Research in the diabetes field has taken two main directions: improving current therapies, and exploring radical new approaches. Improvements in current therapy include making glucose monitoring and insulin delivery less invasive and more patient-friendly, and many significant advances have been made in this context in the past two decades. Among these have been the development of insulin pumps and of non- or minimally-invasive techniques for sampling blood. New, fast-acting forms of insulin have been introduced. There has been considerable research in non-injection dosage forms for insulin, and the first inhaled insulin product has recently been approved. This could herald a new era in insulin therapy.
Another ground-breaking development will be the successful development of an “artificial pancreas.” This is the term used to describe a system in which continuous glucose monitoring is linked electronically to continuously variable insulin delivery, effectively making diabetes control automatic and freeing the patient to get on with his/her life. The technology behind an artificial pancreas is still being developed but it is at an advanced stage.
More radical approaches to diabetes mellitus, also the subject of vigorous research, include ways of replacing the whole cumbersome business of glucose testing and insulin administration. Transplantation of healthy pancreatic islets into diabetic patients has been explored, but the problems of rejection are a significant hurdle. More promising is the modification of adult or embryonic stem cells so that they develop into pancreatic beta-cells capable of being implanted in the patient and serving as a replacement for the insulin-secreting cells that have been destroyed.
Further in the future are developments based on genetic manipulation. Several gene anomalies have been identified as related to the development of type 1 diabetes in particular, and these may present targets for intervention to prevent the disease from developing.
From "Diabetes Management: Products, Technologies, Markets and Opportunities Worldwide 2009-2018", Report #D510.
At the forefront of those technologies seeking to reverse diabetes or at least target the underlying disease are the cell-based options to restore normoregulated blood glucose levels. These include pancreas transplants, islet cell transplants and a number of stem cell transplant options.
Pancreas transplantation has been widely practiced for some years and has been successful in a majority of patients. It is not appropriate for all diabetics as it is, for example, too invasive for children, and cost is a major deterrent. Also, immune rejection of the transplanted organ is a constant threat which must be counteracted by daily immunosuppressant drugs. Another major problem is the shortage of available organs for transplantation compared with the much larger demand.
Pancreas-alone transplants are performed when there is normal or near-normal kidney function. This option may be recommended for patients who have frequent insulin reactions or poor blood glucose control despite best efforts to manage the disease. Most transplant recipients are 55 years or younger, have type 1 diabetes and are healthy enough to undergo the procedure. About 95% of pancreas transplantation are performed in patients with renal disease or who had a previous functioning kidney transplant. In the United States, roughly 1,200 people receive pancreas transplantations each year. If insulin treatment and monitoring strategies are working, a transplant is unlikely to be a better option. According to pancreas transplantation results reported to the Scientific Registry of Transplant Recipients of the United Network for Organ Sharing and the International Pancreas Transplant Registry, survival rates for recipients of a simultaneous pancreas-kidney (SPK, i.e., from the same donor) transplant were 85%–95%. Compared to diabetic patients receiving just a kidney, long-term patient and kidney graft survival improved for patients who also received a pancreas. Survival rates were 78%–83% for those patients who received only a pancreas or a pancreas some time after a kidney transplant.
As such, roughly 75% of all pancreas transplants are performed along with a kidney transplant (in an SPK procedure) in diabetic patients with renal failure. (About 15% of pancreas transplantation are performed after a previously successful kidney transplantation and 10% consist of pancreas alone in nonuremic patients with very labile and problematic diabetes.) The strategy is to give the patient a healthy kidney and pancreas that is unlikely to contribute to diabetes-related kidney damage in the future. This dual transplant appears to contribute to better survival rates for both organs. After five years, the survival rate for the pancreas in a simultaneous transplant is 70%, while the organ survival rate for other pancreas transplants is only 52%.
Islet Cell Transplants
Islet cell transplantation (ICT) may eventually become an effective diabetes therapy by replacing whole pancreas transplantations, but at this point, it is experimental and not yet as efficient as pancreas transplantation. ICT involving just those parts of the pancreas, called islets, where insulin is produced. Theoretically, the process is based on the enzymatic isolation of the pancreatic islets from an organ procured from a cadaver donor. The islets obtained are injected into the liver in the recipient via percutaneous catheterization of the portal venous system. This procedure allows the selective transplantation of the insulin-producing cell population, thus avoiding open surgery as well as the transplantation of the exocrine pancreas with related morbidity.
Initial experience with ICT was only modestly promising. The immunosuppression regimen was similar to the one used in solid organ transplantation, based on high dose steroids and calcineurin inhibitors, both of which are agents with diabetogenic effects. Results improved markedly with improved manipulation of the islets and changes in immunosuppression strategy using sirolimus, tacrolimus and daclizumab. This protocol was initiated by investigators at the University of Alberta in Edmonton, Canada. Generally, their protocol requires two islet cell infusions in order to attain the critical cell mass necessary to achieve insulin-independency. The changes in treatment were adopted as the Edmonton Protocol, which is used now in several transplant centers worldwide.
Stem Cell Transplants
Stem cell research allows scientists to explore how to control and direct stem cells so they can grow into other cells, such as insulin-producing beta cells found in the pancreas. Creating new beta cells could lead to cure for type 1 diabetes as they would serve as a replenishable source of cells for islet cell transplantation. They could also provide an additional means for controlling type 2 diabetes.
The American Diabetes Association strongly supports all forms of stem cell research to find effective diabetes therapies, examples of which include embryonic stem cells, cord blood stem cells and adult stem cells.
Researchers have made several advances to demonstrate the potential of human embryonic stem cell (hESC) research and are beginning to understand how this research could benefit diabetes. Already, many of the genes involved in pancreatic development have been identified, and recent discoveries have allowed scientists to overcome the difficult task of getting stem cells to produce the necessary proteins in the correct sequence that will allow them to become insulin-producing islet cells.
Due to the ongoing ethical challenges raised by the use of embryos for stem cell therapies (despite the rescinded funding ban on federally funded embryonic stem cell research), alternatives that avoid these issue have been, and will continue to be investigated aggressively, including cord blood cells and adult stem cells. Cord blood is obtained from the umbilical cord at childbirth after the cord has been detached from the newborn. This blood contains stem cells, including hematopoietic cells, which can be used in the research of many types of therapies, including diabetes. This includes such studies as the regeneration of islet cells. Adult stem cells hold promise, particularly as autologously-derived cells that can be directed to differentiate into pancreatic islet cells that, due to their autologous sourcing, will avoid immunogenic response and its complications (and cost) in treatment.
Report #D510 details the status of programs and products in the development for cell-based therapies for diabetes.
A great many medical technologies are seizing opportunity in healthcare as a result of a wide range of advances. Â Here are a few we wish to highlight:
Radiofrequency devices are in a growth phase as device manufacturers recognize the potential to monitor device location and performance. Â RFID potential includes tags enabling the secure tracking of instruments (and sponges) during surgery, patient tracking in healthcare facilities, glucose-sensing RFID implants for diabetes and many others.
Technologies to approach clinical challenges by harnessing and manipulating the patient’s own nervous system — for reduction of pain, control of incontinence, even spinal cord stimulation for treatment of congestive heart failure and others are opening up a whole new field of clinical intervention. Â Driven by companies like Medtronic and others, the field is poised for dramatic growth in clinical applications and device markets.
Interventional (percutaneous)Â technologies
Catheters used to represent little more than tubes to drain fluids, but have evolved to remotely deliver and deploy a remarkable range of devices from stents, to heart valves to vena caval filters and many others. Â Taking advantage of the highly prevalent skillsets of interventional cardiologists, new interventional technologies are pushing the boundaries of procedures that can be performed without incision. Â And as clinicians’ skills increase, manufacturers are further developing interventional technologies that can access ever-smaller vasculature, such as via radial arteries instead of femoral.
Natural orifice transluminal endoscopic surgery (NOTES)
The relentless drive to make surgical procedures less traumatic has driven surgeons away from even the relatively inconsequential laparoscopic incision to a growing volume of surgical procedures that can be performed entirely endoscopically using the patient’s “natural orifice”. Â As a practical matter, NOTES is effectively a natural result of the continued development of endscopy, but the drive to eliminate external incisions and further reduce trauma, combined with great advances in endoscope and endoscopic instrumentation development, is accelerating the shift away from traditional surgery and toward truly least invasive surgery.
No longer are medical devices inert, structural implants, but they have become biocompatible, bioerodible/biodegradable and provide other functions including drug delivery, stimulation of cell migration and others. Â The science of engineering polymers and other unique materials is complementing advances in understanding and control of cell and tissue biology to produce a dramatic increase in the functional interface between device and disease.
Whether commercialized as nanocoatings or as nanoparticles to provide targeting or drug delivery or a host of other “very small” functions, nanotechnology applications in medicine are proliferating. Â The applications are too numerous to mention, revealing that there is in reality little in common between many different nanotechnologies, other than size.
Adult and other non-embryonic stem cells
When the ethical challenge of embryonic stem cells caused federally funded research to be put on hold, the incentive was raised for research to ferret out the potential of adult stem cells, cord blood cells and other sources of stem cells, many of which may ultimately avoid both the ethical challenge and the tendency of embryonic cells to become cancerous. Nonetheless, the potential of embryonic remains (as does the ethical risk), but adult stem cells may prove more pragmatic in the long run.
Many more technologies are arising from advances in basic scientific research and from the highly innovative development by medical device and other technology companies than have been mentioned here, but this provides a sampling of the technologies that are seizing opportunity as a result of advances in scientific application that meets clinical demand.
It occurred to me that in my position performing, directing and reviewing market research on a global scale that it would be worthwhile to highlight recent insights that have come to me regarding the global medical technology market. Some of these insights, of course, may only be meaningful to me (and those who have a perspective on medtech markets similar to mine), but I hope that some insights may be useful to some of my niche audiences in medtech. Keep in mind that some of the insights I have come from proprietary sources, whose identities I am not able to reveal (lest they elect to no longer do business with me!), but I will nonetheless reveal as much non-proprietary information as I can.
The global economy is down from two years ago, but is measurably if not significantly up from one year ago. I gauge this based on the overall level of business we directly receive and the feedback my authors receive from researching medtech companies. This should be no surprise to anyone who reads other business news on a regular basis.
U.S. markets, for a number of reasons, seem to be lagging markets in the global economy in this period of economic recovery. If I simply use the measure of the number of medtech company inquiries to us originating from U.S. versus OUS companies, I have seen a clear trend that started with a global decline in 2008 followed by a flat 2009 followed by a steady growth in inquiries from OUS companies in 2010 and relative smattering of U.S. company inquiries. Why this is so may be the subject of countless speculation, but one reason, I believe [insert personal insight here] is that OUS companies (whose pockets weren't so deep as those in the US) felt the hit of the global recession before the US companies and they sooner ran out of patience waiting for markets to rebound, electing instead to move forward on product development, market development and other initiatives.
The trend of OUS emerging from the global recession before the US is one that runs counter to the other truth I see, which is that the U.S. is almost universally a market leader (with the exception of areas like cell therapy, in which academia and business OUS has been more than happy to push forward in research while the U.S. vacillates between right- and left-wing politics). Almost without fail, I continue to see the most advanced technologies emerging principally from US rather than OUS companies.
There has been more activity emerging from China and (rogue island) Taiwan in medtech over the past two years than I have ever seen. This activity — purchase of market research, formation of companies or commercialization in general — has a concentration in academic organizations or institutes apparently seeking to commercialize research discoveries originating from "pure" research.
Hope springs eternal in the U.S. Despite two full years of economic woes in the U.S., a surprisingly steady stream of new medtech companies continue to be founded, as entrepreneurs commit to the commercialization of technologies they see warranting the rigorous development, clinical testing, FDA and other hurdles en route to the market. But to temper the idea that in the US there is a greater abundance of adventurous entrepreneurs, I must note that a remarkable number of new companies in the US recently have been started by serial entrepreneurs, who have so often previously run the gauntlet demanded of startups that they are fully prepped to make new runs with new technologies.
Minimally invasive is minimally invasive (is better). Lower long term cost is better. With few real "untapped" clinical targets being the subject of new medtech development, the vast majority of activity is clearly centered around improvements in care that lend to the argument of better clinical outcomes and/or reduced cost of patient care. The thrust of R&D is on yielding advantages that reduce invasiveness, speed the treatment process and/or time to healing or simply provide competitive clinical costs at or lower than alternatives.
Notwithstanding the prevalence of developments noted above, in reducing cost/invasiveness, there are distinct areas of new technology development that center on providing outcomes where few, if any, effective therapies existed previously. A good point (perhaps the most salient example) is in cell therapies, deriving from autologous, embryonic or adult stem cell technologies. Despite ongoing ethical/policy/legal battles regarding embryonic stem cells, cell therapy has moved rapidly to the foreground as one of the most significant drivers of new technologies soon to spawn therapies for previously untreated diseases. While this field may certainly characterized as simply being en vogue, and is therefore only momentarily benefiting financially from recent attention, there are very real advances in the science and technology of cell therapies that are moving these to clinical and market fruition.
These are some of the insights I have picked up and can reveal from our market research. It would certainly be intriguing to me to hear what readers have themselves witness that either corroborates, or refutes, what I see.
The market for tissue engineering and cell therapy products is set to grow to nearly $32 billion by 2018. This figure includes bioengineered products that are themselves cells or are actively stimulating cell growth or regeneration, products that often represent a combination of biotechnology, medical device and pharmaceutical technologies. The largest segment in the overall market for regenerative medicine technologies and products comprises orthopedic applications. Other key sectors are cardiac and vascular disease, neurological diseases, diabetes, inflammatory diseases and dental decay and injury.
An overview (map) of the spectrum of clinical applications in tissue engineering and cell therapy is shown below:
Much attention has been paid to the development of cell therapies with cardiovascular applications. According to the Institute of Cardiovascular Regeneration, more than 1,500 patients with cardiovascular diseases are treated with adult progenitor cells worldwide. Much success has been achieved in this sector and cardiovascular cell therapies are increasingly becoming viable technologies.
The primary competitors in the field of tissue engineering and cell-based therapies for cardiovascular applications are shown in the exhibit below illustrating the stages in which they have cardiology/cardiovascular applications in development.
Key Competitors in Tissue Engineering and Cell Therapies for Cardiovascular Applications
Note: See specific products in development detailed in report #S520.
Tissue engineering and cell therapy comprise a market for regenerative products that is expected to grow worldwide from $6.9 billion in 2009 to almost $32 billion by 2018. This market spans many specialties, the biggest of which is therapies for degenerative and traumatic orthopedic and spine applications. Other disorders that will benefit from cell therapies include cardiac and vascular disease, a wide range of neurological disorders, diabetes, inflammatory diseases, and dental decay and/or injury. Key factors expected to influence the market for regenerative medicine are continued political actions, government funding, clinical trials results, industry investments, and an increasing awareness among both physicians and the general public of the accessibility of cell therapies for medical applications.
There are key market drivers affecting the relative growth of cell therapy and tissue engineering in specific regions or countries. One historical driver has been the dynamics of stem cell research in the United States. The unavailability of additional stem cells due to President Bush’s Presidential Executive Order in 2001 (since rescinded in 2009 by President Obama) had the affect of decelerating the number of new embryonic stem cell research projects launched, thus postponing the optimistic timeline anticipated by some researchers. This directly delayed the commercialization of products based on embryonic stem cell research, which had the effect of dampening the overall U.S. market. Simultaneously, this also drove increased research and development of the science (if not technologies as well) in areas outside the U.S., especially in the EU. While this distinction between the U.S. and Europe does not account for all the market size and growth differences, it is a distinct, identifiable cause. (The U.S. also has in many respects a more mature — or at least more penetrated cell/tissue market — and the EU is simply catching up.)
Below for comparison is the relative U.S. and European share of the cell therapy and tissue engineering market in 2009 and 2019.
The subject of "tissue engineering and cell therapy" is, by some accounts, an artificial amalgam of the two separate subjects, particularly since cell therapy per se, as a result of its inextricable link to embryonic stem cells and abortion, seems to demand (at least by some) a wholly separate consideration. From a scientific basis, of course, there is merit in the distinction, but from an industry-driven commercial consideration of diseases, disorders and trauma to be addressed — and patients served — the amalgam of cell therapy and tissue engineering is indeed warranted. For those such as we who track the developments and markets pursued by medical technology in an era when devices compete with and/or are complementary with drugs, biotechs, biomaterials and every other technology paradigm, it is little more than an educational but largely academic exercise to make the distinction. Medtech markets have been dramatically characterized of late, as a result of a cost- and reform-driven fixation on clinical solutions and outcomes that are achieved by any technological route. Yes, tissue engineering, biopharmaceuticals, biomaterials and other technologies are indeed distinct in nature from cell therapies in general and stem cell therapies in particular, but neither the manufacturer nor the patient particularly care about that distinction.
Cell therapy is defined as a process whereby new cells are introduced into tissue as a method of treating disease; the process may or may not include gene therapy. Forms of cell therapy can include: transplantation of autologous (from the patient) or allogeneic (from a donor) stem cells , transplantation of mature, functional cells, application of modified human cells used to produce a needed substance, xenotransplantation of non-human cells used to produce a needed substance, and transplantation of transdifferentiated cells derived from the patient’s differentiated cells.
Once considered a segment of biomaterial technologies, tissue engineering has evolved into its own category and now comprises a combination of cells, engineering and suitable biochemical and physiochemical factors to improve or replace biological functions. These include ways to repair or replace human tissue with applications in nearly every medical specialty. Regenerative medicine is often synonymous with tissue engineering but usually focuses on the use of stem cells.
For the purposes of definition, tissue engineering and cell therapy comprise bioengineered products that are themselves cells or are actively stimulating cell growth or regeneration. These often comprise a combination of biotechnology, medical device and pharmaceutical technologies.
Researchers have been examining tissue engineering and cell therapy for roughly 30 years. While some products in some specialties (such as wound care) have reached market, many others are still in research and development stages. In recent years, large pharmaceutical and medical device companies have provided funding for smaller biotech companies in the hopes that some of these products and therapies will achieve a highly profitable, commercial status. In addition, some companies have been acquired by larger medical device and pharmaceutical companies looking to bring these technologies under their corporate umbrellas. Many of the remaining smaller companies received millions of privately funded dollars per year in research and development. In many cases it takes at least ten years to bring a product to the point where human clinical trials may be conducted. Because of the large amounts of capital to achieve this, several companies have presented promising technologies only to close their doors and/or sell the technology to a larger company due to lack of funds.
The goal of stem cell research is to develop therapies to treat human disease through methods other than medication. Key aspects of this research are to examine basic mechanisms of the cell cycle (including the expression of genes during the formation of embryos) as well as specialization and differentiation into human tissue, how and when the differentiation takes place and how differentiated cells may be coaxed to differentiate into a specific type of cell. In the differentiation process, stem cells are signaled to become a specific, specialized type of cell when internal signals controlled by a cell’s genes are interspersed across long strands of DNA and carry coded instructions for all the structures and functions of a cell. In addition, cell differentiation may be caused externally by use of chemicals secreted by other cells, physical contact with neighboring cells and certain molecules in the microenvironment.
The end goal of stem cell research is to develop therapies that will allow the repair or reversal of diseases that previously were largely untreatable or incurable.. These therapies include treatment of neurological conditions such as Alzheimer’s and Parkinson’s, repair or replacement of damaged organs such as the heart or liver, the growth of implants from autologous cells, and even regeneration of lost digits or limbs.
In a developing human embryo, a specific layer of cells normally become precursor cells to cells found only in the central nervous system or the digestive system or the skin, depending on the cell layer and the elements of the embryo that direct cell differentiation. Once differentiated, many of these cells can only become one kind of cell. However, researchers have discovered that adult body cells exist that are either stem cells or can be coaxed to become stem cells that have the ability to become virtually any type of human cell, thus paving the way to engineer adult stem cell that can bring about repair or regeneration of tissues or the reversal of previously incurable diseases.
Another unique characteristic of stem cells is that they are capable of self-division and self-renewal over long periods of time. Unlike muscle, blood or nerve cells, stem cells can proliferate many times. When exposed to ideal conditions in the laboratory, a relatively small sample of stem cells can eventually yield millions of cells.
There are five primary types of stem cells: totipotent early embryonic cells (which can differentiate into any kind of human cell); pluripotent blastocyst embryonic stem cells, which are found in an embryo seven days after fertilization and can become almost any kind of cell in the body; fetal stem cells, which appear after the eighth week of development; multipotent umbilical cord stem cells, which can only differentiate into a limited number of cell types; and unspecialized adult stem cells, which exist in already developed tissue (commonly nerves, blood, skin, bone and muscle) of any person after birth.