I don't believe Dr. Robert Langer needs too much of an introduction. His work and creative mind has motivated some of the brightest scientists to reach forward and look to driving change, as an achievable goal. The Langer Lab at MIT has become synonymous with innovation and a can do attitude. A view that permeates throughout the complex interwoven fabric of chemical constructs, nanoscale architectures and biological systems. This is Bob’s culture, as he likes to be called. Those from yesterday and today all have this in common, as will those of tomorrow - the origin story of innovation without peer. The list is long and distinguished and will be so far into the future.
The utility of material science as a foundational springboard for patient centric approaches to medical intervention is not novel. There have been devices, tools and technologies throughout the history of patient care. Some of the most important shifts in medical practice has come by way of devices. The hand of the doc always can and should always be assisted with the very best innovations science can develop.
Up until recently that was the realm of dedicated professionals, each with their own areas of expertise. Bob was one of those that looked to change that, perhaps as a result of his requirement to improve what he saw as inefficiencies and his innate ability to bridge between the professional definitions that ordered things. To seek out compatible solutions that mixed disciplines in order arrive at a solution. The utility factor by design. Practical and purposeful from a solutions perspective.
That is what stuck me about Bob during our meeting. His natural ease at distilling a challenge and suggesting a practical pathway to arrive at a solution. Not the only solution, but in most cases a simple solution, which interconnects various synthetic elements to arrive at a bioengineered answer. A product that can work with and within our natural biological systems, often dramatically improving on an existing methodology for the benefit of patient care.
During our conversation we discussed two such technologies that I have been following closely: SQZ Biotech and Gecko BioMedical. In addition, I followed-up with management for further details. Below you'll find a summary of these technologies and the associated Q&A.
A third topic was InVivo Therapeutics, which has been extensively covered by analysts and the media so I’ll only add some color from Bob on the history and developments.
InVivo’s origin story began with a graduate student, Erin Lavik, in the late 90s. She had come to Bob with with her thesis on spinal cord repair as a material scientist student doing her Phd. They talked about creating a scaffold that “looked like the grey and white matter of the spinal cord which we could put neuronal stem cell on.” Erin had been collaborating with Evan Snyder, a stem cell scientist and envisioned a combined biomaterial and stem cell product. The PNAS paper they published with Yang (Ted) Teng, a neurosurgeon, showed “significant improvement in rats” with the scaffold & cell product. Later they showed improvement in monkeys with both scaffold only and to a greater extent with the combined approach with cells. At that time they were approach by Frank Reynolds from MIT Sloan School about Licensing - which launched InVivo. Frank has since stepped down and Mark Perrin now heads the company.
By Bob’s account, “I think Frank and the people at InVivo, thought it best to try to understand things properly, so they started with a scaffold only product. It's also easier from a regulatory standpoint that way.”
By all accounts that decision was correct, as the clinical trial has started and the first three patients have reported improvements.
What no one expected was the first two patients “falling in love & living together - which is amazing!”
Bob says the “long range plans are very exciting, not just for the scaffold but for the scaffold with neuronal cells and possibly the controlled release of different neurotrophic factors, which we’ve done a lot of work on, for the combined product.”
In the meantime there is speculation not only about the source of the neuronal cells, but also about the marriage of Jesi and Jordan, those accidental love birds!
Utility by Design, along with a touch of Karma.
With the advent of cellular therapy the use and in-vitro manipulation of cell populations has become a common occurrence in laboratories and bio-manufacturing centers around the world. The promise of new biologically relevant patient treatments, both personalized and generic, holds great promise for the medical industry and most of all to patients. Along with the advent of this new era in therapies comes the technologies to optimize and enhance the cell productization process.
SQZ Biotech was born to fulfil that mission and uses it’s CellSqueeze technology to do so.
As a doctoral student in Bob Langer and Klavs Jensen’s labs in Boston, Armon Sharei excelled at the study of microfluidics, the process of passing substances through small chambers to mimic naturally occurring dynamics. During this thesis work Armon discovered that it was possible to alter the integrity of cell walls in such a manner that doorways opened into cells. Bob Langer was as surprised as Armon “when cells went through the device and a little pressure applied the cells would open up and things would go in.” After further study it was revealed that all kinds of molecules etc, large and small, would go in and no harm to the cell was observed afterwards.
After filing patents and publishing the work in PNAS, Scientific America called it one of the world changing ideas of 2014 and the company was launched with institutional & seed support and Armon became its co-founding leader full time.
The company has now secured VC backing to the tune of $5 million and is in industry prototype tests, with a good deal of buzz around the potential.
Certainly the technology has got off to a good start, gaining some traction. Also there is a broad uptake in cell system technologies that can customize and safely adapt therapeutic populations. CellSqueeze could very well be the next step up in the in-vitro cell manipulation suite.
I asked Armon a few questions on the technology -
M: What are the best types of cells to "squeeze" and if there is a most suitable cell type model depending on the payload, i.e. primary types, differentiated cells, size or shape?
A: We have found that the concept works with every mammalian cell type we have tried. To your point, the most promising areas have been primary cells such as immune cells and stem cells which are hard to treat by conventional means but respond very well to our technology. The size and shape of the cells do influence their delivery properties and we have a library of chip designs that accommodate different cells. As for payload, because the delivery process appears to be a largely membrane disruption based process, we can deliver a broad variety of payloads including peptides, proteins, polymers, DNA, RNA, nanoparticles, etc.
M: How would you best describe the squeeze technology and can it be considered a transduction system?
A: We have tended to simply call it a "delivery system" or an "intracellular delivery system". Mostly because transduction tends to be used in the context of viruses and transfection implies nucleic acid delivery.
M: I've noticed a few new systems for delivering payloads into cells - what advantage do you see SQZ having over these other developing technologies? e.g. the UCLA Optofluidics system is looking to do something similar & how do you see these different approaches vis-a-vis SQZ...
A: I think we are going through a period of exciting development in MEMS technologies for intracellular delivery. I have seen reports of many exciting new methods such as nanoneedles, microfluidic electroporation and other physical delivery systems. Ultimately I am most optimistic about our technology because it is robust, simple, and scalable by comparison to other approaches. For example, the nanoneedles can be difficult to fabricate and are not well suited for suspension cells while microfluidic electroporation does not overcome some of the inherent toxicity issues and delivery limitations of conventional electroporation. In contrast, our devices can operate at over 1,000,000 cells/s and have demonstrated applicability to over 25 cell types. Moreover, our papers demonstrate 10-100x greater performance compared to conventional approaches in multiple applications.
M: It has been reported that SQZ is actively engaged in trialing its proprietary system with industry - can you expand a little on that?
A: We have active partnerships with multiple pharmaceutical and biotech companies pursuing applications that are uniquely enabled by SQZ's technology. These often involve delivery of materials that cannot be introduced into cells by conventional means.
M: With your recent capital raise what are your next development steps and timelines?
A: We are accelerating our internal therapeutic programs and developing next generation devices. The company is focused on the development of novel cell therapies using multiple cell/molecular engineering modalities to address acute clinical challenges across indications.
As the name inspires, Gecko is a product of nature, developed as a mechanistic solution to the closure and repair of tissue in wet conditions.
As I recall, I was drawn to this technology as a result of my father’s experience as a surgeon and his constant struggle with closure and repair. From his days as a field surgeon in Vietnam to his surgery days at the hospital, he always wished there were more effective closure tools so he could perform better. Occasionally I would listen to him speak about those young soldiers.
The need is real and the solution a potential breakthrough. To be able to close an internal or external wound with the ease and elegance of a bio-patch is a proactive step forward.
Langer again was instrumental in providing the fertile ground, this time for post-doc Jeff Karp, now an Associate Professor at Brigham and Women’s Hospital, Harvard Medical School. As Langer relayed, Jeff loved “to take things out of nature and make them into synthetic materials and one day we were talking about Geckos and if we could make a polymer similar to a Gecko’s grip and we did by nano-printing.” That was the start of development and since then the technology has evolved with advanced glue inspired by snails & worms, along with the integration of light activation chemistry.
Gecko Biomedical is based in Paris and concluded a successful private placement with VCs for $11m, and is running preclinical studies in preparation for first in human trials later this year. Another Langer venture, Moderna, a mRNA company, was the catalyst for the French connection, as he was introduced to Gecko’s future management via Moderna’s executive suite.
I asked Jeff Karp for a little background on the technology and its applications.
M: Can you explain a little about the product solution
J: There is a huge unmet need for better tissue adhesives. Sutures are extremely time consuming as with each pass of the suture needle, the tissue needs to be re-aligned. And the longer a patient is on the operating table the greater the chance for complications. It is also difficult to tie knots in small spaces, such as during laparoscopic procedures. Staples are also problematic as anytime one pushes a staple into tissue, the hole that is created is larger than the staple which tears the tissue, and this can serve as a nidus for bacterial infiltration. And typically you need to bend staples to secure them in place which damages the tissue. Often staple tracks are sites of infection! Also it is challenging to apply staples in small spaces as the devices used can be quite bulky. And sutures and staples have different properties than tissue and this mismatch can cause tissue death over time and lead to leaks.
M: How did you develop the design requirement for the platform
J: We put together a design criteria for the solution -
• We wanted this to work in the harshest environment inside the body, inside a beating heart; it is a highly dynamic environment, it’s very wet, lots of proteins. Many of the glues that exist today that are being used for tissues can become fouled in the presence of blood. As soon as they contact blood they can no longer adhere to tissue so we had to solve that problem.
• We wanted it to be degradable and Biocompatible. What I mean by this is because we are trying to treat kids, we wanted this to facilitate the migration of cells over-top and into it so as the material degrades, it would be replaced with the patient’s own tissue. So at the end of the day, maybe 4 months or 6 months, you’d just be left with the patient’s tissue and that can grow overtime so you don’t have to come in and do revision surgeries.
• It needed to be elastic as the heart is undergoing multiple expansion/contraction cycles.
• Also, we wanted this to resist washout in the heart which is very challenging because there is a high shear stress.
• When we talked to a number of clinicians, they said “There’s certain glues that exist in the clinic that either cure within 1 minute or 10 minutes and we don’t want to be at the mercy of the technology, we want to be in control”; and so we made on-demand adhesion part of our design criteria. We envisioned using light to achieve this.
• We had materials that could address many of these, but not washout & adhesion. We couldn’t figure out a way around it so we turned to nature for inspiration and we synthesized glue inspired by slugs snail and sand castle worms. We produced a viscous prepolymer, that you would apply to the tissue or to a patch and then cure with light to end up with a material that’s very similar to an elastic band. We made this patch you can stretch it over and over again but it’s fully degradable and bio-compatible. It can take a 30% strain, which is what you’d expect in the heart, and we don’t see much change in the mechanical properties of the material. Eventually we showed that we could seal the carotid artery and aorta of a pig, and also attach a patch inside a beating pig heart.
I also asked Christophe Bancel, CEO of Gecko Biomedical, a few questions on the formation of Gecko and the technology platform moving forward.
C: Bernard Gilly (Non-Executive Chairman) and I knew Bob and Jeff Karp and their the work in the field of adhesives in wet and complex environment for a certain time and we followed their progress. Once the 4 of us believed that the technology was ready to start translation into a product, we decided to create Gecko Biomedical.
M: Why Paris and not the US?
C: From a regulatory and development point of view, many innovations in Medtech tend to be developed in Europe first, so we thought that this could be an opportunity. On top of that, Bernard had developed an entrepreneur initiative in Paris, the iBionext Network, that had successfully brought together experienced executives in Biotech and Medtech with support of leading European investors. We were ready to provide the full support for the development of this technology into innovative products for patients.
M: How do you view the underlying technology
C: Gecko Biomedical’ platform allows the development of diverse solutions for adhesion and wound closure in wet and complex environment that can be designed to meet the requirement of specific tissues. Applications range in the different fields of surgery. We have decided to start focusing on vascular reconstruction, but are also developing variants of our polymers for new tissue types.
M: Will there a combined product with biologics in a future generation of products?
C: Indeed, by design, our family of polymers can provide controlled release of active substances (small molecules or biologics) and also encapsulate cells for active delivery.
M: Where are you at present in the product development timeline?
C: Currently we are working with a leading cardiovascular department at Paris Hospital. We are finalizing all the regulatory development under Good Laboratory Practice (GLP) for the non-clinical validation of our first application in vascular reconstruction and intend to start the first clinical trial by year end.