Sample content from the medtech reports of MedMarket Diligence, LLC

Medtech report sample: Worldwide Wound Management, 2007-2016

Tue, 26 Feb 2008 09:19:19 -0800

Report:  "Worldwide Wound Management, 2007-2016:  Established and Emerging Products, Technologies and Markets in the U.S., Europe, Japan and Rest of World," published November 2007. Report #S245.

[See description and table of contents at http://www.mediligence.com/rpt/rpt-s245.htm.  The report may be purchased in its entirety online.]

Section 2.13:  Incidence of Treatments, Growth Rates and Trends

Surgical wounds account for the vast majority of skin injuries. We estimate that there are approximately 100 million surgical incisions a year, growing at 3.1% CAGR, which require some wound management treatment. Approximately 80% of these wounds use some form of closure product: sutures, staples, and tapes. Many employ hemostasis products, and use fabric bandages and surgical dressings.

Surgical procedures generate a preponderance of acute wounds with uneventful healing and a lower number of chronic wounds, such as those generated by wound dehiscence or postoperative infection. Surgical wounds are most often closed by primary intention, where the two sides across the incision line are brought close and mechanically held together.  Overall the severity and size of surgical wounds will continue to decrease as a result of the continuing trend toward minimally invasive surgery.

Surgical wounds that involve substantial tissue loss or may be infected are allowed to heal by secondary intention where the wound is left open under dressings and allowed to fill by granulation and close by epithelialization. Some surgical wounds may be closed through delayed primary intention where they are left open until such time as it is felt it is safe to suture or glue the wound closed.

Traumatic wounds occur at the rate of  50 million or more every year worldwide. They require cleansing and treatment with low-adherent dressings to cover the wound, prevent infection, and allow healing by primary intention.

Lacerations are a specific type of trauma wound that are generally minor in nature and require cleansing and dressing for a shorter period.  There are approximately 20 million lacerations a year, as a result of cuts and grazes; they can usually be treated in the doctors’ surgery, outpatient medical center or hospital A&E departments.

Burn wounds can be divided into minor burns, medically treated, and hospitalized cases. Outpatient burn wounds are often treated at home, at the doctor's surgery, or at outpatient clinics. As a result a large number of these wounds never enter the formal health service system. We estimate that approximately 3.5 million burns in this category do enter the outpatient health service system and receive some level of medical attention. These burns are treated using hydrogels and advanced wound care products, and they may even be treated with consumer-based products for wound healing.

Medically treated burn wounds usually receive more informed care to remove heat from the tissue, maintain hydration, and prevent infection. Advanced wound care products are used for these wounds. There are approximately 6.0 million burns like this that are treated medically every year.

Hospitalized burn wounds are rarer and require more advanced and expensive care. These victims require significant care, nutrition, debridement, tissue grafting and often tissue engineering where available. They also require significant follow-up care and rehabilitation to mobilize new tissue, and physiotherapy to address changes in physiology. Growth rates within the burns categories are approximately 1.0% per annum.

Chronic wounds generally take longer to heal, and care is enormously variable, as is the time to heal. There are approximately 4.5 million pressure ulcers in the world that require treatment every year. Many chronic wounds around the world are treated sub-optimally with general wound care products designed to cover and absorb some exudate. The optimal treatment for these wounds is to receive advanced wound management products and appropriate care to address the underlying defect that has caused the chronic wound; in the case of pressure ulcers a number of advanced devices exist to reduce pressure for patients. There are approximately 9.7 million venous ulcers, and approximately 10.0 million diabetic ulcers in the world requiring treatment. Chronic wounds are growing in incidence due to the growing age of the population, and the growth is also due to increasing awareness and improved diagnosis. Growth rates for pressure and venous ulcers are 6-7 percent in the developed world as a result of these factors.

Diabetic ulcers are growing more rapidly due mainly to increased incidence of both Type I and maturity-onset diabetes in the developed (high-GDP) countries around the world. The prevalence of diabetic ulcers is rising at 9% annually. At present this pool of patients is growing faster than the new technologies are reducing the incidence of wounds by healing them.

Wound management products are also used for a number of other conditions including amputations, carcinomas, melanomas, and other complicated skin cancers, which are all on the increase.
A significant feature of all wounds is the likelihood of pathological infection occurring. Surgical wounds are no exception, and average levels of infection of surgical wounds are in the range 7-10 percent dependent on the procedure. These infections can be prevented by appropriate cleanliness, surgical discipline and skill, wound care therapy, and antibiotic prophylaxis. Infections usually lead to more extensive wound care time, the use of more expensive products and drugs, significantly increased therapist time, and increased morbidity and rehabilitation time. A large number of wounds will also be sutured to accelerate closure, and a proportion of these will undergo dehiscence and require aftercare for healing to occur.

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Companies Profiled Include:

3M Group, AciesHealth, Acrymed Inc., Advanced BioHealing, Advanced Medical Solutions Group plc, Agennix, AGT Sciences Ltd, Anodyne Therapy LLC, Applied Tissue Technologies, Argentum Products LLC, Bard Medical Division, Biocore Medical Technologies Inc., Biomarin Pharmaceuticals Inc., BioMedical Life Systems Inc, BioTissue Technologies AG, BlueSky Medical Group (Smith & Nephew), Brennen Medical Inc., Carrington Laboratories Inc., Celltran Limited, CliniMed, Coloplast Group, ConvaTec Inc., Covidien, Derma Rite Industries LLC, Derma Sciences Inc., Dermacor Inc., DeRoyal Industries Inc., Diapulse Corp of America, E.S. Cell International, Electromedical Products International Inc., Encelle Inc., Ethicon (Johnson & Johnson), Ferris  Manufacturing Corp., Fibrogen, Fidia Group, Geistlich Pharma, Gentell Inc., Genzyme Biosurgery, Geritrex Corp., Globalcare Medical, Hartmann Group, HemCon Inc, Hollister Incorporated, Hymed Group Corporation, Innocol, Inc., Inogenetics, Integra Life Sciences Holdings Corp., Integra Life Sciences Inc., IsoTis S.A, Kinetic Concepts Inc., L.A.M. Pharmaceutical Corp., Laboratoires Urgo, Lifewave Ltd, Lohmann and Rauscher International GmbH and Co. KG, Longport Inc., Medline Industries, Microban International Ltd, Microvas Technologies, Modex Therapeutics, Mölnlycke Health Care AB, Nagor Ltd., Organogenesis Inc., Ortec International Inc., Perry Baromedical Corp., Roho Inc., Smith and Nephew Group, SSL International Plc, Swiss American Products, Inc., UDL Laboratories (Mylan Labs.),

Source:   MedMarket Diligence, LLC; report #S245, "Worldwide Wound Management, 2007-2016."

Tags: wound, debridement, ulcer, medtech

Medtech report sample: Worldwide Market for the Clinical Management of Obesity, 2007-2015

Thu, 20 Sep 2007 09:38:23 -0700

Report:  "Worldwide Market for the Clinical Management of Obesity, 2007-2015," published September 2007. Report #S825.

[See description and table of contents at http://www.mediligence.com/rpt/rpt-s825.htm.  Report may be purchased in its entirety online.]

Section 4:  Clinical Trends

As a result of research, as well as treatment trial and error, major clinical trends have emerged during the last few years in the field of bariatrics. One is that there is a legitimate field called bariatrics. Another is that great emphasis is being put upon prevention; it is much easier and cheaper to prevent disease than it is to treat or cure it. However, much work remains to be done, not the least of which is the education of physicians in the etiology of obesity.

        4.1  Prevention and Intervention
With growing clinical awareness of obesity as a multi-factorial condition, increased attention is being paid to prevention of overweight and obesity, and intervention when the patient begins to gain weight. Consequently, the stigma formerly attached to morbid obesity is slowly decreasing and compassionate treatment is increasing. Now, instead of ignoring the patient’s weight gain or just handing the patient a printed diet on the way out the door, the physician is making the diagnosis of obesity, and taking the opportunity to gently educate the patient about the increased risk of developing a host of conditions related to overweight and obesity. In addition, the physician has the chance to point out some of the numerous causes of obesity; while the patient must still be personally responsible for dealing with the problem, it helps if the individual can understand that obesity is a complicated, difficult problem to solve. Ultimately, the physician will partner with the obese patient to find the right combination which leads to weight loss and maintenance of that loss.

The medical community, as well as government organizations such as the National Institutes of Health (NIH), has become cognizant of the fact that there are sub-groups within the population which display different characteristic patterns of weight gain and appearance of co-morbidities. The characteristic picture of obesity varies with age (children versus adults, and pre-menopausal versus post-menopausal women), some minority groups (African Americans, Hispanics), sex, environment, and to an extent even income level. As a result, one treatment does not work for all patients. More research is required to learn about obesity within these subgroups; but the clinical tendency is at least moving in the right direction.

Proper prevention of obesity has become an important trend as well. This takes place primarily among children, as government groups emphasize nutritional education, improved school meals, encouraging exercise and sports, and teaching the parents how to help the child to develop better habits with regard to food and exercise or play. But prevention is also beginning to take hold in the workplace. Companies are realizing how employee obesity will seriously increase healthcare costs, inevitably affecting the bottom line. More enlightened firms are consequently incorporating various means of preventing obesity or intervening at the workplace. These methods include work site exercise classes, support groups, and greater availability of healthy meals and snacks.

        4.2  Drug Developments
One of the major difficulties inherent in the treatment of obesity is that the disease has a tangled skein of causes, woven of the interplay between biochemical, genetic, environmental, psychological, emotional and physical elements. These causes may differ in relative importance from individual to individual—over time, by age, by race, or by the patient’s genetic make-up or physical characteristics.  The development of pharmaceutical treatments for obesity is equally intricate, as well as highly competitive. Add to this the rigors of clinical testing and regulatory approval, and one has some idea of the complexity of obesity drug development. However, there is always risk involved in allowing the marketing of any new therapeutic, and the risks must be balanced against the benefits of the drug, the treatment of obesity and the avoidance or curing of related co-morbidities.

                4.2.1  Utilizing Combinations of Drugs
Physicians commonly utilize two or more drugs in an attempt to hit upon the right combination for effective treatment—but researchers are now saying that such a strategy may become standard in the treatment of obesity, especially given the biological, genetic, psychological and environmental complexity of obesity. There does not seem to be a drug with strong blockbuster potential close to market launch in the pharmaceutical pipeline, adding to clinicians’ outlook that there may never be a ‘magic bullet’ per se.  Perhaps effective treatment will equate to prescribing two or more drugs, taken simultaneously, in order to help the obese patient to lose weight.

                4.2.2  CNS Versus Gastrointestinal Action
Drugs which act upon the central nervous system, such as rimonabant, are receiving increased FDA scrutiny regarding safety and potential side effects. The CNS is so complex that even the stringent clinical testing required by the FDA may not reveal all of the side effects of drugs that work in this manner; perhaps only long-term use on the market, with patients essentially as test subjects, will show all of the side effects. Perhaps this is what is unfolding in the EU with rimonabant.

Drugs which act upon the gastrointestinal tract, or anti-absorption therapeutics, are viewed as safer than those which act upon the CNS, and are likely to more readily achieve the blessing of FDA market approval. These focus upon decreasing the absorption of ingested fats by the digestive tract (usually the intestine). The best known of these drugs at this time is orlistat, or Xenical, by Roche. Xenical works by the inhibition of pancreatic lipase, the major enzyme (among several) that acts to break down fat molecules from ingested food. Pancreatic lipase inhibitors interfere with the hydrolyzing action by forming covalent bonds with lipases in the stomach and small intestine, and rendering the enzymes powerless to break down dietary fat into an absorbable state. As a result, up to one-third of ingested fat is not broken down. If the fat is not broken down, then it cannot be absorbed by the body, and hence fewer calories, and a lower percentage of fat, are absorbed and weight is lost. The most promising drug in this category at present is Alizyme’s ATL-962, or Cetilistat, which according to the company acts by blocking the intestinal absorption of fat, has 90% fewer side effects than Xenical. If this is the case, then Cetilistat would likely enjoy strong success. Alizyme has a development and distribution agreement with Takeda in Japan, and is actively seeking global partners for the rest of the world market.

Despite the possible unpleasant side effects, anti-absorption therapeutics are generally viewed as safe, albeit having only modest efficacy to date. The mode of operation is less complicated than that of satiety therapeutics or drugs that affect the central nervous system, hence anti-absorption therapeutics are less likely to cause problems in other areas or to interact unfavorably with other medications that the patient may be taking. They are also non-addictive and do not require a weaning-off period as do some drugs whose action is on the CNS.

                4.2.3  Stumble of CB1 Receptor Agonist Class
Rimonabant is out of the picture for now in the US; if Sanofi-Aventis applies again to the FDA for approval to market the drug, the company has admitted that this will probably not be before 2010 or 2011. Industry experts think that the entire class of CB1 cannabinoid receptor agonists may potentially be in the dog house, and not just rimonabant. If true, this damper would also affect Merck’s taranabant. Merck claims to be moving forward with its application to the FDA; more likely, Merck’s researchers are intently re-examining both the clinical data and the strategy with regard to the FDA application.

                4.2.4  OTC alli
In an agreement worked out with Roche, GlaxoSmithKline has added to the available over-the-counter weight loss products by coming out with a half-dose strength of Xenical (orlistat), called alli—and has combined it with a detailed diet, exercise and behavior modification marketing plan. GSK is emphasizing that alli is not the magic bullet; nevertheless, it is the only FDA-approved OTC medication for the treatment of overweight and mild obesity available in the US. It can still cause side effects similar to those caused by Xenical. Some industry experts are predicting that patients will try alli for a couple of months before dropping it. Whether the buying public will make alli a market success remains to be seen.

Despite the mixed bag of clinical trends—promising drug applications withdrawn from FDA consideration; half-dose OTC version of a drug whose sales have been dropping for several years—the fact remains that an effective drug with acceptable side effects and an overall safe profile would very likely be an enormous blockbuster, well worth the gamble and the race.

        4.3  Tailoring the Strategy to the Patient
A key clinical trend is that the medical community is finally realizing that treatment of obesity is not a one-size-fits-all. Treatments, including diets, prescribed type and amount of exercise, behavior modification, self-monitoring, etc., should be adapted to the individual to a much greater extent than has ever been done before. The physician ideally will partner with the obese patient to find the right combination which leads to success, explaining that any treatment also carries side-effects that may adversely affect other systems; that the treatment may work for a while then become ineffective; that the patient may not be able to tolerate a particular treatment; or that insurance may not cover the best treatment, forcing the physician and patient to the fallback position of attempting treatment choice number two.

As more drugs and devices reach the market, and as physicians’ experience with these new treatments increase, the new options will be adopted into the clinical management plan of the obese patient. For example, in the future, perhaps as early as 2009, the physician may start the patient with a regimen of Cetilistat. Having lost twenty or thirty pounds, perhaps the patient and physician will decide to stop there, depending on factors such as starting weight and the patient’s age and general physical condition—because a loss of even 5% of excess weight can produce dramatic improvements in co-morbidities. Or, the patient may want to try a stomach pacemaker, less drastic than gastric bypass or stomach banding, and entirely reversible. If that doesn’t work, then perhaps at that point the decision will be made to try gastric bypass or banding. Treatment will become more refined and much more tailored to the individual patient’s situation, which can only be beneficial and will serve to improve the overall success rate of treatment.

        4.4  Bariatric Surgery
Surgery as a treatment for obesity has been around for a number of years. The gold standard in the US is still gastric bypass, but in the EU this procedure is considered passé and rather primitive, and the gold standard there has moved to adjustable gastric banding.
Physicians tend to agree that, at this time , the best, and perhaps only, effective treatment for morbid obesity seems to be surgery.

                4.4.1  Gastric Bypass Versus Banding
There are clinical trends occurring in the area of the surgical treatment of obesity as well as in the drug area.  In Europe, gastric bypass, specifically the Roux-en-Y procedure, is practiced much less often than in the US; bariatric surgeons in Europe feel that the Roux-en-Y is a rather primitive procedure when compared to the procedures currently available. They use the vertical banded gastroplasty, the mini-VGB, the biliopancreatic diversion/duodenal switch (BPD/DS) and gastric banding much more often than gastric bypass.  This may be explained in part by the fact that European physicians’ experience with gastric banding is several years’ longer than the medical community’s experience in the US; gastric banding was first introduced in Europe in 1985, whereas the first device in the US, the Inamed LapBand®, was only approved and introduced into this market in 2001. Allergan’s LapBand® remains the only approved gastric banding device on the US market. In the US the gastric bypass is still by far the most popular surgical treatment for obesity, far outnumbering the use of the LapBand®. The bypass is most often performed laparoscopically, unless conditions contraindicate this. Surgeons also use the vertical banded gastroplasty and the BPD, but nearly 85% of procedures are performed as gastric bypasses.

                4.4.2  Bariatric Surgery for Teens
Data from the Center for Disease Control (CDC) says that there may be as many as two million adolescents in the US who are severely obese, with co-morbidities previously seen only in adults. Just a couple of years ago, the medical community argued about whether morbidly obese adolescents should be allowed to receive bariatric surgery. One side argued that these patients, like morbidly obese adults, had developed co-morbidities which threatened their health, as well as depression and a lower quality of life, especially in light of the importance of peer acceptance and self-image during this stage of life. The other side argued that the long-term effects of permanently rerouting the intestinal tract (in the case of bypass) was little known in adults, never mind in teenagers; and that furthermore, the adolescent body was still developing. Perhaps such surgery, if performed, should be put on hold until the patient had physically and mentally matured. Perhaps teens are more malleable than adults and can and should learn proper nutrition and exercising, and that society is partially to blame for allowing the teens too much liberty.

While debate continues, the trend is towards understanding that whatever causes morbid obesity in adults may cause it in teens as well; that it’s not simply a matter of proper discipline and lots of fruits and vegetables. Research is also showing that bariatric surgery for teens is no more harmful than for adults, and that in fact the adolescents generally handle the surgery (whether bypass or banding) better than the adults. One theory is that the risks of the surgery are less in teens because the obesity has had less time to damage internal organs. Recent research out of NY University Medical Center of lap banding in patients under the age of 17 revealed that the patients on average lost 50% of their excess weight by one year post-op. In the US at this time, NYU physicians have the most experience with the use of lap band surgery in teens. The teens’ quality of life shows strong increases in all areas. Surgery for teens still represents a very small fraction of total bariatric surgeries—about 771 teens versus 120,000 adults in the US in 2003—triple that of 2000, but still less than 1% of all bariatric surgeries in the US. It is definitely still considered the option of last resort for teens, after all other methods have been tried and have failed.

                4.4.3  Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS)
In a five-year prospective study begun in June 2006, the Teen-LABS consortium, which consists of four clinical centers, is gathering data and assessing the health benefits and risks of bariatric surgery in adolescents. The consortium was awarded a $3.9 million NIH grant to carry out this work. It is the adolescent version of the on-going adult LABS program. The ultimate aim is to develop common clinical protocols and a database which can provide evidence-based recommendations for effective patient evaluation, selection and post-op follow-up. A further goal of the study is to add to the body of knowledge regarding the etiology, pathophysiology and behavioral facets of morbid obesity in young adults and over time.

The consortium consists of the following centers:

Cincinnati Children’s Hospital Medical Center
Texas Children’s Hospital
Children’s Hospital of Alabama
University of Pittsburgh

Led by Thomas Inge, MD, PhD, and Meg Zeller, PhD, from Cincinnati Children's Hospital Medical Center, the consortium will also examine whether the complications associated with morbid obesity are best addressed at a younger age, via surgery if necessary, rather than waiting until the individual is an adult. Results of Teen-LABS will be combined with the adult LABS work to produce one of the most complete, well-rounded studies of severe obesity ever conducted.

Source: MedMarket Diligence, LLC, report #S825.

Tags: obesity, bariatric, lapband, medtech

Medtech report sample: Worldwide Surgical Sealants, Glues & Wound Closure 2007

Fri, 17 Aug 2007 11:15:47 -0700

Report: "Worldwide Surgical Sealants, Glues & Wound Closure 2007," published February 2007. Report #S145.

[See description and table of contents at http://www.mediligence.com/rpt/rpt-s145.htm. Report may be purchased in its entirety online.]

Surgical wounds are projected to increase in number at an annual rate of 3%, but overall the severity and size of surgical wounds will continue to decrease over the next five years as a result of the continuing trend toward minimally invasive surgery.

Surgical procedures generate a large number of uncomplicated acute wounds with uneventful healing, and a lower number of chronic wounds such as those generated by wound dehiscence or post-operative infection. On the skin surface, surgical wounds are most often closed by “primary intent”, using products such as sutures, staples, or glues, where the two sides across the incision line are brought close and mechanically held together. The use of glues for closure has rapidly become adopted for treatment of minor cuts and grazes over the last decade, and products in this category are now being promoted for use in theatre where they offer certain advantages over sutures. Benefits for use on the skin surface include reduced need for anesthesia, reduced infection, and reduced scarring. A growing number of wounds created as part of the surgical procedure are becoming infected by pathogens that exhibit some resistance to antibiotics. Recent figures indicate that an average of 8% of wounds are infected in the hospital during surgical procedures. Adjunctive surgical closure and securement products have been shown to reduce infection levels, and, for example, cyanoacrylate adhesives have been approved in the USA for use to prevent post surgical infections.

Surgical hemostats, tissue sealants, and glues are used for a spectrum of surgical procedures ranging from closure of skin wounds to significant hemostasis to prevent blood replacement during major surgical procedures.

Hemostats are used to reduce bleeding during surgical procedures. These products work by coagulating blood quickly and accelerating the normal clotting mechanisms. Blood clotting is part of the body’s natural defense mechanism. After tissue damage, blood invades the damaged area. Platelets are activated to convert prothrombin into thrombin, which converts fibrinogen in the blood to form viscous polymers of fibrin. The fibrin is subsequently cross-linked by activated factor XIII to further bind the fibrin polymers into a viscous three-dimensional mat of fibrin. This is the basis of a blood clot which prevents further bleeding. Later in the healing process the fibrin clot is acted on by the enzyme fibrinolysin which breaks up fibrin as this material is no longer required. Fibrinolysis begins a cascade of healing by releasing fibrino-peptides which act to stimulate angiogenesis and cell-activated-repair.

The natural clotting process has been used by manufacturers to design new products that can mimic the body’s hemostatic action. Hemostatic products have been developed using collagen and degraded collagen (gelatin) to stimulate the hemostasis cascade. These hemostatic products depend on a cascade of blood factors to initiate and drive the full clotting process; they therefore tend to be slower-acting than products based on fibrin and thrombin which act later in the cascade to produce immediate hemostatic results. In addition, synthetic polyanionic materials (such as Johnson & Johnson/Ethicon’s Surgicel) and some naturally occurring biological polymers (such as calcium alginate and chitosan) have been developed to stimulate the same cascades; companies have recently evolved these simple hemostatic materials to develop hemostasis products that can also seal bleeding tissues.

Fibrin and synthetic sealants offer a significant advantage over pure hemostats because they do not rely on the full complement of blood factors to produce hemostasis. Sealants provide all the components necessary to prevent bleeding and will often prevent bleeding from tissues where blood flow is under pressure, and the damage is extensive.

In addition to hemostats and sealants, a number of companies have developed tissue glues to reduce (and in some cases replace) the requirement for sutures. These products are capable of providing a degree of repair strength which is at least an order of magnitude greater than that achieved with fibrin and synthetic sealants.
It is recognized that these products have potential to replace sutures in some cases where speed and strength of securement are priorities for the surgical procedure. Tapes, sutures and staples are also applicable to a growing range of procedure-specific internal securement cases.

Approximately 70 million surgical and procedure-based wounds are created annually worldwide that offer potential for use of adjunctive surgical closure and securement products; over 20 million of these wounds are created during surgical procedures in the USA.

Although healing of all these wounds might be improved through use of adjunctive surgical closure and securement products, it is likely that increased usage of these products will be limited, on economic grounds, to a fraction of procedures. It is realistically estimated that some 10-15% of these procedures would benefit from increased use of newly-developed adjunctive surgical closure and securement products.

Source: MedMarket Diligence, LLC, report #S145.

Tags: medtech, fibrin, sealant, wound

Medtech report sample: Orthopedic Biomaterials Worldwide 2007

Mon, 23 Apr 2007 08:12:27 -0700

Report:  "Emerging Trends, Technologies and Opportunities in the Markets for Orthopedic Biomaterials, Worldwide," published December 2006. Report #M625.

[See description and table of contents at http://www.mediligence.com/rpt/rpt-m625.htm.  Report may be purchased in its entirety online.]

2.4  Ceramics

Calcium sulphate, also known as gypsum, is the prototype that led to the development of calcium-based ceramic material for medical use. In its alternate guise as Plaster of Paris it has been used to form hard setting bandages since the seventeenth century, but it was first used internally to fill bony defects in 1892. Medical grade calcium sulphate is crystallized in a highly controlled environment to produce regularly shaped crystals of similar size and shape. Its advantages include the fact that it can be used in presence of infection and it is comparatively cheap.

Calcium phosphate was first used in the form of powders; the most commonly used calcium phosphate ceramics are hydroxyapatite (coral based or synthetic) and tricalcium phosphate, used in the form of implant coatings and defect fillers. These materials require high temperature and high pressure processing to produce dense, highly crystalline, bioinert ceramics.

In 1975, Chiroff et al recognized that corals made by marine invertebrates have skeletons with a structure similar to both cortical and cancellous bone, with interconnecting porosity. Coral-like implants may be produced either by using coral directly in calcium carbonate form, or to convert converts calcium carbonate to hydroxyapatite. This compound is, in fact, the main mineral component of dental enamel, dentin, and bone.

Ceramics (especially alumina) are now being extensively used in total hip replacement, knee replacement and other joint replacement surgeries. Ceramics are also used for bone bonding (e.g. hydroxyapatite), bone spacing (e.g. porous alumina) and small orthopedic joints such as fingers and spinal inserts.

The first all-ceramic hip - comprising 32 mm alumina heads and alumina cups - was developed and used in 1970 by a French surgeon, Pierre Boutin, M.D. The implant lasted for 17 years, until the patient died. When examined post-mortem the implant showed very little wear.

The first FDA approval for ceramic-polymer implants was in 1990, when alumina and zirconia were used along with polyethylene cups for hip replacements. Stryker, Wright Medical & CeramTec AG, are among companies to have developed ceramic-on-ceramic (both cup and head made of ceramic) hip implants.

Exhibit 2-4:  Ceramic-Based Products

Company	Country of origin	Brands
Amedica	USA	MC2, CsC, ArX
Angstrom Medica	USA	NanOss
Apatech	UK	ApaPore
Berkeley Advanced Biomaterials	USA	Ostetic
CeramTec	Germany	Biolox
Encore Medical	USA	Keramos
Interpore Cross	USA	ProOsteon, BioPlex
Japan Medical Materials	Japan	LFA Total Knee System, TNK Ankle, J Alumina Ceramic Elbow
Morgan Ceramics	UK	HIP Vitox, Ziranox
NovaBone Products	USA	Biogloss, PerioGlas
OrthoVita	USA	Vitoss Foam
OsteoBiologics	USA	Polygraft BGS, Immix CB
Stryker	USA	Trident Ceramic Hip
Teknimed	France	Ceraform, Cementex, TriHA+
Wright Medical Technologies	USA	Osteoset Bone Graft Substitute, Cellplex TCP Graft

Source: MedMarket Diligence, LLC

Tags: medtech, orthopedic, biomaterial, allograft

Medtech report sample: Worldwide Surgical Sealants, Glues & Wound Closure, 2007

Tue, 20 Mar 2007 11:54:56 -0700

Exhibit ES-5: U.S. FDA Approved Uses of Sealants, Glues, and Hemostats

	Hemostats	Sealants	Adhesives
Cardiovascular	Y	Y	N
Orthopaedic	Y	Y	N
Neurological	Y	Y	Y*
Gastrointestinal	Y	Y	N
Paediatric	Y	Y	N
Thoracic	Y	Y	N
Pulmonary	Y	Y	N
Skin	Y	N	N

Y=Yes
N=No

*Specific indication (few procedures per year) approved

Source: MedMarket Diligence, LLC

Evolution of Commercial Markets for Sealants and Adhesives

The use of fibrin and other hemostats expanded rapidly in the 1980s in Japan driven by the strong cultural desire to avoid the need for blood transfusions in that market. In addition, regulatory barriers to launching homologous pooled plasma-derived products in Europe were not as stringent as those imposed by the US FDA in the late 1980s and 1990s. As a result the scientific literature from Asia and Europe records many novel and experimental uses for sealant and haemostasis products across all surgical disciplines from ENT to major open heart surgery.

In addition to commercial sources of sealant products, surgical centers in all regions of the world also prepare autologous fibrin for surgical procedures in efforts to save on commercial product costs, and to avoid potential for product-borne infection. Delays to the introduction of fibrin-based products in the USA led to a pent-up unmet need, which was addressed in the 1990s by the preparation of autologous fibrin in medical centers prior to surgical operations.

Historically, closure of surgical incisions has been achieved through an ever-evolving portfolio of suture, staple and tape products. In the early 1990s physicians involved in sports medicine were the first non-military practitioners to adopt cyanoacrylate glues to achieve immediate closure of small cuts and lacerations, and an awareness of this opportunity developed in large multinational manufacturers of sutures and staples. Joint development efforts were commenced at Davis and Geck (now U.S. Surgical), and Ethicon (subsidiary of Johnson and Johnson), and in a number of companies manufacturing cyanoacrylates which ultimately resulted in topical cyanoacrylate closure products being launched around the world during the 1990s.

Postoperative adhesion prevention evolved as a market in the early 1990s, and expanded with the addition of new entrant products from Genzyme, Focal, and others. Lifecore and Ethicon have developed a surgical adhesion prevention product based on hyaluronic acid. Angiotech, Fidia, Fziomed and Tissuemed all have adhesion-prevention products that are CE approved in the European Union.

Exhibit ES-6: Synthetic and Biological Sealant Competitors (Non-Fibrin Sealants)

Company	Product	Notes
Focal (Lexington, MA) division of Genzyme Biosurgery	Focal Seal L	Available for lung resections in Europe and under evaluation for orthopedic sealing
Angiotech	CoSeal	Approved for chronic wound care applications... Also evaluating for cardiovascular, general, and laparoscopic applications
Baxter Healthcare	Floseal	Marketing for cardiovascular procedures, adrenalectomy and tonsillectomy; also targeting spine, head and neck procedures
U.S. Surgical	Spraygel	Targeting vascular sealing
Davol, a division of C.R. Bard (Murray Hill, NJ)	Collagen sealant	Hemostat product under development for aortic dissections
Angiotech	Dynastat	Targeted at orthopedic spine and neuro applications
Angiotech	Costasis	General surgery, cardiovascular and general procedures
Tissuemed (Leeds, U.K.)	Tissuebond	A light-activated hemostat adhesive used as an aid to anastomosis
CryoLife (Atlanta, GA)	Bioglue	Bioadhesive made from glutaraldehyde cross-linked bovine serum albumin

Source: MedMarket Diligence, LLC

Tags: medtech, sealant, fibrin

Medtech report sample: Worldwide Ophthalmology Market 2007

Tue, 14 Nov 2006 14:32:14 -0800

Exhibit 3-10: Medical Device Products for the Treatment of Glaucoma

Manufacturer	Product	Brands	Status
AMO	Glaucoma shunt	Baerveldt Shunt for refractory glaucoma	Commercially available
Aquasys	(Early stage product)	Early stage development for treatment of primary open angle glaucoma using a “soluble duct” that reduces IOP by creating a drainage pathway for excess fluid to flow from the anterior chamber into the sub conjunctiva	Development stage device
Glaukos	Implantable device	Early stage development of a micro technology for the treatment of glaucoma	Development stage
IOP	Moltina valves	Drainage valves for alleviation of IOP to treat glaucoma	Commercially available
Iridex	IRIS Medical IQ810	Infrared photocoagulator for ophthalmic minimal intensity photocoagulation (MIP)	Approved for retinal disorders as well as glaucoma
iScience Interventional	(Early stage product)	Early stage development of device for treatment of glaucoma	Development stage
Lumenis	Selecta II Selective Laser Trabeculoplasty	SLT Nd:YAG laser system works by using a specific wavelength to irradiate and target only the melanin-containing cells in the trabecular meshwork	Approved for use in the U.S. in 2001 and available worldwide
NeoMedix	(Early stage product)	Trabecome system for treatment of glaucoma includes a microelectrocauter system with irrigation, aspiration and handheld instrument	Development stage
New World Medical	Ahmed Glaucoma Valve (AGV)	Controls IOP for patients with all types of glaucoma	Commercially available
OccuLogix	SOLX GMS (gold micro shunt)	A 24-karat gold ultrathin implant, one-third the thickness of a human hair contains numerous micro-tubular channels that bridge the anterior chamber and suprachoroidal space to maximize uveoscleral outflow and reduce IOP	CE Mark approval for sale in Europe; investigational in the U.S.
OccuLogix	SOLX TiSaLT (Titanium Sapphire Laser)	DeepLight 790 nm wavelength trabeculoplasty laser penetrates the trabeclar meshwork to lower IOP	CE Mark approval for sale in Europe; investigational in the U.S.
STAAR Surgical	AquaFlow	Collagen glaucoma drainage device to be used with a non-penetrating deep sclerectomy, lowers IOP and reduces the need for medication	Approved for commercial distribution in 2001

Source: MedMarket Diligence, LLC

Tags: medtech, opthalmology, glaucoma

Medtech report sample: Worldwide Wound Management, #S225

Thu, 7 Sep 2006 12:29:33 -0700

From "Worldwide Wound Management," report #S225...

Pharmacological Products in Wound Management

        Overview

In the context of advanced wound management there are a number of companies developing and commercializing technologies in the pharmacological field. These technologies include recombinant growth factors and growth factor mixtures, gene therapy, chemical cell stimulants, natural plant extracts, and other pharmaceuticals.
Advanced wound care practices and dressings have focused on removal of the underlying cause of the wound, altering physical environments, and providing a moist wound care environment. These efforts have greatly improved wound care by supporting the body's own repair and regenerative processes. Recent interest and efforts have evolved beyond facilitative wound repair to products and procedures designed to actively manipulate the wound healing process.

Historically, active products comprised those topical wound care products that were regulated and reimbursed as pharmaceuticals. These products fell into the two categories: topical pain control and antibiotic control. These are long-established categories and are not considered to fall within the area of advanced wound management. More recently, products have been developed or are under research to improve healing by addressing active stimulation in the categories Growth Factors,

        Non-Growth-Factor Modulators, and Gene Therapy Agents.

                Product Examples

                        Growth Factors

In academic circles the potential for growth factor intervention to improve the speed and quality of wound healing has been an area of intense activity in recent years. Growth factors are responsible for recruiting the necessary and appropriate cells to the wound site and for directing their activities in the repair process over time. As wound healing progresses, different growth factors are called into play and active cell populations and activities change. There have been a number of attempts to unravel which growth factors are responsible for different elements of wound repair, and to determine whether addition of exogenous growth factors might be used to accelerate wound repair.

Many involved in the use of advanced dressings suggest that the success of these products has been due, at least in part, to their ability to concentrate growth factors found in wound exudate over the surface of the wound bed. The mix of growth factors produced by the wound would be appropriate to the wounds needs at the time and advanced wound dressings thus represent a way to facilitate the use of the body’s own growth factors.

Growth factors play an important part in the manufacture of skin replacements and other tissue engineered products by facilitating and speeding up the culture process. Some of the activity of skin substitutes is also credited to the growth factors produced by cells within the substitute or sequestered in the intracellular matrix of the product during expansion of cells to form the product, and after application to the product to the wound.

Application of recombinant gene technology now allows the production of large amounts of specific growth factors for clinical trial. Since the late 1980s companies have been entering the clinic with active growth factors to evaluate their efficacy. Unfortunately, sound predictive models for chronic wounds do not exist, despite great effort that has been invested in this quest. The scientific literature is littered with literally hundreds of different growth factor studies that have started off well, established safety, and even indicated activity in wound repair at Phase II level, only to prove to be non-efficacious in Phase III trials. Despite this, manufacturers are devoting considerable effort to more closely duplicate naturally occurring forms of growth factors or to develop analogues with more potent activity.

The identification and understanding of growth factors involved in wound repair has encouraged the use of these substances to directly intervene and control the wound healing process.

The term “growth factor” is widely used in the wound care literature, but the nomenclature of active peptides is far from clear. Historically, the name given to a newly discovered regulatory peptide has been greatly influenced by the scientific specialty or research field that discovered it. For example a peptide with growth regulating properties would be called a cytokine by cell biologists, an interleukin by an immunologist and a colony-stimulating factor by a hematologist or oncologist. The tissue and/or cell type from which the factor was first isolated has also influenced names. Thus an epidermal growth factor may be later be found to be secreted by many other cell types but retains the name under which it was discovered. As the science progresses a unified system of categorization and nomenclature should evolve to simplify communication in the field.

When discussing wound healing, growth factors are those protein molecules (polypeptides) responsible for directing and coordinating cell behavior which normally leads to repair of the injured tissue. Growth factors are responsible for recruiting the necessary and appropriate cells to the wound site and for directing their activities in the repair process over time. As wound healing progresses, different growth factors are called into play and active cell populations and activities change. Growth factors can exist within cells or bound in inactive forms linked to carrier molecules in serum or the extracellular matrix of connective tissue between cells. Tissue injury results in bleeding and formation of a fibrin clot. The clotting cascade causes a number of related and amplifying effects that lead eventually to degradation of the fibrin clot by fibrinolysis, and the release of platelets and their factors. The degradation products and fibrinolysis products lead to chemo-attractant activity that attracts a phased spectrum of repair cells into the wound site for the initial (inflammatory) phase of wound healing. Monocytes and infection fighting white blood cells engulf bacteria, debris and necrotic tissue until the wound is prepared for proliferative healing. Growth factors provided by the macrophage and other cells control the rate and extent of angiogenesis, granulation, contraction, and finally epithelialization to fill and cover the defect. As healing progresses, growth factors are incorporated in newly formed tissues serving to direct the maturation and remodeling of the wound.

The basic sequence of growth factor interaction during acute wound healing has been worked out. At injury, platelets release alpha granules into the wound. Alpha granules release a mix of growth factors including platelet derived growth factor, transforming growth factor alpha, and epidermal growth factor. Neutrophils are attracted to the wound site by the presence of these growth factors (cytokines) and begin to produce transforming growth factor beta and interleukins (growth factors that attract and modulate the activity of immune cells and macrophages). Macrophages accumulate in the wound site and secrete large quantities of TGFs, PDGF, FGFs, interleukins and macrophage angiogenesis factors stimulating the production of granulation tissue to fill the wound defect and wound contraction. Fibroblasts and endothelial cells produce IGFs and endothelins and EGF and PDGF stimulate keratinocytes to migrate over granulation tissue to seal the wound.

Elaborate regulation of growth factor activity is evident by the large number of such factors and the distribution of receptors for the molecules over cell membrane surfaces. The function of a particular polypeptide mediator may differ in vitro or in vivo. Activity can differ when a growth factor is present on its own or in the presence of other growth factors or differ depending on the concentration presented to a cell population (low concentration –stimulate, high concentration – inhibit). Growth factors may stimulate one cell type and inhibit the function of another. Once introduced into the wound through normal biological activity or by human intervention, the ½ life of growth factors is short. Several protease enzymes found in exudate rapidly degrade the proteins.

These considerations complicate the delivery of manufactured growth factors to the wound site and much research is required to determine how to deliver the right mix of growth factors at the appropriate time, in the appropriate concentrations, while prolonging their activity in the wound to achieve the desired results.
Many involved in the use of advanced dressings suggest that the success of these products has been due, at least in part, to their ability to concentrate growth factors found in wound exudate over the surface of the wound bed. The mix of growth factors produced by the wound would be appropriate to the wounds needs at the time and advanced wound dressings thus represent a way to facilitate the use of the body’s own growth factors.

Growth factors play and important part in the manufacture of skin replacements and other tissue engineered products by facilitating and speeding up the culture process. Some of the activity of skin substitutes is credited to the growth factors produced by cells within the substitute or sequestered in the intracellular matrix of the product.
Application of recombinant gene technology now allows the production of large amounts of specific growth factors for clinical trial. While exact chemical copies of the protein chains that make up growth factors can be made, current manufactured products may present subtle biological and structural differences to those found in nature. One form of human recombinant PDGF is produced as a homodimer of two beta chains whereas the natural form of PDGF incorporates three polypeptide chains. Naturally occurring growth factors are often found in a glycosylated state that is not duplicated in the manufactured product (granulocyte macrophage colony stimulating factor, GM-CSF). Such differences may affect the biological activity of recombinant products and manufacturers are devoting considerable effort to more closely duplicate naturally occurring forms or develop analogues with more potent activity.

The wound care community has expressed considerable skepticism that the huge investments made in growth factor technology will lead to successful and useful commercial products. There are doubts that the complex interactions between growth factors and the wound can be worked out or that their use will be cost effective compared to current technology. Many believe they will be limited to use in certain wounds or that they may prove to be carcinogenic. Others believe that growth factors will begin to play an important part in a paradigm shift away from current facilitative practices to active control of wound repair in the very near future.
A standardized classification and nomenclature for growth factors has yet to be developed. Early names given to these regulatory polypeptides were derived from the tissues in which they were discovered, the target cells they were first seen to affect, or their activity in cell cultures. Additional confusion was introduced when it became apparent that a regulatory molecule discovered and named by one scientific subspecialty could have activity of interest to another specialty using different criteria for naming the molecules (growth factor may = cytokine may = CSF). Later it was discovered that individual growth factors may have multiple functions, may be produced by many tissue and cell types, and may have multiple target cells in vivo. Two growth factors with similar names may in fact have little structural similarities while two with quite different names may in fact be closely structurally related. For example, TGF alpha and beta have similar names but do not share similar chemical structure while TGF alpha shares close chemical structure to EGF. As more growth factors are discovered the need to rationalize and standardize nomenclature will grow.
One of the characteristics that may be employed to categorize growth factors is a consideration of their source and target cells. Growth factors that are produced and used to communicate with the same cell are termed autocrine (EGF). Mediators that are produced by one cell type and used by another are paracrine (TGF and PDGF). Regulators produced in one part of the body and delivered to another via the blood stream are termed endocrine (IGF I and IGF II). Most growth factors studied thus far are autocrine or paracrine and act locally near their site of production. Growth factors interact with their target cells by binding to receptors present on the surface of the target cells. Binding of the growth factor to the receptor initiates a cascade of intracellular events that initiates the cell's response. The potential therefore exists to classify growth factors by their corresponding receptor molecules.

The functions of growth factors include; attraction of cells to the wound site (chemotaxis), stimulation of cell division/proliferation (mitogenic competence/progressive), differentiation of cells into specific phenotypes (transformation), and, stimulation of cells to perform functions or secrete other growth factors.
Chemotactic growth factors recruit specific cell types to the area of injury insuring an adequate population of cells are available to perform a task. Leukotrienes are chemotactic for the white blood cells (leukocytes) necessary for digesting necrotic tissue and debris and fighting infection. Chemotactic factors can affect the motion of cells by providing a chemical homing signal where cells follow a concentration gradient indicating the direction of the target or by increasing the speed of cell motion (chemokinetic factors).

Mitogenic growth factors can be further sub classified into competence and progressive factors. Cells in their resting stage (G0) must be stimulated to replicate DNA (mitosis) before cell division can take place. Competence factors move the cell from resting stage (G0) to the G1 state where they are ready to divide. Once in the G1 state stimulation from progressive factors induces cell division increasing the number of available cells. Platelet derived growth factor and EGF are competence factors involved in preparing cells for division and IGF-I is an example of a progressive factor that triggers cell division.

Transforming growth factors (TGF beta) induce a particular cell type (phenotype) to transform into another cell type. Monocytes are transformed into macrophages by a TGF.

Differences observed in the effects of growth factors in vitro and in vivo may be due to the fact that the in vivo preparations provide a complex mix of factors that can influence growth factor activity. The growth factor under study may be a progressive factor with no function observable unless the necessary competence factor is present. Growth factor activity is strongly affected by the presence of other growth factors in the immediate environment. For example TGF-beta stimulates the proliferation of fibroblasts in the presence of PDGF but is inhibitory to the growth of fibroblasts in the presence of EGF. The activity of growth factors is also strongly linked to their concentration in the cellular media. Both FGF and PDGF stimulatory at low concentrations but become inhibitory as their concentrations rise.
Two types of fibroblast growth factors have been identified and their structures determined. Basic FGF (bFGF) consists of a 146 amino acid chain with a molecular weight of 18 kilodaltons. Acidic FGF weighs 16 kilodaltons and is assembled from 140 amino acids. Both factors are commonly found bound to heparin. Basic fibroblast GF is produced from a gene located on chromosome 4 and the gene for production of aFGF resides on chromosome 5. The two factors are 50 to 55% homologous in composition suggesting they share a common ancestral gene, which produced the current genome through the process of duplication and divergent evolution.
Both bFGF and aFGF are active on a wide variety of target cell types and are widely distributed in the body suggesting they have important reparative function. Basic FGF is 30 to 100 times more potent than aFGF. FGFs appear to be released from the host cell by tissue injury or during cell death (apoptosis) again strongly suggesting a role in reparative function. Of all the growth factors currently under investigation only bFGF appears to be able to trigger all the events associated with angiogenesis and granulation. Basic FGF affects endothelial cells (endocardium, capillaries, and large blood vessels), vascular smooth muscle cells, fibroblasts, myoblasts, chondrocytes, osteoblasts, melanocytes, and mesothelial cells inducing proliferation and chemotaxis or providing an inhibitory action. FGFs are strongly bound to heparin and occur in significant amounts in the extracellular matrix. The occurrence of inactive FGFs in the extracellular matrix indicates that they may be a primary stimulation factor available immediately at the site of injury.

FGF beta bound to a collagen matrix has been used to culture human keratinocytes for use as a collagen based skin replacement. In full thickness wounds recombinant bFGF has been shown to increase the thickness of granulation tissue, promote capillary proliferation and to increase the tensile strength of the healed wound.

Many studies on recombinant bovine basic fibroblast growth factor (rbFGF) on healing have been now been reported. For example a randomized placebo-controlled trial of 600 patients in 1999 with superficial or deep second-degree burns received a topical application of the rbFGF growth factor or placebo. The rbFGF was found to decrease healing time and improve healing quality.

TGF- alpha and TGF-beta are structurally distinct. The gene for TGF-alpha is located on chromosome 2 and encodes for a transmembrane protein of 140 amino acid that weighs 5.7 kilodaltons. TGF- alpha bears little resemblance to TGF-beta but does share a 35 to 42% homology to EGF and binds to the EGF receptor. It also exhibits a 30% homology to the vaccinia growth factor and will bind to its receptor. TGF –beta contains 112 amino acids in its polypeptide chain and has a molecular weight of 25
kilodaltons.

TGF-alfa is produced by keratinocytes, activated macrophages and is released during degranulation by platelets. It has chemotactic, angiogenic and mitogenic activity on endothelial cells and has been shown to accelerate healing in burns and to increase the regenerative ability of epithelium. TGF-beta has been shown to stimulate angiogenesis and the production of fibronectin and collagen by fibroblasts. The activity of TGF-beta is influenced by the presence of other growth factors. In vitro TGF-beta stimulates the growth of fibroblasts in the presence of PDGF and inhibits fibroblast proliferation in the presence of EGF. TGF-beta one and two have been suggested to accelerate wound repair. On the other hand TGF-beta three has been suggested in the scientific literature as a modulator of scarring.

Epidermal Growth Factor is synthesized as a transmembrane protein precursor; the EGF polypeptide chain is 53 amino acids long and weighs 6 kilodaltons, and has a gene that is located on chromosome 4. Levi-Monthalcini and Cohen received the 1986 Noble prize for their work delineating the role of growth factors including EGF. Most animals tend to lick their wounds and EGF has been detected in significant amounts in saliva. Experimenters in 1979 noted that removal off the submandibular salivary glands of mice resulted in reduced rates of wound healing compared to control animals with the glands intact. Application of EGF to the experimental wounds resulted in a return to normal rates of healing substantiating the role of EGF in healing. EGF serves as a competence factor inducing epithelial and mesenchymal cell populations to replicate DNA and enter the G1 phase of mitosis. EGF has been show to be angiogenic and chemotactic for endothelial cells and to posses mitogenic activity during epithelialization and keratinization. In partial thickness wounds, EGF stimulates the proliferation of the dermis and increases the tensile strength of healed surgical incisions. EGF activity affects the production of other growth factors and can modulate the activity of other growth factors within the wound.

Investigations are underway to examine the activity of EGF on skin appendages such as hair follicles, sweat glands, and the arrectores pilorum muscles. Its activity on these structures may lead to its use in the treatment of male pattern baldness.

Platelet-Derived Growth Factors are also important in wound healing. The 124 amino acid cationic glycoprotein chain of platelet-derived growth factor (PDGF) has a molecular weight between 30 and 32 kilodaltons. PDGF was originally isolated from platelets but has also been found in monocytes, macrophages, endothelium, and smooth muscle cells. The factor is chemotactic for neutrophils and macrophages and does not require the presence of other growth factors for its chemo-attractant effect. The angiogenic and mitogenic activity of PDGF is affected by other growth factors including IGF, which increases the rate of granulation and collagen deposition over PDGF alone. This behavior indicates PDGF is a competence factor that prepares the target cells for division and that cell division follows with the arrival of progressive growth factors from other sources. Released by platelets soon after the initial injury and maintained in the wound bed by macrophages, PDGF is mitogenic for fibroblasts, glial cells and smooth muscle cells. It appears to regulate initial inflammatory responses and granulation. Epithelial and endothelial cells do not possess receptors for PDGF and are not stimulated by its presence insuring epithelialization does not take place before sufficient granulation tissue has been produced to support an epidermis.

Insulin-like growth factors belong to a class of molecules referred to as somatomedins. Somatomedins circulate in the bloodstream in an inactive state bound to other proteins (protein binding factors, BPs). IGFs exhibit insulin like activity and can bind to insulin receptors on cell surfaces. They share 50% homology to proinsulin and one IGF (IGF-II) has been found to be identical in composition to Somatomedin-C. IGF polypeptides promote anabolic activity functioning to stimulate the synthesis of glycogen, proteins, and glycosaminoglycans found in the extracellular matrix. Like insulin, IGFs are involved in the transport of glucose across cell membranes and they also participate in the transport of amino acids the precursors of proteins.

Fibroblasts and endothelial cell receptors have a high affinity for IGFs and somatomedins have been used to stimulate collagen synthesis in fibroblast cultures. IGF –1 (somatomedin-C) is a known mitogen for osteoblasts, smooth muscle cells and fibroblasts. Of all the growth factors studied the IGF group is present in the highest concentrations in the bloodstream indicating their role is crucial in wound repair.

Interleukins have also been shown to be important factors for healing. Early work on interleukins (between white blood cells) was conducted mainly by immunologists drawn to their activity in regulating the body’s cell-mediated immune response. Interleukins are chemotactic for white blood cells, pyogenic (fever producing) and gained the interest of wound healing specialists for their important role in mediating the inflammatory phase of wound healing. An example of the class, Interleukin-2 is a 15.5 kilodalton polypeptide, produced by activated T-lymphocytes, which enhances the T cell mediated immune response. Interferon and the Leukotrines are other examples of proteins involved in the attraction and interactions of immune cells. Interleukins appear to affect fibroblast proliferation and the activity of synovial cells to produce and remodel tendon, cartilage and bone.

Growth factors currently under study have short ½ lives in the wound environment, which creates the need for frequent application of products containing growth factors to the wound site. Frequent, two or more times daily, application reduces interest in the products by managed care organizations seeking methods to reduce the number of skilled interventions required to treat wounds. Growth factors will need to show overriding healing benefits that reduce patient stay in an expensive care environment, or, that reduce the overall treatment cost.

Regranex is the first purified recombinant human growth factor to be marketed; this product sold by Johnson and Johnson has demonstrated that, at least for some growth factors, shelf life can be managed as well as storage and transportation issues involved in delivering active concentrations of inherently unstable molecules. Future commercial potential of all these products will be affected by storage and stability issues. As the activity of a growth factor can vary widely with the delivered concentration, delivery systems will need to be developed that regulate release levels over time. The interactions between growth factors suggests that delivery systems will be required to handle multiple growth factors and provide for balanced release of many factors in the right place, in the right mix at the appropriate time.
As wound requirements and healing processes change over time clinicians can expect that different growth factors will be required at different stages during the healing process and that any one wound may actually require different growth factor mixes on different parts of its surface. Wound assessment will need to evolve to allow determination of which mixes are appropriate for the type of wound and stage of healing. Growth factor formulas will need to be produced for inflammatory, granulating and epithelializing needs. The wound edges may require stimulation of epithelialization which would be counter productive in the wound crater where stimulation of granulation is still required. The management of these details will evolve as growth factors enter wide spread usage.

From the viewpoint of would-be manufacturers of wound healing growth factor products, a number of aspects of the Regranex product serve to illustrate the changing dynamic in the wound care industry. Exceptional resources have been used to deliver this new technology to the market. These resources start with 30% of sales paid for cost of goods and royalties to Chiron for the active component of the product. Substantial investment of several hundred million dollars was invested by McNeil to deliver the product through manufacture, clinical, and regulatory hurdles and into the market with substantial advertising and marketing investment for pre-launch commercialization. Such investment is atypical in the wound management market where development costs for wound care device-type products have historically been below a million dollars and advertising and marketing spend at launch in the tens of thousands of dollars.

Johnson and Johnson has chosen to sell Regranex through a pharmaceutical sales force and has developed this product on a pharmaceutical scale. In the past, customers responsible for procurement decisions within the wound management industry have traditionally been slow to convert to new technologies, and companies have responded with substantial sustained investment over many years to educate and train nurses and physicians in the new techniques based on sound principles. This approach was under challenge by Johnson and Johnson, and a number of other pharmaceutical companies are addressing this market with other technologies. This change in scale of investment is a challenge to companies that do not have the scale to compete, and represents a risk to companies who may have the scale and technologies but are without a depth of knowledge in this market.

A number of growth factor technologies have been developed to the stage of clinical evaluation or launched on the market.

Biopharm (Heidelberg, Germany), has discovered a growth factor called Growth Differentiation Factor 5 which they are developing for a number of medical repair indications. Early work at Biopharm suggests that this molecule may have a role in the repair of human skin.
Growth Factor Mixtures have also been developed by a number of companies. Platelet-derived growth factors derived from the patient’s own blood have been used for many years in the wound treatment programs provided by Curative Health Services Inc. (formerly Curative Technologies Inc). Over 170 centers in the USA that are affiliated with Curative provide wound care in accordance to formal algorithms including assessment, treatment (aggressive debridement and advanced wound care), prevention measures and patient education. Selected patients receive Procuren (autologous growth factor therapy) solution. Procuren is prepared from a blood sample taken from the patient and centrifuged to concentrate the blood cells. The patient’s platelets are then induced to de-granulate and the PDGF releasate is incorporated into the Procuren solution. Platelet releasate contains at least five locally acting growth factors including PDGF, PDAF, platelet –derived EGF, TGF-beta, and platelet factor 4 (PF-4). The product is included in this section since it is most commonly associated with PDGF; however this product is really an autologous mixture of growth factors. In selected patients, Procuren has been shown to stimulate the formation of capillary rich granulation tissue and to induce epithelialization. In one dose ranging study 63% of the releasate patients healed compared with 29% of the control group. The 1:100 concentration produced the highest rates of healing (80%). In cost effectiveness studies, savings of up to 38% were found vs. comprehensive wound care alone. Procuren has also been shown to reduce the need for amputations. As an autologous procedure using the patient’s own blood for the production of the growth factor solution, Procuren was not subject to FDA regulation when it was introduced in the early 1990s.

Daewoong Pharmaceutical, (Korea), is in development in Phase II clinical research with its recombinant human Epidermal Growth Factor (EGF) for repair of diabetic ulcers. This material has been produced under conditions designed to encourage the natural configuration of the EGF molecule and to enhance the specific activity of the EGF in the final product formulation.

Gropep, an Australian Biotechnology company has a mixture of growth factors extracted from cow’s milk, which have been purified and formulated into a hydrogel system for delivery to chronic wounds as a wound stimulant product. This mixture is in the clinical phase of development and targeted at the European and USA, as well as the domestic market.

Johnson and Johnson has the first growth factor to be released for sale in the wound healing market, a recombinant form of PDGF indicated for the treatment of diabetic neuropathic foot ulcers that extend into the subcutaneous tissue and beyond and that possess an adequate blood supply. The product is called Regranex Gel 0.01% (becaplermin) and is composed of two identical beta chains in contrast to the naturally occurring form that incorporates three chains. Regranex is manufactured and marketed by Ortho McNeil a division of Johnson and Johnson in the USA. During development, Ortho McNeil took on responsibility for regulatory, marketing and sales functions in the USA. The product was approved in the USA in December 1997. The gel contains a PDGF (platelet derived growth factor) known as becaplermin which is supplied by Chiron. The gel is approved for the treatment of diabetic foot ulcers and is the first recombinant human growth factor product to be approved for wound care. Marketing activities stress the importance of good wound care including debridement and pressure off-loading to insure the wound is ready for the proliferation stage and has adequate blood supply to support granulation. The product is applied twice a day.

Regranex is not indicated for shallow wounds where epithelialization requires a different set of growth factors. Johnson & Johnson's Regranex product has been launched in the USA, as well as the UK and several other European countries since 1999. In Europe the product is being promoted by Janssen-Cilag (Johnson & Johnson). The US clinical trial data is used to support claims for the launch of the product in Europe. The gel is approved for the treatment of full thickness diabetic foot ulcers. The cost to the UK National Health Service for this product is quoted at £275 per tube, although J&J report that the product should actually cut the cost of treating diabetic ulcers which are difficult to heal in comparison with current treatments and should also reduce the number of subsequent amputations needed. Clinical trials by McNeil found that Regranex was associated with complete wound closure in 50 per cent of patients compared to 35 per cent of those receiving the placebo. The time to heal also decreased by 32 per cent using the Regranex gel.

Researchers at Regeneron, investigating a class of receptors known as the Tie receptors, have identified the first of a new family of growth factors specific for the regulation of blood vessels. Regeneron scientists have demonstrated that the vascular endothelial growth factor (VEGF) and the Tie growth factors work together in the regulation of blood vessel formation central to granulation/angiogenesis. Tie receptors are also expressed on hemopoietic stem cells that give rise to all other blood cells produced by the body. Regeneron has received Patent No. 5,521,103 on the gene that encodes for the human Tie-2 ligand protein and the method utilizing the gene to make the Tie-2 ligand protein.

Selective Genetics Inc (San Diego, California) was formed in April 1998 from the combination of Matrigen Inc and Prizm Pharmaceuticals Inc. They have developed intellectual property for the delivery of genes on collagen delivery systems, and have developed this to deliver fibroblast growth factor (FGF). Selective Genetics is evaluating the technology for the treatment of diabetic ulcers.

Thermogenesis also makes a device for creating a growth factor mixture; the company provides a CryoFactor machine for human PDGF preparation from autologous blood for treatment of diabetic ulcers. This material is prepared from the patients own blood and contains a mixture of the patients own growth factors which are contained in the blood at natural levels and following removal and concentration these are then used to stimulate repair.

Recombinant human growth hormone is under study at the University of Texas for the treatment of chronic pressure ulcers in paraplegic patients. Recent reports indicate that systemic administration of rhGH improves wound healing and protein synthesis in sever burn patients and increased plasma pre-albumen and retinol binding protein concentration in malnourished surgical patients indicating promising potential for increasing inflammatory and proliferative wound healing.

Vanderbilt University is studying the activity of Epidermal Growth Factor (EGF) and EGF-like ligands, their receptors and phosphorylated substrates. The EGF signaling cascade is being studied in migrating and proliferation keratinocyte populations both in vitro and in vivo superficial wounds (mouse tail stripping). Deeper full thickness wounds (excised porcine wounds, human burns and chronic wounds) are being studied to define and contrast growth factor mechanisms controlling extracellular matrix protein deposition.

------------------------
Source: "Worldwide Wound Management, 2005-2014:  Established and Emerging Products, Technologies and Markets in the U.S., Europe, Japan & Rest of World," report S225, published by MedMarket Diligence, LLC

Medtech report sample: Virtual Reality in Surgery & Imaging, #S165

Tue, 5 Sep 2006 12:42:11 -0700

Exhibit 4-2: Companies with Diagnostic VR Products

COMPANY	PRODUCT	FEATURES
Able Software	3D-DOCTOR	3D-DOCTOR is a software image-processing system for creating real-time grayscale and color 3D surface models and volume rendering from 2D cross-section MRI, CT, PET, and microscopy images. It supports images in numerous formats, including DICOM, TIFF, Interfile, GIF, JPEG, PNG, BMP, PGM, and RAW. Current applications include: orthopedic 3D Bone Model from CT Image, 3D Jaw Model for Dental Implant, 3D Model from MRI, Volume Calculation, and Quantitative Analysis.
AccuImage Diagnostics (part of Merge eFilm)	Advanced Visualization	This software package is used by radiologists, cardiologists, gastroenterologists, pulmonologists and orthopedic surgeons to visualize diagnostic images in 3D.
AccuImage Diagnostics (part of Merge eFilm)	3D/4D Review	This system provides 3D and 4D visualization of diagnostic images with real-time editing tools for on-the-fly removal of overlying structures.
AnalyzeDirect, Inc.	Analyze 6.0	Analyze software provides volume rendering, image segmentation, image fusion, surface rendering, and ROI measurements on diagnostic medical imaging dataset including MR, CT and PET.
AnalyzeDirect, Inc	The Analyze Brain Atlas Add-On	This software module allows fusion of brain MRI images to a Co-Planar Stereotaxic Atlas of the Human Brain so that brain images can be visualized simultaneously in axial, coronal, sagittal orientations along with color-coded Talairach-Tournoux structures.
Biomedicom	SONOReal	This software package provides 3D imaging capabilities from ultrasound data. It provides multiplanar 3D volumetric mammography, cardiology, gynecology, interventional radiology, obstetrics, surgery, and urology images that can be viewed from any orthogonal plane with the inclusion of the SONOSensor positional sensor.
Boston Scientific Corporation	Intravascular Ultrasound (IVUS)	The Intravascular coronary ultrasound (IVUS) system consists of a miniature ultrasound "camera" that is inserted into the coronary arteries to image the vessels from the inside-out. This visualization procedure allows the physician to determine the juncture of the normal artery wall and plaque.
Cedara Software	I-Report CT	I-Report is designed for 3D volume rendering of CT data sets, and includes navigation tools, MPR, and measurement tools. It supports orthopedic templates, and Cedara’s latest plug-ins
Cedara Software	OrthoWorks	A suite of orthopedics plug-ins, OrthoWorks planning and digital templating enables pre-operative planning for orthopedic procedures through the use of. 3D volume rendering. MPR
E-Z-EM, Inc	InnerviewGI	This workstation, which renders 3D images from CT data sets for use in virtual colonoscopy procedures, provides interactive navigation within multiple 3D views or within coregistered 2D and 3D views of the colon.
Medison America	Accuvix XQ	Acuvix XQ is an ultrasound imaging system with 2D/3D/4D capabilities, including 3D eXtended Imaging™, full spectrum imaging, volume resolution of 4D images, MPR, and See-Thru Doppler Rendering.
Medison America	SonoAce 8000 Live	SonoAce 8000 Live is designed primarily for obstetric and gynecological applications where it provides real-time color and gray-scale 3D and volume 3D imaging, Tissue Doppler Imaging, Tissue Harmonic Imaging, Pulsed Inversion Harmonic Imaging, 128-frame cine imaging, and 3D volume measurement.
Next Dimension Imaging	Anatomy Analyzer 2	This Windows XP application is used for creating 3D anatomical models with merge and dissect capabilities. It provides a means of quantifying surface area, volume and distance within anatomical images.
Sintef		As part of the Center of Competence for3D Ultrasound in Surgery, Sintef has developed a surgical guidance and navigation system based on a. System FiVe digital ultrasound scanner and a magnetic or optical positioning system for use as a 3D diagnostic ultrasound.
TeraRecon, Inc.	Aquarius Workstations	These diagnostic radiology workstations for viewing ultrasound, multi-slice CT and MRI data sets provide 2D, 3D, and 4D reconstruction, real-time visualization, and measurement capabilities/
VayTek, Inc.	VoxBlast	This 3D digital imaging application offers a volume rendering program for 3D volume visualization and volume measurement from coregistered stacked 2D images. VoxBlast uses an alpha blending or surface rendering algorithm to create 3D projections from any viewpoint with pseudo-color, transparency, and variable lighting capabilities, as well as permitting 2D and 3D measurements, 2D slice viewing, cropping, and movie-loop generation.
ViTAL Images, Inc.	Vitrea 2	This software system provides 2D, 3D, and 4D visualization from 2D image CT, MRI, and PET data sets. Add-on packages provide diagnostic visualization capabilities in several medical specialties.
ViTAL Images, Inc.	3D-Angio	This option to Vitrea2 permits viewing of angiographic data sets in 2D and 3D from any viewing angle.
ViTAL Images, Inc	Automated Vessel Measurement (AVM)	This option to Vitrea2 enables physicians to measure minimum and maximum vessel diameters and vessel length, and provides maximum tortuosity information and automatic centerlines.
ViTAL Images, Inc	ViTAL Connect	ViTAL Connect is a medical diagnostic tool designed to permit physicians to use PCs to access 2D, 3D, and 4D images with a web-enabled browser, and to measure, rotate, analyze and segment the images. It also allows simultaneous viewing of the images by physicians at multiple locations.
Volume Graphics	VGL	VGL 3D graphics technology is applicable to imagery obtained with CT, digital X-ray, MRI, PET, fluoroscopy, ultrasound, and other modalities; and provides volume images in mammography, angiography, ophthalmology, and other diagnostic imaging specialties.

Note: 2D = Two-dimensional; 3D = Three dimensional; 4D = Four dimensional; BMP = Bitmap; CT = Computed Tomography; DICOM = Digital Imaging and Communications in Medicine; GIF = Graphics Interchange Format; JPEG = Joint Photographic Experts Group; MPR = Multiplanar Reformatting; MRI = Magnetic Resonance Imaging; PET = Positron Emission Spectroscopy; PNG = Portable Network Graphics; RAW = Raw image files; ROI = Region of interest; TIFF = Tagged Image File Format

Source: "Virtual Reality in Surgery & Imaging," report #S165, published by MedMarket Diligence, LLC

Medtech report sample: Executive Summary (excerpt) from Diabetes Management Worldwide, #D500

Wed, 23 Aug 2006 13:46:22 -0700

[From "Diabetes Management Worldwide", Report #D500.]

Diabetes Market Growth

In some respects, the diabetes market is reaching a state of satisfaction. Glucose meters have reached a level of sophistication which satisfies most market needs, and the same is true of insulin pumps. The main remaining product innovation opportunities in the devices sector are the development of truly non-invasive glucose metering instruments, and the development of an automatic closed-loop system linking glucose metering with insulin administration: the “artificial pancreas”. This latter development will eventually drive significant, perhaps dramatic, growth in the devices sector but this is not likely to happen in less than 4-5 years.

In the pharmaceutical sector, a number of insulin analogues are now available which go far to satisfy the market’s needs. New classes of oral antidiabetic drugs continue to be developed but the older classes are still widely used.

Exhibit ES-1: Total Diabetes Market, 2004

Segment	Market
Medications	$15,000 million
Diagnostic Devices	$8,000 million
Insulin Therapy Devices	$275 million
Insulin Pumps	$1,000 million
TOTAL	$24.3 billion

Source: MedMarket Diligence, LLC

Until the goal of managing diabetes more thoroughly and holistically by tackling the underlying genetic and immunological causal mechanisms, growth in this market is likely to be driven mainly by the increasing prevalence of both main types of diabetes, especially in the developed world, with incremental growth resulting from the introduction of improved versions of current drugs and devices.  Consequently, this report estimates an annual growth rate around 6% in the diabetes market over the next ten years. Major technological and/or scientific breakthroughs could, of course, make it necessary to revise this forecast.

        The Diabetes Industry
The structure and membership of the diabetes industry reflects the wide range of products used in the management of diabetes.  It includes some of the major global pharmaceutical companies and also companies which have a commanding presence in the IVD (in vitro diagnostics) sector.

        Pharmaceutical Companies
The insulin market is the fiefdom of two companies: Eli Lilly in the USA and Novo Nordisk in Denmark. Sales of Lilly’s insulin products in 2004 were slightly more than $2 billion, while the total for Novo Nordisk’s diabetes products (mainly insulins) was $3 billion. The French group Sanofi-Aventis has gained a substantial foothold in the insulin marketplace with its insulin analogue Lantus, selling at $1 billion in 2004.
The heterogeneous market for oral antidiabetic drugs is dominated by Glaxo SmithKline’s Avandia, with sales of $2 billion in 2004, and Takeda’s Actos (co-marketed with Lilly in the USA) with sales of $1.5 billion. Several oral antidiabetics are out of patent now, and their sales in volume terms outpace those of the market leaders.

        Medical Device Companies
The leading contenders in the blood glucose testing (BGT) marketplace are Johnson and Johnson and Bayer, whose diabetes diagnostic sales are estimated around $2 billion. Abbott has a range of BGT products with sales totaling around $800 million in 2004. Roche has diabetes-related sales of $2 billion, mainly attributable to BGT products but partly also to sales of insulin pumps. Other leading participants in the insulin pump market sector include Medtronic and Dana Diabecare.

Apart from the handful of companies at the top of the diabetes market tree,  the field is thickly populated with smaller companies and those for whom diabetes is just one of a number of market segments in which they are involved.  Some 80 of these are briefly described in section 6 of this report. Many are marketing or developing blood glucose meters and associated products.

Tags: medtech, diabetes, glucose, insulin

Medtech report sample: "Cancer Diagnostics and Therapy", from Micro/Nanomedicine report T625

Wed, 23 Aug 2006 06:27:08 -0700

[From "Micro- and Nanomedicine:  Technologies, Applications, Industry, and Markets Worldwide", Report #T625.]

2.1.1 Cancer Diagnostics and Therapy

        2.1.1.1 Silica Nanospheres

Dr. Victor Shang-Yi Lin, associate professor of chemistry, and his research group are developing a nanotechnology platform involving materials called mesoporous silica nanospheres. These structures contain numerous duct-like channels which present a unique opportunity for nanoscopic chemical storage and delivery, whether the payload is anti-tumor drugs, nutrients or material. Different drugs or imaging agents can be hidden inside the nanospheres, which then act like a Trojan Horse. The delivery of chemotherapy drugs to tumor sites is one application. Cancer patients undergoing chemotherapy have long experienced debilitating and dangerous side effects when the healthy cells of their body are attacked by anti-tumor drugs, but the porous nanostructures offer a new way to circumvent the problem. For the nanospheres to function effectively as carriers, they must be capable of entering a cell without being destroyed.

The main focus of the group’s current research is development of mechanisms that hold the drugs inside the nanostructures and prevent them from being released where they may be unwanted or harmful. One recent success has been the use of magnetically charged chemicals; an external magnet can be used to direct the nanospheres and deliver the drug with great accuracy. The research group is now focusing on a new method in which the nanospheres release drugs in tumor cells only, without the need for external control.

The chemical gates of these nanospheres could also be designed to open only in the presence of specific chemicals. Biologists could take advantage of this technology to investigate the levels of different chemicals inside of living cells without damaging them. Both the National Science Foundation and the Department of Energy are supporting the project.

        2.1.1.2 Nanoscale Hydrogel Shells

Alnis BioSciences is developing magnetic nanoparticles called NanoGels that may be used to detect tumors through magnetic resonance imaging, or MRI. They could also be used as a treatment; if the magnetic field is alternated, the core heats up, melts the shell and releases chemotherapeutic drugs. The research project has been underway for eight years and the company received $2.7 million in 2004 from the National Cancer Institute to continue the programme.

        2.1.1.3 Carbon Nanoparticles

An experimental treatment that couples directed radio waves with carbon nanoparticles has proved powerful enough to kill cancer cells. The approach was developed by an entrepreneur named John Kanzius and nanotechnology researchers at Rice University. The combined technology developed by Kanzius with carbon nanoparticles developed by Rice chemist Richard Smalley. Kanzius developed his part of the radiowave-nanoparticle theory while undergoing treatments for non-Hodgkin's lymphoma in 2003 and 2004. He engineered equipment that would generate high-powered radio waves and direct those waves into a patient's body.

In theory, the radio waves heat up cancer cells enhanced with minerals. The heat kills the cancer cells without harming the neighboring healthy cells.
Kanzius filed a patent outlining the procedure in May 2004. Since then, he has been working with researchers in Pittsburgh and Houston who are interested in researching whether the technology could be used as part of a new treatment protocol.

Rice University chemist Richard Smalley learned of Kanzius' radio wave idea through fellow scientists in Houston in 2005 and began talking with the inventor about the possibility of marrying radio waves with carbon nanoparticles.

Smalley, who died in October 2005 after his own battle with cancer, is widely credited with discovering buckyballs, more formally known as fullerenes. That research won him the Nobel Prize in chemistry in 1996.

He believed if carbon nanoparticles could be attached to cancer cells, the nanoparticles would be able to destroy the cells if exposed to Kanzius' directed radio waves.
The move into animal testing is the next step in what will likely be a lengthy process for researchers hopeful that they can turn the early test-tube success into an effective treatment for human patients.

        2.1.1.4 Photodynamic Therapy and Gold

The University of East Anglia (UEA) in England has received the backing of the world’s leading cancer research charity to develop a unique nanotechnology-based treatment that can deliver anti-cancer drugs direct to cancerous cells. Cancer Research UK’s £150,000 ($280,000) grant will enable the UEA to take the nano-treatment, which combines photodynamic therapy (PDT) with optimised cancer therapies, out of the test tube and into toxicity testing. Appropriate medication is attached to tiny particles of gold, which is then steered through the body.

Though the patented technology is yet to enter pre-clinical trials, it has already been the subject of a licensing deal with an unnamed drug development company. The UEA team has been working on proof-of-principle studies in collaboration with a group from Italy. The group successfully demonstrated that the technology worked with different targets, which highlighted its commercial potential and persuaded Cancer Research to provide funding to take the work onto the next level.

“The idea is to deliver a light-activated drug to cancer tumours,” said Prof Russell, head of the group. “We have done this in cells in a dish and are now moving onto in vivo work with the funding from Cancer Research UK. Our technique can be adapted for use with existing drugs.”

        2.1.1.5 Dendrimer Conjugates

Dendritic polymers, or dendrimers, are synthesized as spherical structures ranging from 1 to 10 nanometers in diameter. Synthesis, characterisation and therapeutic application of dendrimers have been undertaken by Avidimer Therapeutics (previously Nanocure).

Avidimers is investigating dendrimers as a vehicle for delivery of anti-cancer therapeutics. PAMAM dendrimers have been used as a scaffold for the attachment of several types of biologic materials. This work has focused on the preparation of dendrimer-antibody conjugates for use in in vitro diagnostic applications, for the production of dendrimer-chelant-antibody constructs, and for the development of boronated dendrimer-antibody conjugates for neutron capture therapy. These conjugates have also been employed in the magnetic resonance imaging of tumors. When administered in vivo, antibodies can direct dendrimer-associated therapeutic agents to antigen-bearing tumors. Dendrimers have also been reported to enter tumors and carry either chemotherapeutic agents or genetic therapeutics. In particular, studies show that cisplatin complexed polymers have increased efficacy and are less toxic than free drug. Further, dendrimers have been constructed as co-polymers where the outer portions of the molecule may be digested with either enzyme or light-induced catalysis. This would allow the controlled degradation of the polymer to release therapeutics at the disease site and could provide a mechanism for an external trigger to release the therapeutic agents.

        2.1.1.6 Ligand-Targeted Emulsion Technologies

Kereos develops targeted therapeutics and molecular imaging agents designed to detect and treat cancer. Because the targeted therapeutics seek out definitive disease biomarkers and carry powerful payloads of proven chemotherapeutics, their specificity and potency make them potentially more effective and less toxic in treating disease. Similarly, the company’s molecular imaging agents make possible earlier and more definitive diagnosis of disease.

Kereos' technology is based on proprietary ligand-targeted emulsion technologies. Individual emulsion “particles” consist of a perfluorocarbon core surrounded by a lipid monolayer which stabilizes the particle and provides a virtually unlimited number of anchoring sites for targeting ligands and payload molecules. The result is an oil-in-water emulsion of particles with an average size of approximately 250nm, leading some to refer to them as “targeted nanoparticles.”

KI-0001 is an MRI agent for tumor detection, due to enter the clinicin 2006. It allows earlier detection and diagnosis of a wide variety of solid tumors. Using a targeting ligand proven in human trials, KI-0001 provides MRI-based molecular imaging of the angiogenesis signal essential to the viability of tumors as small as 1 mm in size.
KI-1001, the company’s targeted chemotherapeutic for solid tumors, is designed to target the same biomarker of angiogenesis as the imaging agent KI-0001.

        2.1.1.7 Linear Cyclodextrin-Containing Polymers

Insert Therapeutics is designing, developing and commercializing delivery-enhanced therapeutics using its patented CyclosertT family of linear cyclodextrin-containing polymers.. Under an IND approved by the FDA in March 2006, Insert will conduct a Phase I study for IT-101, its first anti-cancer therapeutic, a nanotechnology-based therapeutic that combines Insert's Cyclosert technology and the anti-cancer compound camptothecin. The Phase I trial will be an open-label, dose-escalation clinical trial of IT-101 in patients with all types of cancer. The trial is expected to enroll between 24 and 48 patients and has been designed to determine safety and tolerability of IT-101.

        2.1.1.8 Smart Lipid-based Nanocarriers

LiPlasome Pharma is developing a combination of a protected blood transporting nanocarrier system and a tumour-specific activation. The key principle behind the innovative drug delivery concept is that smart lipid-based nanocarriers can be used for targeted transport of anticancer drugs to cancer tissue. The drug delivery platform consists of two main components: a lipid-based drug delivery system (LiPlasomes) for intravenous transportation of anticancer drugs and prodrugs, formulated with polyethylene glycol (PEG) to prolong the serum half-life of the payoad; and an activating release mechanism to ensure that the prodrugs and drugs are released specifically at the tumor target site. The trigger is based on an endogenous lipid-degrading enzyme, secretory phospholipase A2 (PLA2), which is present in high concentrations in all human solid tumors investigated to date. Examples include prostatic, pancreatic, colorectal, gastric, and breast tumors.

The carrier nanoparticles are composed of special prodrug lipids whose degradation products, after exposure to PLA2, are converted to active drugs such as anticancer lysolipids and/or fatty acid drug derivatives. PLA2 hydrolysis products also act as locally generated permeability enhancers that promote the absorption of the released drugs across cancer cell membranes into putative intracellular target sites.

The concept is very flexible and allows for the incorporation of different conventional cancer chemotherapeutics as well as new anticancer prodrugs.

        2.1.1.9 Thermotherapy Using Magnetic Nanoparticles

MagForce Nanotechnologies AG has developed a patented therapy which allows the targeted destruction of tumors using magnetic nanoparticles. This is a form of nano-cancer therapy termed thermotherapy using magnetic nanoparticles (nanotherapy). It involves direct instillation of a magnetic fluid (specifically coated magnetic nanoparticles in an aqueous dispersion) into a tumor and subsequent heating in an alternating magnetic field. This technique allows targeting of almost any part of the human body with millimeter precision and maximum tumor-cell specificity at temperatures ranging from 43-46°C (hyperthermia) to 47-70°C (thermoablation). The technology has been applied in several clinical trials at the Charité Hospital Berlin and the Bundeswehrkrankenhaus Berlin since March 2003.

        2.1.1.10 Targeted Cell Destruction

NanoBiodrugs, developed by the company Nanobiotix, precisely target abnormal cells and destroy them through the controlled generation of physical or chemical reactions triggered by external activation.

NanoBiodrugs are nanoparticles with a controlled diameter smaller than 100 nanometers (or 1000 Angstroms). The core of the nanoparticle is a prodrug in an inactive form which can subsequently be activated to generate the therapeutic effect. The surface of the NanoBiodrug contains a specific recognition bioagent, enabling molecular targeting. This targeting directs the prodrug towards the pathological cells or tissues. After the NanoBiodrug accumulates in the target tissues, an external physical stimulus is applied that generates a local and physical therapeutic effect destroying the pathological cells. This stimulus is achieved by a magnetic field similar to that of an MRI machine, or by a laser or other energy field. So far, both the accuracy of the targeting and the tolerance of the NanoBiodrugs currently under development have been demostrated both in vitro and in vivo. Experiments have validated the concept of cell destruction through external activation and the absolute control of this process, with a correlation between time of activation and cell destruction. Promising large-animal studies on various cancer models and different compounds are currently under way.

        2.1.1.11 Nanoshells

AuroShell microparticles, developed by the company Nanospectra Biosciences, are a new type of optically tunable particle composed of a dielectric core coated with an ultra-thin metallic layer. When this core-shell structure is smaller than a wavelength of light, common materials have fundamentally "new" properties which open up new commercial applications. For oncology applications, Nanospectra uses a silica core surrounded by an ultra-thin gold shell. The total diameter of the particle is approximately twice the size of a virus.

Nanospectra is using these Auroshell particles to develop a therapy broadly applicable to virtually all solid tumors; the object is to selectively destroy these tumors. AuroShell microparticles can be made either to preferentially absorb or scatter light by varying the absolute size of the particle relative to the wavelength of the light at their optical resonance. For cancer applications, AuroShell microparticles of the type designed to absorb near-infrared wavelengths are used. Metals convert absorbed light into heat with a high efficiency (to illustrate, metal surfaces exposed to sunlight become very hot in the summer). Thus, AuroShell microparticles become a very specific heat generator within a tumor, destroying the tumor from within.

The company intends to seek FDA approval to commence a human trial for the treatment of head and neck cancers in 2006. Other cancer applications will be developed after these initial trials.

Tags: medtech, cancer, nanotechnology