BioCer Entwicklungs GmbH is a young and innovative company. Now on the basis of its comprehensive knowledge our developer team succeeded to provide health care with two seminal products according to the model of the nature.
With the help of a nanotechnological surface coating, implant materials are modified in a way that the medical devices grow in faster and more optimized. These biocom-patible coatings are now applied for the first time to polymer meshes, which are used as soft tissue reinforcement for hernia repair. In cooperation with experts from the textile branch BioCer Entwicklungs GmbH managed to develop a medical device which fulfills together with its optimized surface all demands of a modern mesh im-plant.
Also the development of our innovative hemostatic powder HaemoCer® was per-formed according to nature. HaemoCer® consists of plant based particles with an extremely high hygroscopicity, so that the natural coagulation cascade is accelerated. Hemostasis occurs within short time and HaemoCer® will be completely absorbed from the body within a few days.
With its new products BioCer Entwicklungs GmbH supports the surgeon as well as the patient in healing and restoration of the health.
Click Thumbnail Below for Presentation (note this presentation has been updated at the companies request)
BIOCER ENTWICKLUNGS-GMBH
Ludwig-Thoma Straße 36c
95447 Bayreuth
Telefone: +49 (0) 921 78 77 70 0
Telefax: +49 (0) 921 78 77 70 79
info@biocer-gmbh.de
Saturday, October 9, 2010
Friday, October 8, 2010
Arterial Closure Device Recommendations
The number and quality of clinical studies on arterial closure devices for cardiovascular procedures limits their widespread use, but new recommendations issued by the American Heart Association are intended to aid cardiologists considering use of these technologies. The recommendations were published online Oct. 4 in Circulation.
(HealthDay News) — The number and quality of clinical studies on arterial closure devices (ACDs) for cardiovascular procedures limits their widespread use, but new recommendations issued by the American Heart Association are intended to aid cardiologists considering use of these technologies. The recommendations were published online Oct. 4 in Circulation.
Manesh R. Patel, M.D., chair of the American Heart Association writing committee issuing the statement, and colleagues summarized the current state of vascular access, including patient risks, the evidence for use of various ACDs, and recommendations for their use. Seven million invasive cardiovascular procedures are performed each year, with numbers expected to increase in the future, and vascular access complications may be as high as 6 percent, the authors write.
After an extensive literature review of both passive and active closure devices, the committee issued five recommendations regarding ACD use. According to the recommendations, patients considered for use of femoral ACDs should undergo a femoral angiogram to ensure anatomic suitability for their use; facilities using manual compression should aim to achieve low vascular complication rates (below 1 percent); ACDs should not be used routinely, but can reasonably be used for faster hemostasis, and possibly improved patient comfort, as long as risks are weighed against benefits; and data on complications should be systematically collected via registry and reported to the U.S. Food and Drug Administration. Click Thumbnail below to view.
(HealthDay News) — The number and quality of clinical studies on arterial closure devices (ACDs) for cardiovascular procedures limits their widespread use, but new recommendations issued by the American Heart Association are intended to aid cardiologists considering use of these technologies. The recommendations were published online Oct. 4 in Circulation.
Manesh R. Patel, M.D., chair of the American Heart Association writing committee issuing the statement, and colleagues summarized the current state of vascular access, including patient risks, the evidence for use of various ACDs, and recommendations for their use. Seven million invasive cardiovascular procedures are performed each year, with numbers expected to increase in the future, and vascular access complications may be as high as 6 percent, the authors write.
After an extensive literature review of both passive and active closure devices, the committee issued five recommendations regarding ACD use. According to the recommendations, patients considered for use of femoral ACDs should undergo a femoral angiogram to ensure anatomic suitability for their use; facilities using manual compression should aim to achieve low vascular complication rates (below 1 percent); ACDs should not be used routinely, but can reasonably be used for faster hemostasis, and possibly improved patient comfort, as long as risks are weighed against benefits; and data on complications should be systematically collected via registry and reported to the U.S. Food and Drug Administration. Click Thumbnail below to view.
Romed to Distribute Z-Medica QuikClot Products for the First Time to Hospitals in Belgium
WALLINGFORD, Conn.--(BUSINESS WIRE)--Z-Medica Corporation, a medical device company developing innovative hemostatic agents, today announced that it has signed an exclusive distribution agreement with Romed, a medical device distribution company focused on providing products and services to cardiac surgery, general surgery and anesthesia professionals. Romed will have the exclusive rights to sell and distribute Z-Medica’s full line of QuikClot® hemostatic agents to hospitals and healthcare professionals throughout Belgium.
QuikClot products received CE Mark from the European Union in November 2009 and the company has been negotiating distribution agreements with a series of best-of-breed medical device distributors such as Romed in European markets since then.
“We are pleased to enter the Belgium market through our partner Romed, one of the most well -respected medical device distributors in the country,” said Brian Herrman, Chief Executive Officer, Z-Medica. “Through the success of this agreement we take another step closer to our goal of global distribution of QuikClot’s growing line of life-saving hemostatic gauze products.”
QuikClot is a surgical gauze impregnated with kaolin, an inert mineral with no known contraindications, and can achieve hemostasis in severe bleeding situations in as little as three minutes. QuikClot is widely used throughout several clinical specialties, including cardiology, interventional radiology, critical care, dermatology, emergency medicine, orthopedics and OB/Gyn, and after months of testing against 12 other hemostatic products in the marketplace, the military version of the kaolin gauze (“Combat Gauze”) was chosen as the exclusive product for use by all US Military Forces in 2008. It continues to be the exclusive product used by all USA military forces for first line treatment of bleeding hemorrhage.
“We are pleased to be able to offer healthcare professionals and emergency personal throughout Belgium QuikClot’s line of innovative life-saving hemostatic dressings,” said Patrick Rosa, CEO of Romed. “We are impressed with what we have seen from QuikClot and we anticipate strong demand throughout our network of medical care providers.”
The QuikClot line of products to be distributed by Romed includes:
QuikClot® Combat Gauze™ is a soft, white, sterile, nonwoven 3” by 12 feet rolled or z-folded gauze impregnated with kaolin. Each roll of QuikClot Combat Gauze is individually wrapped in an easy rip, military grade foil pouch. Indicated for temporary external control of traumatic bleeding, QuikClot Combat Gauze is flexible and pliable and contours to all wounds. Recommended as the number one hemostatic agent by the COTCCC (Committee on Tactical Combat Casualty Care Committee), QuikClot Combat Gauze is the only product carried by all branches of the US Military to control life-threatening hemorrhage.
QuikClot® Emergency Dressing™ is an easy-to-use dressing which can achieve hemostasis in as little as three minutes, helping to prevent loss of life and limb. Because QuikClot requires very little training to administer, it can be effectively used by medical personnel, civilian first-responders and medical professionals in the field and in clinical environments. This dressing comes in various sizes, including a 4-ply 4” by 4” (10cm x 10cm) and a 6-ply 2”x2” (5cm x 5cm) format.
QuikClot® Interventional™ Hemostatic Bandage consists of a soft, white, double sterile, hydrophilic pad impregnated with kaolin. It is double-wrapped in a blister package and foil pouch for aseptic technique. QuikClot Interventional Hemostatic Bandage is applied topically as an adjunct to manual compression and is indicated for the local management and control of external bleeding from vascular access sites and percutantous catheters or tubes utilizing sheaths up to 12 Fr.
QuikClot® Pad™ consists of a soft, white, double sterile, three-ply 12”x12” (30cm x 30cm) pad impregnated with kaolin. It is double-wrapped in a peelable foil package for aseptic technique. QuikClot Trauma Pad is indicated for temporary external use to control traumatic bleeding and is also x-ray detectable to ensure proper removal.
QuikClot products received CE Mark from the European Union in November 2009 and the company has been negotiating distribution agreements with a series of best-of-breed medical device distributors such as Romed in European markets since then.
“We are pleased to enter the Belgium market through our partner Romed, one of the most well -respected medical device distributors in the country,” said Brian Herrman, Chief Executive Officer, Z-Medica. “Through the success of this agreement we take another step closer to our goal of global distribution of QuikClot’s growing line of life-saving hemostatic gauze products.”
QuikClot is a surgical gauze impregnated with kaolin, an inert mineral with no known contraindications, and can achieve hemostasis in severe bleeding situations in as little as three minutes. QuikClot is widely used throughout several clinical specialties, including cardiology, interventional radiology, critical care, dermatology, emergency medicine, orthopedics and OB/Gyn, and after months of testing against 12 other hemostatic products in the marketplace, the military version of the kaolin gauze (“Combat Gauze”) was chosen as the exclusive product for use by all US Military Forces in 2008. It continues to be the exclusive product used by all USA military forces for first line treatment of bleeding hemorrhage.
“We are pleased to be able to offer healthcare professionals and emergency personal throughout Belgium QuikClot’s line of innovative life-saving hemostatic dressings,” said Patrick Rosa, CEO of Romed. “We are impressed with what we have seen from QuikClot and we anticipate strong demand throughout our network of medical care providers.”
The QuikClot line of products to be distributed by Romed includes:
QuikClot® Combat Gauze™ is a soft, white, sterile, nonwoven 3” by 12 feet rolled or z-folded gauze impregnated with kaolin. Each roll of QuikClot Combat Gauze is individually wrapped in an easy rip, military grade foil pouch. Indicated for temporary external control of traumatic bleeding, QuikClot Combat Gauze is flexible and pliable and contours to all wounds. Recommended as the number one hemostatic agent by the COTCCC (Committee on Tactical Combat Casualty Care Committee), QuikClot Combat Gauze is the only product carried by all branches of the US Military to control life-threatening hemorrhage.
QuikClot® Emergency Dressing™ is an easy-to-use dressing which can achieve hemostasis in as little as three minutes, helping to prevent loss of life and limb. Because QuikClot requires very little training to administer, it can be effectively used by medical personnel, civilian first-responders and medical professionals in the field and in clinical environments. This dressing comes in various sizes, including a 4-ply 4” by 4” (10cm x 10cm) and a 6-ply 2”x2” (5cm x 5cm) format.
QuikClot® Interventional™ Hemostatic Bandage consists of a soft, white, double sterile, hydrophilic pad impregnated with kaolin. It is double-wrapped in a blister package and foil pouch for aseptic technique. QuikClot Interventional Hemostatic Bandage is applied topically as an adjunct to manual compression and is indicated for the local management and control of external bleeding from vascular access sites and percutantous catheters or tubes utilizing sheaths up to 12 Fr.
QuikClot® Pad™ consists of a soft, white, double sterile, three-ply 12”x12” (30cm x 30cm) pad impregnated with kaolin. It is double-wrapped in a peelable foil package for aseptic technique. QuikClot Trauma Pad is indicated for temporary external use to control traumatic bleeding and is also x-ray detectable to ensure proper removal.
Cytomedix Secures $13 Million in Committed Funding
GAITHERSBURG, Md., Oct 8, 2010 (GlobeNewswire via COMTEX) -- Cytomedix, Inc. (GTF 0.44, -0.03, -5.75%), a leading developer of biologically active regenerative therapies for wound care, inflammation and angiogenesis, announced today that the Company has secured approximately $13 million in current and future funding via a registered direct offering and commitments under two separate equity purchase agreements.
The Company has entered into a securities purchase agreement with certain existing shareholders and a new institutional investor for the sale of 3,727,677 shares of its common stock in a registered direct offering priced at $0.40 per share for non-affiliates and $0.53 for affiliates. In addition, warrants to purchase an aggregate of 1,863,839 shares of common stock will be issued to the investors. The warrants are exercisable beginning April 6, 2011, expire five years after initially exercisable and have an exercise price of $0.60 per share. Lincoln Park Capital Fund, LLC ("LPC" or "Lincoln Park") led the transaction with a $500,000 investment in this registered direct offering. Gross proceeds of the offering, before agent fees and offering expenses, are expected to be approximately $1.50 million. Subject to customary closing conditions, this transaction is expected to close on or before October 11, 2010. These securities were offered through a prospectus supplement pursuant to the Company's effective shelf registration statement and base prospectus contained therein.
"We are pleased to have secured this funding as it provides us with the immediate capital to honor our commitment to the Sorin Group and provides us incremental capital to pursue our business strategy," said Martin P. Rosendale, President and Chief Executive Officer. "Over 35% of the capital raised came from significant shareholders, insiders, and employees. We appreciate the continued support of these existing shareholders and welcome our new ones. "
In addition, the Company entered into two separate purchase agreements with Lincoln Park. The first is for $10 million for which a new registration statement will be filed and the second is for $1.5 million using the existing shelf registration. The pricing terms, maturity, and other relevant economic terms are consistent across the two agreements.
Under the existing shelf registration statement, in the case of the $1.5 million purchase agreement, and after the SEC has declared the registration statement effective, in the case of the $10 million purchase agreement, the Company has the right over the 25 month period to sell 150,000 shares of common stock to LPC every other business day. The Company will control the timing and amount of any sales of shares to LPC and in neither agreement, is the Company obligated at any time to sell shares to LPC. Should the Company elect to sell shares to LPC under either of the agreements, the purchase price would be fixed on the date of sale and based on the prevailing market prices of the Company's shares for a period immediately preceding the sale.
In consideration for entering into the $10 million purchase agreement, the Company issued 305,944 of unregistered shares of common stock. The Company further agreed to issue up to 428,322 shares of common stock on a pro-rata basis as commitment shares in connection with LPC purchases up to $7 million of the aggregate $11.5 million commitment amount. Sale or transfer of the commitment shares, when they are issued, is prohibited until the expiration of the term or Company termination of the agreement. There are no warrants associated with any purchases under the agreement and the agreements prohibit any shorting or hedging by LPC.
The net proceeds from these financings will be used for continuing product development, sales and marketing, and general corporate purposes.
Mr. Rosendale further commented, "We are pleased by the commitment from Lincoln Park, a fundamentally oriented investor. We are under no obligation to utilize the facility, but plan to use any proceeds to support and accelerate the development of our regenerative therapies and to expand our marketing efforts."
A more detailed description of the agreements with Lincoln Park is set forth in the Company's current Report on Form 8-K, as filed earlier today with the SEC.
This press release does not constitute an offer to sell or a solicitation of an offer to buy the securities in this offering, nor will there be any sale of these securities in any jurisdiction in which such offer solicitation or sale are unlawful prior to registration or qualification under securities laws of any such jurisdiction.
The Company has entered into a securities purchase agreement with certain existing shareholders and a new institutional investor for the sale of 3,727,677 shares of its common stock in a registered direct offering priced at $0.40 per share for non-affiliates and $0.53 for affiliates. In addition, warrants to purchase an aggregate of 1,863,839 shares of common stock will be issued to the investors. The warrants are exercisable beginning April 6, 2011, expire five years after initially exercisable and have an exercise price of $0.60 per share. Lincoln Park Capital Fund, LLC ("LPC" or "Lincoln Park") led the transaction with a $500,000 investment in this registered direct offering. Gross proceeds of the offering, before agent fees and offering expenses, are expected to be approximately $1.50 million. Subject to customary closing conditions, this transaction is expected to close on or before October 11, 2010. These securities were offered through a prospectus supplement pursuant to the Company's effective shelf registration statement and base prospectus contained therein.
"We are pleased to have secured this funding as it provides us with the immediate capital to honor our commitment to the Sorin Group and provides us incremental capital to pursue our business strategy," said Martin P. Rosendale, President and Chief Executive Officer. "Over 35% of the capital raised came from significant shareholders, insiders, and employees. We appreciate the continued support of these existing shareholders and welcome our new ones. "
In addition, the Company entered into two separate purchase agreements with Lincoln Park. The first is for $10 million for which a new registration statement will be filed and the second is for $1.5 million using the existing shelf registration. The pricing terms, maturity, and other relevant economic terms are consistent across the two agreements.
Under the existing shelf registration statement, in the case of the $1.5 million purchase agreement, and after the SEC has declared the registration statement effective, in the case of the $10 million purchase agreement, the Company has the right over the 25 month period to sell 150,000 shares of common stock to LPC every other business day. The Company will control the timing and amount of any sales of shares to LPC and in neither agreement, is the Company obligated at any time to sell shares to LPC. Should the Company elect to sell shares to LPC under either of the agreements, the purchase price would be fixed on the date of sale and based on the prevailing market prices of the Company's shares for a period immediately preceding the sale.
In consideration for entering into the $10 million purchase agreement, the Company issued 305,944 of unregistered shares of common stock. The Company further agreed to issue up to 428,322 shares of common stock on a pro-rata basis as commitment shares in connection with LPC purchases up to $7 million of the aggregate $11.5 million commitment amount. Sale or transfer of the commitment shares, when they are issued, is prohibited until the expiration of the term or Company termination of the agreement. There are no warrants associated with any purchases under the agreement and the agreements prohibit any shorting or hedging by LPC.
The net proceeds from these financings will be used for continuing product development, sales and marketing, and general corporate purposes.
Mr. Rosendale further commented, "We are pleased by the commitment from Lincoln Park, a fundamentally oriented investor. We are under no obligation to utilize the facility, but plan to use any proceeds to support and accelerate the development of our regenerative therapies and to expand our marketing efforts."
A more detailed description of the agreements with Lincoln Park is set forth in the Company's current Report on Form 8-K, as filed earlier today with the SEC.
This press release does not constitute an offer to sell or a solicitation of an offer to buy the securities in this offering, nor will there be any sale of these securities in any jurisdiction in which such offer solicitation or sale are unlawful prior to registration or qualification under securities laws of any such jurisdiction.
U.Va. Start-Up HemoSonics Secures $2M in Federal Funding
HemoSonics LLC, a medical device company founded on technology developed at the University of Virginia, recently secured three federal grants worth nearly $2 million.
The funding came from two highly competitive programs administered by the U.S. Small Business Administration. Small Business Innovation Research, known as SBIR, and Small Business Technology Transfer, known as STTR, seek to further economic development by awarding funding from participating federal agencies to small businesses conducting high-tech research with commercial potential.
Founded in 2004 by U.Va. researchers William F. Walker, Francesco Viola and Michael B. Lawrence, HemoSonics is developing technology to rapidly assess patients' blood for abnormal clotting characteristics. This information could allow physicians to respond more effectively to patients with excessive bleeding or overactive clotting in the operating room, the emergency room and many other clinical settings.
"Most people don't realize that bleeding and blood clots are the main causes of death in the developed world," said Walker, president of HemoSonics and U.Va. professor of biomedical engineering and of electrical and computer engineering. "Heart attack, stroke and pulmonary embolism are all conditions that kill via a blood clot, and studies indicate that pulmonary embolism kills more people than breast cancer.
"Our technology will shed new light on these problems and, we believe, have a notable impact on human health."
HemoSonics' platform technology, sonorheometry, is a novel, ultrasound-based tool developed by the researchers to ascertain specific information about a patient's blood. In determining the time it takes blood to clot, the firmness of a clot and the rates at which a clot forms and dissolves, this technology could enable physicians to identify specific clotting defects and treat them effectively.
The U.Va. Patent Foundation has filed two international patent applications on this technology, which it licensed to HemoSonics for further development and commercialization.
"The research and innovations developed at the University of Virginia are of the highest caliber," said Miette H. Michie, executive director and CEO of the Patent Foundation. "HemoSonics' technology has the potential to have a dramatic, positive impact on patients, and we are proud to be a partner in bringing this technology forward."
Since July, HemoSonics has been awarded nearly $2 million in federal funding through the SBIR and STTR programs, including $1.6 million from the National Institute of Diabetes and Digestive and Kidney Diseases; $298,000 from the National Heart, Lung and Blood Institute; and $70,000 from the Office of Naval Research.
Thomas C. Skalak, U.Va. vice president for research, said such major federal awards are critical to new technology-based ventures. "We are very proud to see this U.Va. research being moved to the marketplace, where it will have an impact on people's health and potentially create new jobs," he said.
He added, "The accelerated pace of HemoSonics' growth is a tribute to the vision and persistence of its technical leaders: Bill Walker, Francesco Viola and Mike Lawrence."
With its new funding, HemoSonics plans to develop a point-of-care diagnostic device called the Global Hemostasis Analyzer, which will bring the technology to the patient's bedside and seek to eliminate the guesswork associated with treating bleeding conditions.
"In patient care settings, bleeding patients are often treated by blind administration of blood products," said Viola, HemoSonics' vice president of engineering and technology and research assistant professor of biomedical engineering at U.Va. "This process is clearly inefficient, often resulting in wasted resources, increased costs and even harmful consequences for the patient.
"Our initial product will quickly provide the necessary information to guide transfusion, therefore saving lives, money and resources," added Viola, who is the principal investigator of the grants.
This technology has also been funded by the Wallace H. Coulter Translational Research Partnership, the National Institutes of Health and angel investors.
Skalak said, "The researchers' original work inside of the University was a team effort that exemplifies the U.Va. translational research partnership with the Wallace H. Coulter Foundation, which is committed to realizing the dream of science serving humanity."
The funding came from two highly competitive programs administered by the U.S. Small Business Administration. Small Business Innovation Research, known as SBIR, and Small Business Technology Transfer, known as STTR, seek to further economic development by awarding funding from participating federal agencies to small businesses conducting high-tech research with commercial potential.
Founded in 2004 by U.Va. researchers William F. Walker, Francesco Viola and Michael B. Lawrence, HemoSonics is developing technology to rapidly assess patients' blood for abnormal clotting characteristics. This information could allow physicians to respond more effectively to patients with excessive bleeding or overactive clotting in the operating room, the emergency room and many other clinical settings.
"Most people don't realize that bleeding and blood clots are the main causes of death in the developed world," said Walker, president of HemoSonics and U.Va. professor of biomedical engineering and of electrical and computer engineering. "Heart attack, stroke and pulmonary embolism are all conditions that kill via a blood clot, and studies indicate that pulmonary embolism kills more people than breast cancer.
"Our technology will shed new light on these problems and, we believe, have a notable impact on human health."
HemoSonics' platform technology, sonorheometry, is a novel, ultrasound-based tool developed by the researchers to ascertain specific information about a patient's blood. In determining the time it takes blood to clot, the firmness of a clot and the rates at which a clot forms and dissolves, this technology could enable physicians to identify specific clotting defects and treat them effectively.
The U.Va. Patent Foundation has filed two international patent applications on this technology, which it licensed to HemoSonics for further development and commercialization.
"The research and innovations developed at the University of Virginia are of the highest caliber," said Miette H. Michie, executive director and CEO of the Patent Foundation. "HemoSonics' technology has the potential to have a dramatic, positive impact on patients, and we are proud to be a partner in bringing this technology forward."
Since July, HemoSonics has been awarded nearly $2 million in federal funding through the SBIR and STTR programs, including $1.6 million from the National Institute of Diabetes and Digestive and Kidney Diseases; $298,000 from the National Heart, Lung and Blood Institute; and $70,000 from the Office of Naval Research.
Thomas C. Skalak, U.Va. vice president for research, said such major federal awards are critical to new technology-based ventures. "We are very proud to see this U.Va. research being moved to the marketplace, where it will have an impact on people's health and potentially create new jobs," he said.
He added, "The accelerated pace of HemoSonics' growth is a tribute to the vision and persistence of its technical leaders: Bill Walker, Francesco Viola and Mike Lawrence."
With its new funding, HemoSonics plans to develop a point-of-care diagnostic device called the Global Hemostasis Analyzer, which will bring the technology to the patient's bedside and seek to eliminate the guesswork associated with treating bleeding conditions.
"In patient care settings, bleeding patients are often treated by blind administration of blood products," said Viola, HemoSonics' vice president of engineering and technology and research assistant professor of biomedical engineering at U.Va. "This process is clearly inefficient, often resulting in wasted resources, increased costs and even harmful consequences for the patient.
"Our initial product will quickly provide the necessary information to guide transfusion, therefore saving lives, money and resources," added Viola, who is the principal investigator of the grants.
This technology has also been funded by the Wallace H. Coulter Translational Research Partnership, the National Institutes of Health and angel investors.
Skalak said, "The researchers' original work inside of the University was a team effort that exemplifies the U.Va. translational research partnership with the Wallace H. Coulter Foundation, which is committed to realizing the dream of science serving humanity."
Thursday, October 7, 2010
The Business of Recombinant Protein Production
Since the development of recombinant technology in the late 1970s, the use of recombinant proteins in therapeutics has become an attractive strategy for altering the biology of disease progression. In the early 1980s, recombinant human insulin from Escherichia colibecame the first recombinant pharmaceutical to enter the market. Development of several growth hormones produced in bacteria followed, as did production of monoclonal antibodies such as infliximab and ritxumiab from mammalian cell lines. By January of 2009, the number of protein-based recombinant pharmaceuticals licensed by the U.S. Food and Drug Administration and European Medicines Agency reached 151.1
Although recombinant protein technology provides a wealth of commercial opportunities, bringing a recombinant protein to the marketplace requires a substantial investment of time and resources. Because the synthesis and purification processes are technically complex and vary with each protein, estimating resources and timelines can be challenging at best. Yet for small companies, meeting these challenges is vital, says Vladimir Kostyukovsky, senior technical manager at Kymanox, Inc. “With start ups, you need to hit your milestones by a certain date, or you’re out of business.”
The most common expression systems for recombinant pharmaceuticals are derived from bacteria (usually E. coli), yeast (usually Saccharomyces cerevisiae), or mammalian cells. Key properties of individual expression systems affect convenience and quality of production. Characteristics inherent to a target protein also affect production capabilities. Making the transition from producing a laboratory stock of protein to commercial quantities also requires strategic planning and flexibility.
Protein synthesis and purification Microbial systems versus mammalian systems
Recombinant protein production in microbial systems (mainly bacteria or yeast) tends to be faster and cheaper than in mammalian systems. The robust cellular structure of bacteria and yeast make them amenable to culturing, but mammalian cells—derived from multicellular organisms—are not adapted to survive outside the body and are thus sensitive to external conditions like shear stress and osmotic shock. Bacteria and yeast replicate every 20 minutes to 2 hours, while mammalian cells do so every 24 hours to 2 days. Mammalian cells require complex—often proprietary—media with amino acids. Bacterial cell medium consists of simple carbon and nitrogen sources and inorganic salts. The cost for bacterial cell media is 90% lower than for mammalian Chinese hamster ovary (CHO) media. Fermentation or bioreactor runs take 24 to 72 hours in bacteria or yeast versus 14 days to 3 weeks in CHO cells.
Yeast and mammalian cell lines have inherent mechanisms for secreting properly folded, active proteins in culture medium. In E. coli, synthesized protein accumulates internally, and cell lysis is required to isolate the target protein. The process of lysis releases intracellular contents such as proteases or endotoxins, which can decrease yield and complicate purification. Recently, a strain of the gram-positive Corynebacterium glutamicum, which does not have endotoxins, has been engineered to express correctly folded, active recombinant proteins directly into the extracellular fermentation broth.
The following characteristics of target proteins influence their likelihood of being expressed and purified in a functionally active state:
Protein size. Eukaryotic cells, such as mammalian and yeast, have the advantage of being able to express proteins of 200 to 250 kDa, the size of most monoclonal antibodies. In some cases, expression of proteins as large as 400 kDa is possible. In E. coli, it is difficult to obtain proteins larger than 60 kDa in soluble forms.
Protein complexity. The number of protein subunits is inversely related to the likelihood of functional expression. Again, eukaryotic cells have a greater advantage in producing fully assembled, functional, multidomain proteins. Monoclonal antibodies, which consist of 4 subunits, can be secreted by eukaryotic cells as fully assembled complexes. E. coli can be used to express multidomain proteins, but they often lack activity.
Glycosylation. Posttranslational addition of sugar motifs to proteins profoundly affects biological activity, function, clearance from circulation, and antigenicity. Patterns of glycosylation are highly species-specific, and mammalian cell lines have glycosylation repertoires most similar to humans.
Common Challenges
Potential complications lie at every step of the process of recombinant protein expression and purification. The complications vary with each specific protein, but because proteins share common motifs, certain technical pitfalls are encountered frequently.
Protein aggregation. Suboptimal conditions during protein expression, purification, or storage can alter structure and result in aggregation or loss of activity. In bacterial expression systems, intracellular accumulation of protein can lead to formation of inclusion body aggregates.
Aggregation can sometimes be reversed by adjusting media composition, growth temperature, inducer concentration, promoter strength, or plasmid copy number. However, inclusion bodies formed by proteins native to eukaryotes but produced in bacteria tend to be resistant to solubilization. Even proteins that are successfully solubilized can become denatured and thus require potentially complicated in vitro refolding processes.
Refolding. The process of refolding is often preceded by a partial purification to remove host cell proteins that could aggregate with the target protein. Because refolding techniques vary and are often empirical, the online database REFOLD provides refolding protocols that have been successful for a wide range of proteins.2
Proteolytic degration. Host proteases, which can degrade the target protein, are commonly active during cell disruption, as intracellular contents are released. Genetic engineering can be used to remove a host’s more active proteases.
Disulfide bond generation. Disulfide bridges, which stabilize protein structure, are often abundant in secreted proteins. As with refolding, disulfide bond generation and maintenance are achieved through empirical processes. Possible strategies include targeting a specific extracellular excretion pathway or overexpression of chaperones or foldases.
Contamination. Contaminants can originate from host cells or from growth medium. Contaminants can interfere with protein function or cause adverse reactions in human consumers, such as through human pathogens harbored in mammalian expression systems or endotoxins in gram-negative bacteria. The process of removing contaminants can be extensive—often involving several rounds of chromatography—and each additional step diminishes yield.
Making the Transition to Clinical Production
The early steps in developing a recombinant pharmaceutical often require multiple iterations to optimize expression and purification of functionally active protein. As development moves closer to commercialization, schedules, pricing, and other aspects of managing a supple chain become paramount. This transition from focusing on technical concerns to the context of the clinic and broader marketplace can be challenging.
Shailesh Maingi, CEO and president of Kineticos Life Sciences, suggests there are key issues to consider throughout the process of production. First, are you going to make the protein yourself or outsource production? “From a business perspective, this decision is probably the most critical,” Maingi says. “If you want to produce it yourself, there is a huge investment required, not only in money, but in time and resources. If you’re a small, virtual company, you’re almost always going to outsource. If you’re a large company, you’re almost always going to insource because you have the capability and you have the technology.”
Smaller companies have the option of producing a lab supply of protein that can be used in preclinical toxicology studies. Outsourcing for larger-scale production can be done prior to initiating clinical trials.
If you decide to outsource, how do you choose a vendor? At the stages of protein expression and purification, working with a vendor that is flexible in its approach is important, because it is impossible to predict how complex the process will be for a given protein. Any vendor should be able to provide a clear proof of concept and performance history of the technology. Cost, quality, and convenience are important considerations as well. During the expression phase, proximity to the vendor can provide convenience for evaluating efficiency and yield of the process.
In summary, while the path to producing a functionally active and meaningful recombinant pharmaceutical can lead to great commercial opportunity, it can also be plagued with technical pitfalls and failures. Careful consideration of various strategies at every step of the process can optimize use of time and resources.
Although recombinant protein technology provides a wealth of commercial opportunities, bringing a recombinant protein to the marketplace requires a substantial investment of time and resources. Because the synthesis and purification processes are technically complex and vary with each protein, estimating resources and timelines can be challenging at best. Yet for small companies, meeting these challenges is vital, says Vladimir Kostyukovsky, senior technical manager at Kymanox, Inc. “With start ups, you need to hit your milestones by a certain date, or you’re out of business.”
The most common expression systems for recombinant pharmaceuticals are derived from bacteria (usually E. coli), yeast (usually Saccharomyces cerevisiae), or mammalian cells. Key properties of individual expression systems affect convenience and quality of production. Characteristics inherent to a target protein also affect production capabilities. Making the transition from producing a laboratory stock of protein to commercial quantities also requires strategic planning and flexibility.
Protein synthesis and purification Microbial systems versus mammalian systems
Recombinant protein production in microbial systems (mainly bacteria or yeast) tends to be faster and cheaper than in mammalian systems. The robust cellular structure of bacteria and yeast make them amenable to culturing, but mammalian cells—derived from multicellular organisms—are not adapted to survive outside the body and are thus sensitive to external conditions like shear stress and osmotic shock. Bacteria and yeast replicate every 20 minutes to 2 hours, while mammalian cells do so every 24 hours to 2 days. Mammalian cells require complex—often proprietary—media with amino acids. Bacterial cell medium consists of simple carbon and nitrogen sources and inorganic salts. The cost for bacterial cell media is 90% lower than for mammalian Chinese hamster ovary (CHO) media. Fermentation or bioreactor runs take 24 to 72 hours in bacteria or yeast versus 14 days to 3 weeks in CHO cells.
Yeast and mammalian cell lines have inherent mechanisms for secreting properly folded, active proteins in culture medium. In E. coli, synthesized protein accumulates internally, and cell lysis is required to isolate the target protein. The process of lysis releases intracellular contents such as proteases or endotoxins, which can decrease yield and complicate purification. Recently, a strain of the gram-positive Corynebacterium glutamicum, which does not have endotoxins, has been engineered to express correctly folded, active recombinant proteins directly into the extracellular fermentation broth.
The following characteristics of target proteins influence their likelihood of being expressed and purified in a functionally active state:
Protein size. Eukaryotic cells, such as mammalian and yeast, have the advantage of being able to express proteins of 200 to 250 kDa, the size of most monoclonal antibodies. In some cases, expression of proteins as large as 400 kDa is possible. In E. coli, it is difficult to obtain proteins larger than 60 kDa in soluble forms.
Protein complexity. The number of protein subunits is inversely related to the likelihood of functional expression. Again, eukaryotic cells have a greater advantage in producing fully assembled, functional, multidomain proteins. Monoclonal antibodies, which consist of 4 subunits, can be secreted by eukaryotic cells as fully assembled complexes. E. coli can be used to express multidomain proteins, but they often lack activity.
Glycosylation. Posttranslational addition of sugar motifs to proteins profoundly affects biological activity, function, clearance from circulation, and antigenicity. Patterns of glycosylation are highly species-specific, and mammalian cell lines have glycosylation repertoires most similar to humans.
Common Challenges
Potential complications lie at every step of the process of recombinant protein expression and purification. The complications vary with each specific protein, but because proteins share common motifs, certain technical pitfalls are encountered frequently.
Protein aggregation. Suboptimal conditions during protein expression, purification, or storage can alter structure and result in aggregation or loss of activity. In bacterial expression systems, intracellular accumulation of protein can lead to formation of inclusion body aggregates.
Aggregation can sometimes be reversed by adjusting media composition, growth temperature, inducer concentration, promoter strength, or plasmid copy number. However, inclusion bodies formed by proteins native to eukaryotes but produced in bacteria tend to be resistant to solubilization. Even proteins that are successfully solubilized can become denatured and thus require potentially complicated in vitro refolding processes.
Refolding. The process of refolding is often preceded by a partial purification to remove host cell proteins that could aggregate with the target protein. Because refolding techniques vary and are often empirical, the online database REFOLD provides refolding protocols that have been successful for a wide range of proteins.2
Proteolytic degration. Host proteases, which can degrade the target protein, are commonly active during cell disruption, as intracellular contents are released. Genetic engineering can be used to remove a host’s more active proteases.
Disulfide bond generation. Disulfide bridges, which stabilize protein structure, are often abundant in secreted proteins. As with refolding, disulfide bond generation and maintenance are achieved through empirical processes. Possible strategies include targeting a specific extracellular excretion pathway or overexpression of chaperones or foldases.
Contamination. Contaminants can originate from host cells or from growth medium. Contaminants can interfere with protein function or cause adverse reactions in human consumers, such as through human pathogens harbored in mammalian expression systems or endotoxins in gram-negative bacteria. The process of removing contaminants can be extensive—often involving several rounds of chromatography—and each additional step diminishes yield.
Making the Transition to Clinical Production
The early steps in developing a recombinant pharmaceutical often require multiple iterations to optimize expression and purification of functionally active protein. As development moves closer to commercialization, schedules, pricing, and other aspects of managing a supple chain become paramount. This transition from focusing on technical concerns to the context of the clinic and broader marketplace can be challenging.
Shailesh Maingi, CEO and president of Kineticos Life Sciences, suggests there are key issues to consider throughout the process of production. First, are you going to make the protein yourself or outsource production? “From a business perspective, this decision is probably the most critical,” Maingi says. “If you want to produce it yourself, there is a huge investment required, not only in money, but in time and resources. If you’re a small, virtual company, you’re almost always going to outsource. If you’re a large company, you’re almost always going to insource because you have the capability and you have the technology.”
Smaller companies have the option of producing a lab supply of protein that can be used in preclinical toxicology studies. Outsourcing for larger-scale production can be done prior to initiating clinical trials.
If you decide to outsource, how do you choose a vendor? At the stages of protein expression and purification, working with a vendor that is flexible in its approach is important, because it is impossible to predict how complex the process will be for a given protein. Any vendor should be able to provide a clear proof of concept and performance history of the technology. Cost, quality, and convenience are important considerations as well. During the expression phase, proximity to the vendor can provide convenience for evaluating efficiency and yield of the process.
In summary, while the path to producing a functionally active and meaningful recombinant pharmaceutical can lead to great commercial opportunity, it can also be plagued with technical pitfalls and failures. Careful consideration of various strategies at every step of the process can optimize use of time and resources.
Source: Joel White, Business Manager, Biotechnology; Ajinomoto AminoScience, Raleigh, North Carolina
Drug Discovery & Development - October 07, 2010
Ceremed's AOC® Awarded Best New Technology in Biomaterials for Spine Care in 2010
ORLANDO, Fla., Oct. 5 /PRNewswire/ -- Ceremed's patented implantable polymer material known as AOC® won Orthopedics This Week's annual award for Best New Technology for Spine Care in 2010 in the Biomaterials category. AOC® was selected winner by a panel of neurosurgeons, orthopedic surgeons and veteran clinical buyers, based on the technology's originality, clinical relevance, and the likelihood that it will improve current standards of care.
"I am proud of AOC®'s success," said Ceremed's chairman, Tadeusz Wellisz, M.D. "AOC® is a versatile technology that has been well received by physicians and scientists. This award serves as continued validation for AOC® as Ceremed strives to develop more products that aid the surgeon and improve the patient's quality of care."
About AOC®:
AOC® is Ceremed's proprietary implantable polymer material. It is composed of a blend of Alkylene Oxide Copolymers that are commonly used in the medical field. This unique blend is an ideal carrier because it dissolves without swelling and is eliminated from the body within 48 hours. Unlike most resorbable polymers, AOC® does not require metabolic or inflammatory processes to break down. AOC® is synthetic and can be formulated in a range of consistencies with a unique combination of properties, including anhydrous formulations, making it an ideal carrier for compounds that are not stable in aqueous solutions. The material is proving to be a versatile, soluble carrier that delivers a broad range of therapeutics to the surgical site without compromising the healing process.
AOC® is already used in spinal fusion products, as a soluble coating system for orthopedic and neurosurgical implants, and for bone hemostasis. Ceremed is able to custom-manufacture compounds using any OEM proprietary material in combination with the AOC® biomaterial.
About Ceremed:
Ceremed, Inc. is a privately held medical device corporation founded in Los Angeles, California in 2002. Ceremed's mission is to utilize its proprietary implantable polymer formulations to enhance the "Standard of Care" by replacing aging and possibly harmful materials with safe and effective materials and devices that provide for better patient outcomes by improving healing and reducing post-surgical complications. The company manufactures a variety of surgical implantable devices marketed both directly and through partnership licensing and manufacturing arrangements. Ceremed's signature product is the highly successful Ostene® Bone Hemostasis material (www.ostene.com).
"I am proud of AOC®'s success," said Ceremed's chairman, Tadeusz Wellisz, M.D. "AOC® is a versatile technology that has been well received by physicians and scientists. This award serves as continued validation for AOC® as Ceremed strives to develop more products that aid the surgeon and improve the patient's quality of care."
About AOC®:
AOC® is Ceremed's proprietary implantable polymer material. It is composed of a blend of Alkylene Oxide Copolymers that are commonly used in the medical field. This unique blend is an ideal carrier because it dissolves without swelling and is eliminated from the body within 48 hours. Unlike most resorbable polymers, AOC® does not require metabolic or inflammatory processes to break down. AOC® is synthetic and can be formulated in a range of consistencies with a unique combination of properties, including anhydrous formulations, making it an ideal carrier for compounds that are not stable in aqueous solutions. The material is proving to be a versatile, soluble carrier that delivers a broad range of therapeutics to the surgical site without compromising the healing process.
AOC® is already used in spinal fusion products, as a soluble coating system for orthopedic and neurosurgical implants, and for bone hemostasis. Ceremed is able to custom-manufacture compounds using any OEM proprietary material in combination with the AOC® biomaterial.
About Ceremed:
Ceremed, Inc. is a privately held medical device corporation founded in Los Angeles, California in 2002. Ceremed's mission is to utilize its proprietary implantable polymer formulations to enhance the "Standard of Care" by replacing aging and possibly harmful materials with safe and effective materials and devices that provide for better patient outcomes by improving healing and reducing post-surgical complications. The company manufactures a variety of surgical implantable devices marketed both directly and through partnership licensing and manufacturing arrangements. Ceremed's signature product is the highly successful Ostene® Bone Hemostasis material (www.ostene.com).
CryoLife Gets Japanese Regulatory Approval For BioGlue
(RTTNews) - CryoLife, Inc. (CRY: News) said its BioGlue Surgical Adhesive has received Shonin approval from the Japanese Ministry of Health, Labor and Welfare, or MHLW, for use in the repair of aortic dissections.
CryoLife's partner Century Medical, Inc., or CMI, will distribute BioGlue in Japan for use in this subset of cardiac surgery. Prior to distribution, MHLW will need to complete certain additional steps, most notably an on-site inspection of CryoLife pursuant to Japanese Quality Management System requirements and required product reimbursement paperwork for Japanese authorities.
As a result, management estimates that distribution in Japan will begin in the first half of 2011. CryoLife will remain the exclusive supplier of BioGlue to CMI.
CryoLife's partner Century Medical, Inc., or CMI, will distribute BioGlue in Japan for use in this subset of cardiac surgery. Prior to distribution, MHLW will need to complete certain additional steps, most notably an on-site inspection of CryoLife pursuant to Japanese Quality Management System requirements and required product reimbursement paperwork for Japanese authorities.
As a result, management estimates that distribution in Japan will begin in the first half of 2011. CryoLife will remain the exclusive supplier of BioGlue to CMI.
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