial support.

The Federal Government invested $2.89 billion between 2012-2014 on regenerative medicine, money which primarily went to the development of therapeutic techniques and technologies.

Current funding programs developing new regenerative medicine products and technologies come from DoD, Food and Drug Administration (FDA), NIH, NIST, DOE National Nuclear Security Administration, NSF, and the Department of Veterans Affairs (VA).

Some of the investment programs supported by these agencies include the FDA’s Mesenchymal Stem Cell Consortium, DoD DARPA’s various macrophysiological systems programs, HHS NIH NHLBI’S Stem Cell-Derived Blood Products for Therapeutic Use Program and more.

The report highlights that future support for regenerative medicine manufacturing technologies will require collaborative work. Specifically, the report lists some expectations from teams developing future technologies which will lead to more efficient products. These include, quoted directly from the report:

To manufacture specific tissues, a project team must have advanced engineering skills combined with a deep understanding of the physiology of those tissues and the organ systems in which those tissues function

Controlling and characterizing the biologic activity through discovery, triggers, and terminations of the appropriate effector and control mechanisms at the individual cell and population levels will require the expertise of genomic scientists

Efficiencies at each step are essential to keep costs and raw materials usage down, and to keep fragile products (i.e., cells, tissues) viable, while a constant focus on usability will ultimately help enable adoptability.

Biomanufacturing for Regenerative Medicine is also listed as one of the areas of future investment for which the Government has issued a Request for Information to create a Manufacturing Innovation Institute.

Encouraging interest from the US Government in supporting further development in regenerative medicine highlights the need for more innovation in new products, technologies and strategies for cost reduction in regenerative medicine.