The future (of medicine) is biology

It was once quite convenient for manufacturers of deluxe medical widgets to worry only about other manufacturers of deluxe medical widgets. Manufacturers must now widen their perspective to consider current and future competition (and opportunity) from whatever direction it may come. –> Just thought I might chime in and suggest that, if you do make such widgets, it might be a good idea to maybe throw at least an occasional sidelong glance at biotech. (Most of you are, great, but some of you think biotech is too far away to compete…)

Organ Bioengineering is years away and poses little challenge to medical devices …FALSE.  Urinary bladders have been engineered for pediatric applications. Bioengineered skin (the “integumentary” organ) is now routinely bioengineered for burns, chronic wounds, and other wound types. Across a wide range of tissue types (bone, cardiac, smooth muscle, dermal, etc.) scientists — clinicians — have rapidly developed technologies to direct the construction and reconstruction of these tissues and restore their structure and function.

Cell Biology. Of course cells are engineered into tissues as part of the science of tissue engineering, but combine this with advances in engineering not just between cells but between cells AND within cells and (…sound of my head exploding). With the sum of the understanding and capacity to control we have gained over cellular processes over the past few decades now rapidly accelerating, medical science is fast approaching the point at which it can dictate outcomes for cell, tissues, organs, organ systems, and humans (I am not frightened, but excited, with caution).  Our understanding and proficiency gained in manipulating processes from cell division to pluripotency to differentiation to senescence to death OR NOT has profound consequences for fatal, debilitating, incurable, devastating, costly, and nearly every other negative superlative you can conceive.

CRISPR*: This is a new, relatively simple, but extraordinary tool allowing researchers or, more importantly, physicians to potentially swap out defective genes with healthy ones. See Nature.
(* clustered regularly interspersed short palindromic repeats)

Biotech has, over its history, often succeeded in getting attention, but has had less success justifying it, leaving investors rudely awakened to its complexities.  It has continued, however, to achieve legitimately exciting medical therapeutic advances, if only as stepping stones in the right direction, like mapping the human genome, the development of polymerase chain reaction (“PCR”), and biotech-driven advances in molecular biology, immunology, gene therapy, and others, with applications ripe for exploitation in many clinical specialties, Sadly, the agonizing delay between advanced and “available now” has typically disappointed manufacturers, investors, clinicians and patients alike. CRISPR and other tools already available (see Genetic Engineering News and others) are poised to increase the expectations – and the pace toward commercialization – in biotechnology.

Vaccines and Infectious Disease: Anyone reading this who has been under a rock for lo these many years, blissfully ignorant of SARS, Ebola, Marburg, MRSA, and many other frightening acronyms besides HIV/AIDS (more than enough for us already) should emerge and witness the plethora of risks we face (and self-inflict through neglect), any one of which might ultimately overwhelm us if not medically then economically in their impacts. But capitalists (many altruistic) and others have come to the rescue with vaccines such as for malaria and dengue-fever and, even, one for HIV that is in clinicals.

Critical Mass, Synergies, and Info Tech. Biotechnology is succeeding in raising great gobs of capital (if someone has a recommended index/database on biotech funding, let me know?).  Investors appear to be forgetful increasingly confident (in the 1990s, I saw big layoffs in biotech because of ill-advised investments, but that was then…) that their money will result in approved products with protected intellectual property and adequate reimbursement and manageable costs in order to result in attractive financials. The advances in biological and medical science alone are not enough to account for this, but such advances are almost literally being catalyzed by information technologies that make important connections faster, yielding understanding and new opportunities. The net effect of individual medically-related disciplines (commercial or academic) advancing research more efficiently as a result of info tech and info sharing/synergies between disciplines is the expected burst of medical benefits ensuing from biotech. (Take a look also at Internet of DNA.)

Applications, global markets in tissue engineering and cell therapy

Screen Shot 2014-04-17 at 7.37.44 AMThe market for tissue engineering and cell therapy products is set to grow from a respectable $8.3 billion in 2010 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.


Factors that are expected to influence this market and its explosive growth include political forces, government funding, clinical trial results, industry investments (or lack thereof), and an increasing awareness among both physicians and the general public of the accessibility of cell therapies for medical applications. Changes in the U.S. government’s federal funding of embryonic stem cell research has given a potentially critical mass of researchers increased access to additional lines of embryonic stem cells. This is expected to result in an increase in the number of research projects being conducted and thus possibly hasten the commercialization of certain products.


Source: Report #S520, “Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018.”

Another factor that has influenced the advancement of regenerative technologies is found in China, where the Chinese government has encouraged and sponsored cutting-edge (and some have complained ethically questionable) research. While China’s Ministry of Health has since (in May 2009) established a policy requiring proof of safety and efficacy studies for all gene and stem cell therapies, the fact remains that this research in China has spurred the advancement of (or at least awareness of) newer applications and capabilities of gene and stem cell therapy in medicine.

Meanwhile, stricter regulations in other areas of Asia (particularly Japan) will serve to temper the overall growth of commercialized tissue and cell therapy–based products in that region. Nonetheless, the growth rate in the Asia/Pacific region is expected to be a very robust 20% annually.

MedMarket Diligence’s Report #S520 remains the most comprehensive and credible study of the current and project market for products and technologies in cell therapy and tissue engineering.

Tissue engineering and cell therapy market

Stem cell therapy has the potential to treat a broad range of acute and chronic degenerative diseases. These applications include: hematopoietic cells for blood diseases and cancer, myocardial and endothelial vascular tissue for cardiovascular disease, congestive heart failure, myocardial infarction and other cardiovascular disease skin cells for dermatological conditions, retinal pigment epithelium cells as treatment for macular degeneration and retinal pigmentosis, neural cells for spinal cord injury, Parkinson's disease and other neurodegenerative diseases, pancreatic islet ß cells for diabetes, liver cells for hepatitis and cirrhosis, cartilage cells for arthritis, and lung cells for a variety of pulmonary diseases. As populations age in developed countries, the need to treat increasing numbers of people with these disorders is likewise increasing.

With increased attention being paid to the need for these technologies, researchers have been reporting promising results in several areas.

In results reported in 2009, scientists from MIT found that stem cells can improve stem cells’ ability to regenerate vascular tissue by equipping them with genes that produce extra growth factors. These results were produced in mice; specially developed nanoparticles were used to deliver vascular endothelial growth factor to stem cells removed from the mouses’ bone marrow. The enhanced stem cells were then implanted into damaged tissue, where they regenerated blood vessles near the injury, thus allowing the damaged tissue to survive.

Other results reported in 2009 (Proceedings of the National Academy of Sciences, September 2009) showed researchers have had some success in engineering human tissue patches for cardiovascular repair. These clinicians (from the University of Washington, led by Dr. Charles Murry) created disk-shaped patches measuring less than a millimeter up to a half-inch in diameter decided to examine the possibility of creating new tissue with supply lines for oxygen and nutrients needed by living cells. Previously, heart tissue patches composed of only heart muscle cells could not grow big enough or survive long enough to adhere to the heart once implanted. Researchers added to the heart muscle cell mixture two other types of cells similar to those inside blood vessels and cells that provide vascular muscular support. All of the heart muscle cells were derived from embryonic stem cells or a variety of more mature sources such as umbilical cord blood. The result was seen in the formation of tissue containing tiny blood vessels.

On the orthopedic front, adult stem cells were used to regrow a 14-year-old boy’s missing cheekbones at the Cincinnati Children’s Hospital Medical Center. The technique used reengineered autologous stem cells.

In another example, scientists at the University of Bristol developed new scaffolds that can be used to grow such tissues as skin, nerves and cartilage. They built the scaffolds by using proteins from alpha helices to create long fibers (hydrogelating self-assembling fibers or hydrogels).

Unmet Clinical Needs

Allotransplantation (the transplanting of donated organs or tissues from a cadaver or a living donor) works effectively but has a couple of significant drawbacks. First, the number of organs available for donation is always far smaller than the number of organs and tissues needed by patients. According to the U.S. Department of Health and Human Services, there were more than 102,000 people in the United States alone waiting for donated organs in 2007; many of those on the waiting list die before a suitable organ or tissue becomes available. Secondly, even when an organ becomes available, organ transplant is a very expensive procedure. In addition, if the procedure is successful, the transplant recipient may often need to take immunosuppressive drugs, sometimes for life. Yet another factor in the equation is the cost of keeping patients alive while awaiting a donor, or caring for them until they die if no donor is found.  

One solution to this would be to use genetically designed pigs, animals whose organs would present minimal immunologic reaction to the host. Such animals (the pig is often cited because most of its internal organs are similar to human organs) could potentially present an unlimited supply of organs for donation to and implantation in humans. 

Designing a genetically engineered pig that is capable of carrying human immune proteins has been the focus of select researchers at the Shanghai Institute of Biochemistry and Cell Biology. Results published in 2009 in the Journal of Molecular Cell Biology showed how the scientists successfully reprogrammed pig skin and bone marrow cells into an embryo-like state with the potential to form every type of body tissue. The successful creation of pig pluripotent stem cells would enable engineering of transgenic animals for organ transplantation purposes. The embryonic or induced stem cellscould be used to modify the immune-related genes in the pig to make the pig’s organs compatible to the human immune system, thus allowing the pigs to be used as organ donors without triggering an adverse reaction from the patient’s own immune system.

Another solution would be, of course, tissue engineering and cell therapy. There are hundreds of companies working in the field of tissue engineering, expanding the procedures, devices, cell-based products, biomaterial-based products and other products for the repair and regeneration of damaged tissues.

See the current (2011) market for tissue engineering and cell therapy by area of clinical focus.

Source: MedMarket Diligence, LLC; Report #S520, "Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018."


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Cell Therapy and Cardiovascular Disease

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.

Tissue engineering and cell therapy may be considered as comprising 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.

One of the key methods by which to evaluate the potential market opportunities in the early stages of an industry such as tissue engineering and cellular therapy is to look at the number of current procedures that could possibly be augmented or replaced by the new technologies. In the sections that follow, we review the major areas of transplantation and estimate the clinical caseloads that reflect potential uses of tissue engineering. It should be kept in mind that it is highly unlikely that tissue engineering will replace 100% of these particular procedures, even after years of clinical usage. There will always be patients for whom certain procedures are inappropriate; other procedures may not be fully covered by insurance and hence will only be used by those patients who can afford them. Transplant of cadaver organs is likely to continue as long as these organs are available and free of disease, and the cost of transplantation is equal to or less than the cost of tissue engineering. The latter, of course, reflects a key pricing strategy for tissue engineering and cellular therapy. The clinical caseloads for the conditions addressed are enormous, hence, even with the caveats, the potential markets for TE and cell therapy are extremely significant. The competition within the infant industry is fierce, with reason.

Cell Therapy in Cardiovascular Disease

The term “cardiovascular disease” encompasses as large number of diseases of the heart and vasculature. There are an estimated 70 million Americans who could benefit from cell-based therapies for cardiovascular applications. The prevalence and incidence of cardiovascular disease in the United States are shown in the following exhibits.

Source: MedMarket Diligence Report #S520: Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018

Revenues in Cell Therapy and Tissue Engineering Exceeding Expectations

The number of companies with approved products and measurable revenues in the field of cell therapy and tissue engineering has exceeded the expectation of many (though not all) in the industry.

Markets such as cell/tissue are often characterized by overestimated evaluations of commercial potential and underestimated consideration of the actual challenges. Indeed many technology challenges remain to be overcome if any significant portion of the purported potential of tissue engineering or cell therapy (in particular) is to be realized. Nonetheless, our estimate of only a few years ago (which were considered optimistic by some and conservative by others) has been eclipsed by the reality of substantial market growth, with 2009 revenues in cell therapy and tissue engineering at nearly $7 billion.

Source:  In process (draft) projections by MedMarket Diligence, LLC; Report #S520.

Commercial success in tissue engineering, cell therapy and transplantation

Tissue engineering involves taking either autologous, allogeneic or xenogeneic cells and redirecting those cells to carry out fundamental processes. Often the researcher will use a biomaterial matrix and seed the cells into this matrix. The redirection may take the form of stimulating the cells to become stem cells or precursor cells, or it may mean genetic modification of those cells. The processes which may be carried out seem almost infinite in variety: from regenerating heart muscle cells (myocytes) damaged from a heart attack, to regrowing islet cells to answer the body’s need for insulin and glucose regulation, to regrowing a thumb, including bone, cartilage, vasculature and skin. According to current industry and academic research, the potential exists to cure neurological and immunological disorders such as Parkinson’s, multiple sclerosis, and many cancers; to regrow most or all of an organ that has been damaged through disease or trauma, including the kidney, liver, intestine, bone, skin and pancreas; to take a cell sample from a patient and grow it into a new tooth bud which can be transplanted into the patient’s jaw to replace a missing tooth; and to grow blood vessels for use in coronary artery bypass graft, thereby avoiding the surgical process and pain inherent in harvesting the saphenous vein. It seems that tissue engineering and cell therapy may find applications in every system in the body.

At least 250 companies in the US, Europe and the Far East are working in tissue engineering and regenerative medicine. The larger pharmaceutical and medical device companies have initially been cautious about investing in and/or developing tissue engineering therapeutics, but a consensus recognizes that a full consideration of the device or drug industry's competitive landscape is incomplete if not factoring the possibilities of tissue engineered or cell therapy solutions.

tissue-pieThe US alone spends nearly $35 billion annually to care for patients with end stage organ failure. The alternatives are basically organ transplant, living on indefinite hold with an organ substitute such as kidney dialysis, if such a substitute exists, or death. According to the United Network for Organ Sharing (UNOS), at any one time in the US there are some 80,000 people waiting for donated organs, many of whom die before a suitable organ or tissue becomes available. If a suitable organ can be procured, the transplant procedure itself is very expensive, and not always successful. If it succeeds and the organ functions as intended, then the patient usually must take expensive immuno-suppressive drugs for life. Physicians and researchers have long sought other means to treat these patients, and tissue engineering is one avenue of significant promise.

The major areas of clinical need for alternative treatments are generally also those areas most attractive to companies, which must ultimately recoup their heavy research and development investments. These areas include cardiology, neurology, orthopedics, urology, skin, dental and organ replacement and regeneration.

Research and development in tissue engineering and cell therapy have been accelerating, which has led to a steady stream of commercial developments, including product launches.  The existing market therefore already stands at over $500 million and the growth curve on the markets for these technologies does not appear to be leveling soon, with compound annual growth rates for the aggregate of tissue/cell therapy markets exceeding 20%.

The global market for tissue engineering, cell therapy and tissue/organ transplantation is the subject of pending report #S520, from MedMarket Diligence.

Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018

Publishing a new report in December 2009:  Tissue Engineering, Cell Therapy and Transplantation:

Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018.

This report examines the status of technologies, applications and markets for tissue engineering, cell therapy and tissue/cell transplantation. The report reviews therapeutic tissue engineering, tissue reconstruction, cell therapies, tissue/organ transplantation and related technologies under various stages of development at over 150 companies. The report details the technology development, projected market introduction dates and/or current and forecast market size and competitor shares for products being developed to address major causes of death and disease spanning applications in cardiovascular, neurological, orthopaedic, urological, skin, dental, ophthalmological, gastroointestinal, organ transplant, cancer and others. The report details the status of product development and assesses the current and forecast worldwide market for tissue engineering, cell therapy and transplantation.

The report provides market size and share data, with forecast market data to 2018, for the U.S., Europe, Asia/Pacific and Rest of World.

The report establishes the current worldwide market size for major technology segments as a baseline for and projecting growth in the market over a ten-year forecast and assesses and projects the composition of the market as technologies gain or lose relative market performance over this period. 

The report is described, with preliminary table of contents, at link.

Stem cell / gene therapy success in vitro

Researchers at the Salk Intitute for Biological Studies have demonstrated that a technology to correct the genetic defect in human disease and induce cell differentiation at the site of the manifested disease is feasible, an achievement demonstrated previously only in mice.
In the May 31, 2009, edition of Nature, Salk reseachers published their findings for the research, which applied the method to a blood-related disorder called Fanconi’s anemia. (See "Combined stem cell-gene therapy approach cures human genetic disease in vitro" at link.
This development, although still only at the in vitro stage, is a remarkable one, since it demonstrates a synthesis of understanding between genetics and cell biology that is a harbinger of tremendous future clinical successes. But, lest the jaded investor or other biotech follower (who has countless times heard in vain of similar portentous milestones) fear that this, too, is a development that is of only passing significance, it should be noted that this development bears greater impact due to the level of science demonstrated and that it has been made by Salk Institute and published in Nature, neither of which should be underestimated.
Personally, whenever I note a development that has both "gene therapy" and "cell therapy" in the title, my senses are alerted to the great prospect (not guarantee) of what will follow.

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