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1、FORM 10-K INTEGRA LIFESCIENCES HOLDINGS CORP(Annual Report)Filed 3/31/1998 For Period Ending 12/31/1997Address311 C ENTERPRISE DRIVEPLAINSBORO,New Jersey 08536Telephone609-275-0500 CIK0000917520IndustryBiotechnology&DrugsSectorHealthcareFiscal Year12/31SECURITIES AND EXCHANGE COMMISSION WASHINGTON,D
2、C 20549 FORM 10-K ANNUAL REPORT PURSUANT TO SECTION 13 OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended Commission File No.0-26224 December 31,1997 INTEGRA LIFESCIENCES CORPORATION (Exact name of registrant as specified in its charter)Registrants telephone number,including area code:
3、(609)275-0500 Securities registered pursuant to Section 12(b)of the Act:None Securities registered pursuant to Section 12(g)of the Act:Common Stock,par value$.01 per share (Title of class)Indicate by check mark whether the registrant:(1)has filed all reports required to be filed by Section 13 or 15(
4、d)of the Securities Exchange Act of 1934 during the preceding 12 months(or for such shorter period that the registrant was required to file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes/X/No/Indicate by check mark if disclosure of delinquent filers pursuan
5、t to Item 405 of Regulation S-K is not contained herein,and will not be contained,to the best of registrants knowledge,in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K./The aggregate market value of the registran
6、ts Common Stock(its only voting stock)held by non-affiliates of the registrant as of March 20,1998 was approximately$43.8 million.(Reference is made to page 24 herein for a statement of the assumptions upon which this calculation is based.)The number of shares of the registrants Common Stock outstan
7、ding as of March 20,1998 was 29,905,097.DOCUMENTS INCORPORATED BY REFERENCE Certain portions of the registrants definitive proxy statement relating to its scheduled May 18,1998 Annual Meeting of Stockholders are incorporated by reference in Part III of this report.Delaware 51-0317849(State or other
8、jurisdiction of (I.R.S.employer employer incorporation or organization)identification no.)105 Morgan Lane Plainsboro,New Jersey 08536(Address of principal executive offices)(Zip Code)PART I ITEM 1.BUSINESS Integra LifeSciences Corporation(hereinafter referred to as Integra or the Company)was incorpo
9、rated as a Delaware corporation in June 1989.Integra develops,manufactures and markets medical devices,implants and biomaterials primarily used in the treatment of burns and skin defects,spinal and cranial disorders,orthopedics and other surgical applications.Integra seeks to be the worlds leading c
10、ompany specializing in implantable medical and biopharmaceutical therapies to target and control cell behavior,and to build shareholder value by acquiring,discovering,and developing cost-effective,off-the-shelf products that satisfy unmet medical needs.Headquartered in Plainsboro,New Jersey,with a f
11、acility in San Diego,California,Integra markets its products directly as well as through marketing partners and distributors both domestically and internationally in more than 29 countries.The Companys customers include burn,trauma,plastic and reconstructive surgeons,neurosurgeons,orthopedic surgeon
12、s,operating room nurses,private label purchasers,and hospital administrators.Integras products include VitaCuff(TM),BioPatch(TM),BioMend(TM),and the Companys flagship product,the INTEGRA(TM)Artificial Skin,Dermal Regeneration Template(TM)Device(INTEGRA(TM)Artificial Skin),which was the first medical
13、 device specifically designed to enable the human body to regenerate functional dermal tissue to receive a Premarket Approval(PMA)application from by the U.S.Food and Drug Administration(FDA).Cells,and the matrix that surrounds cells,are organized into tissues.Tissues are organized into organs,which
14、 perform essential functions of the body.During development and growth,cells normally produce an infrastructure,which consists of a variety of different proteins including collagen.The Company refers to this infrastructure of proteins and other molecules as the extra-cellular matrix(ECM).The ECM pro
15、vides cells with structural support and biological signals so that they can function properly.Equally important,the ECM provides the integrity that is unique to certain tissues.For example,the matrix of bone is very hard and functions to support the weight of the body.Cartilage,found at sites where
16、bone connects to bone,contains a different cell type and matrix organization that withstands extreme compression,yet allows for almost frictionless motion between the bones of a joint.Muscles,by contrast,consist of very specialized cells and matrix that are designed for movement,while skin is compos
17、ed of cells and matrix that are tough yet flexible and protect the body against abrasion and water loss,as well as infection.For cells to function normally within tissues,the cells must be attached(anchored)to,and interact with,the ECM proteins that surround them.When certain tissues become damaged,
18、normal healthy cells attempt to repair the deficient site by moving into the damaged area,dividing,and depositing new matrix.However,the repaired tissue is often in the form of a scar,which consists of cells surrounded by excessive amounts of matrix.Scars do not function like normal tissue and often
19、 fail entirely.The transplantation of tissues from human donors is restricted by the shortage of such tissues,the difficulty and expense of transportation,the risk of rejection,the danger of disease transmission and the requirement,in certain cases,for life-long use of immuno-suppressant drugs.The g
20、rafting of a patients own tissue(autografting)causes damage to the site where the healthy tissue is harvested and is of limited use for severely wounded patients who have a minimal amount of healthy tissue for grafting.Currently available biomaterials(such as metals,ceramics and plastics)used in per
21、manent implantable devices(such as knee joints or heart valves)are commonly used,but tend to degrade after years in the body,potentially compromising long-term performance.The Company believes that its regenerative medicine technologies have the potential to provide safer,more effective and less exp
22、ensive methods for replacing damaged or diseased tissues when compared to other currently available techniques.The Companys business strategy has been to selectively acquire and further develop several platforms of synergistic biomaterials and ECM technologies.The Company uses the regenerative medic
23、ine technologies and proprietary processes it owns and licenses to fabricate devices manufactured from collagen and other components of the ECM.Once surgically implanted,these devices serve as temporary structures intended to support regeneration of functional tissues.These products are engineered p
24、recisely for specific tissues and are directed to be absorbed into 2 the body during the regeneration process.INTEGRA(TM)Artificial Skin is the first in a series of products that the Company is developing to regenerate a variety of body tissues,including the dura,peripheral nerve,bone,articular cart
25、ilage and cardiovascular graft.The Company also develops,sells and has substantial manufacturing experience with FDA-regulated absorbable medical products that serve a broad range of applications,including drug delivery,surgical hemostasis(the control of bleeding),infection control,dental surgery an
26、d wound care.These products are sold primarily through marketing relationships with a number of established medical companies,including Arrow International,Inc.,Bard Access Systems,Inc.,the Calcitek Division of Sulzermedica(Calcitek),Johnson&Johnson Medical,Inc.(J&J Medical),Johnson&Johnson Professi
27、onal,Inc.(J&J Professional),Quinton Instruments Co.,and Sorin BioMedica,Inc.(Sorin).The Companys commercial products use many of the same biomaterials,manufacturing processes,and materials engineering techniques used to produce INTEGRA(TM)Artificial Skin.The Company intends to further develop and co
28、mmercialize pharmacological medical applications of its technologies,particularly those developed by the Companys Telios Pharmaceuticals,Inc.subsidiary(Telios).The Company refers to the pharmacological applications of its ECM technologies as Matrix Medicine(TM).This technology is directed to the tre
29、atment of human disease characterized by disruption of the normal interactions between cells and the ECM.Matrix Medicine(TM)development includes applications for anti-thrombotics,inhibitors of angiogenesis,prevention of fibrosis and the treatment of cancer.At present,the Company does not intend to e
30、nter human studies for these applications without development partners.The Company believes its management and scientific team,development and manufacturing experience,proprietary technological position and relationships with established medical institutions and other organizations position it to ac
31、hieve its objectives.The Companys research implementation has been to maintain a relatively small core of scientists and researchers within the Company and to conduct a large portion of its research and product development through arrangements with independent medical research centers.The Company be
32、lieves this provides a cost-effective approach to managing its research and product development efforts,while maintaining the ability to respond quickly and effectively to technological changes.The Company is actively engaged in five business areas,each of which is described in detail below:(1)skin
33、defects and burns;(2)neurosurgical;(3)orthopedic;(4)private label medical products;and(5)developing businesses and ventures.Skin Defects and Burns The Companys primary operating business is the repair of skin defects and burns where surgical intervention is required.This business encompasses INTEGRA
34、(TM)Artificial Skin,the Companys leading commercial product,as well as a pipeline of new products including the development of a second generation of the Companys INTEGRA(TM)Artificial Skin utilizing a peptide/collagen matrix for enhanced healing,as well as a number of wound care products under deve
35、lopment.The Company believes the annual severe burn market is approximately$75 million worldwide,and that the annual market for all burns and scar revision procedures is estimated to be$350 million worldwide.Additional indications for plastic surgery and acute wound procedures increase the estimated
36、 market to over$1 billion worldwide.INTEGRA(TM)Artificial Skin INTEGRA(TM)Artificial Skin is designed to enable the human body to regenerate functional dermal tissue.Human skin consists of the epidermis(the thin,outer layer which serves as a protective seal for the body)and the dermis(the thicker,la
37、yer underneath which provides structural strength and flexibility).The dermis also supports the viability of the epidermis through a vascular network.The body normally responds to severe damage to the dermis by producing scar tissue in the wound area.This scar tissue is accompanied by contraction th
38、at pulls the edges of the wound closer which,while closing the wound,often permanently reduces flexibility.In severe cases,this contraction leads to a reduction in the range of motion for the patient,who subsequently requires extensive physical rehabilitation or reconstructive surgery.Physicians tre
39、ating severe wounds,such as full-thickness burns,seek to minimize scarring and contraction.INTEGRA(TM)Artificial Skin was designed to minimize scar formation and wound contracture in full thickness skin defects.3 INTEGRA(TM)Artificial Skin consists of two layers,a thin collagen-lycosaminoglycan(GAG)
40、sponge and a silicone membrane.The product is applied with the sponge layer in contact with the excised wound.The collagen-GAG sponge material serves as a template for the growth of new functional dermal tissue.The outer membrane layer acts as a temporary substitute for the epidermis to control wate
41、r vapor transmission,prevent re-injury and minimize bacterial contamination.INTEGRA(TM)Artificial Skin was approved by the FDA under a premarket approval application(PMA)for the post-excisional treatment of life-threatening full-thickness or deep partial-thickness thermal injury where sufficient aut
42、ograft is not available at the time of excision or not desirable due to the physiological condition of the patient.In 1997,the FDA approved a PMA supplement extending the shelf life for INTEGRA(TM)Artificial Skin from one year to two years.The FDAs approval order includes requirements to provide a c
43、omprehensive practitioner training program and to conduct a post approval study at multiple clinical sites.The Company has contracted with 11 burn centers in the United States to participate in the post approval study,and currently has approximately 70 patients in the study.The Company offers its tr
44、aining program to all surgeons specializing in burns throughout the world,and has trained over 700 surgeons worldwide.The Company also offers programs to the entire hospital team,including operating room personnel,burn unit support staff,and hospital reimbursement specialists.In 1996 and 1997,sales
45、of INTEGRA(TM)Artificial Skin have been largely for the treatment of patients with life-threatening full-thickness or deep partial-thickness burns where conventional autograft is not available or not desirable due to the physiological condition of the patient.While the Company believes that burns ar
46、e an important market for INTEGRA(TM)Artificial Skin,the Company is seeking to expand the approved indications for INTEGRA(TM)Artificial Skin in reconstructive surgery,acute wounds,closure following excision of skin cancers,and chronic wounds.Recently,the Company received CE Mark certification in Eu
47、rope for INTEGRA(TM)Artificial Skin,which included an indication for reconstructive surgery and full thickness injuries.The broader reconstructive surgery indications include scar revision procedures,tumor and skin cancer resection,release of post-burn contractures,congenital skin defects and revisi
48、on of hypertrophic and keloid scars.With the CE mark certification,INTEGRA(TM)Artificial Skin is now approved in 29 countries,including Canada and the United States.The Company sells INTEGRA(TM)Artificial Skin through a direct technical sales organization in the United States,Canada,Ireland and the
49、United Kingdom and through distributors in other international markets.Through its direct sales force and by working closely with its specialized international distributors,the Company maintains a continuous working relationship with clinicians in the field of burn care and reconstructive surgery.In
50、tegra believes these relationships are critical to the long-term success of any new generation product.In 1997,the Company signed an exclusive importation and sales agreement for INTEGRA(TM)Artificial Skin in Japan with Century Medical Inc.(CMI).CMI is headquartered in Tokyo,with sales offices in Sa
51、pporo,Sendai,Nagoya,Osaka and Fukuoka.Over the past two decades,CMI has steadily expanded its medical products distribution business in Japan,and CMIs parent company,ITOCHU Corporation,reported revenues of$155 billion for 1997.Under this agreement,CMI is conducting a clinical trial in Japan at its o
52、wn expense to obtain Japanese regulatory approvals for the sale of INTEGRA(TM)Artificial Skin in Japan.INTEGRA(TM)Artificial Skin sales were$6.0 million and$3.1 million for the years ended December 31,1997 and 1996,respectively and accounted for 43%and 28%of the Companys total product sales,respecti
53、vely.Product Development The Company has begun development of a number of new products for its Surgical Skin Business.The most important of these is a second generation INTEGRA(TM)Artificial Skin which incorporates the proprietary(arginine-glycine-aspartic)amino acid peptide sequence(RGD)which is pa
54、rt of the Companys Telios technology base.The Company expects this product to reduce significantly the healing time for full thickness skin repair.In addition to the effort to expand indications for INTEGRA(TM)Artificial Skin,the Company is aggressively developing adjunctive products with value adde
55、d strategies of particular significance to the wound care business.Additionally,as data is acquired on the clinical performance of INTEGRA(TM)Artificial Skin,that feedback is being utilized to generate potential product improvements necessary to provide the best regenerative dermal matrix product to
56、 Integras customers.4 Neurosurgical Business The neurosurgical business encompasses the Companys dural graft and peripheral nerve conduit products.Artificial Dural Graft The dura mater is the tough connective tissue covering the brain and spinal cord.It acts as a physical barrier and contains the ce
57、rebrospinal fluid(CSF).There is frequently a need for dural grafts to cover defects in the dura mater resulting from neurosurgical procedures or other trauma.The Integra dural regeneration product prevents leakage of the CSF and guides the hystotipic regeneration of the dural membrane without the ad
58、verse effects of scar formation associated with current,non-regenerative methods of dural repair.The collagen matrix is entirely resorbed via normal metabolic pathways during the process of dural regeneration.The Companys dural regeneration template has been implanted in over 600 patients that compr
59、ise two retrospective studies of the products performance.The Company is currently evaluating several potential regulatory strategies for bring this product to market.There are approximately 325,000 procedures performed worldwide annually where a dural graft is required.The Company believes the annu
60、al market size for this indication is potentially$40 million.Additionally,the dural graft material is being clinically assessed for the prevention of fibrosis(adhesions)in spinal surgery.The potential anti-fibrotic market in the U.S.comprises approximately 600,000 spinal and cranial procedures per y
61、ear.The Company believes the annual market size for this indication is potentially$200 million worldwide as an anti-adhesion material.Peripheral Nerve Conduit Although peripheral nerves are one of the few tissues of the body that spontaneously regenerate,they fail,in the majority of cases,to make us
62、eful,functional connections.Consequently,peripheral nerve injuries often result in permanent loss of function.Currently,the only method of treatment for a severed peripheral nerve is microsurgical re-attachment.Integras peripheral nerve regeneration conduit is a thin collagen tube designed to facili
63、tate regeneration of the severed nerve and acts as a bridge between the severed nerve stumps.The collagen conduit supports nerve regeneration and is resorbed.There are approximately 20,000 procedures annually in the U.S.that involve severed peripheral nerves,and the Company believes the worldwide ma
64、rket could amount to approximately$80 million.Scar formation at the nerve repair site is the leading cause of failure in conventional nerve grafting techniques.The Companys collagen tube prevents scar formation and provides guided peripheral nerve regeneration.The Companys pre-clinical studies have
65、demonstrated the closure of 5-cm gaps in peripheral nerves in non-human primates with restored nerve function.The Company initiated Phase I clinical trials in 1996 in Copenhagen,Denmark.Phase II trials are planned for the second quarter of 1998.Japanese Distribution On March 12,1998,Integra and CMI
66、announced a strategic alliance for the export of the neurosurgical product line to Japan.This marks the third agreement for which CMI will receive rights to distribute Integras proprietary medical devices in Japan.Under the terms of this agreement,CMI will pay a licensing fee of$1 million in the fir
67、st quarter of 1998 and will invest$4 million for 500,000 shares of Integra preferred stock in the second quarter of 1998.CMI will also underwrite all costs of the Japanese clinical trials and regulatory approval processes.This seven-year distribution contract begins on the date of regulatory approva
68、l in Japan.5 Product Development Integra has an active research and development program to develop future generations of the dural graft and peripheral nerve products in addition to other regenerative products and technologies that will meet the future needs of the neuro-surgical community.Orthopedi
69、c The Companys orthopedics business is predominantly in the development stage.The Company has a number of projects under way to develop products that support the regeneration of bone,cartilage and connective tissue.Collaborative projects include those being undertaken with J&J Professional,Inc.(JJPI
70、),Genetics Institute,Inc.(GI),Sofamor/Danek Group,Inc.(SDG)and the National Institute of Standards and Technology(NIST).Bone Regeneration The Company supplies GI with a collagen delivery matrix that is used in conjunction with GIs recombinant human bone morphogenic protein-2(rhBMP-2)to stimulate bon
71、e regeneration at defect sites.Human clinical trials conducted by GI have shown the safety and biological activity of the product.GI has initiated additional larger trials.GI expects to continue testing the product in clinical studies for orthopedic,oral/maxillofacial and eventually spine surgery,th
72、e last in conjunction with SDG.The Company has an exclusive supply agreement with GI to provide commercial quantities of the collagen delivery matrix,should GI successfully commercialize its products.Cartilage Regeneration More than 500,000 surgical procedures are performed annually for the treatmen
73、t of traumatized articular cartilage.Damaged articular cartilage,which connects the skeletal joints,is associated with the onset of progressive pain,degeneration and,ultimately,long-term osteoarthritis.Conventional procedures for treating traumatic cartilage damage,such as debridement and drilling,d
74、o not stop joint surface degeneration and often require two or more surgeries.The Company is developing a new device to allow in-vivo regeneration of the patients own articular cartilage.This technology will allow the patients own body to regenerate a smooth,weight-bearing surface.Conventional appro
75、aches result in the formation of fibrocartilage,which is rough and non-weight bearing over prolonged periods.Normal articular cartilage is not highly vascularized,and although it is metabolically active tissue,damaged cartilage generally does not effectively heal.The conventional procedure for treat
76、ing traumatic damage to cartilage involves smoothing damaged portions of the tissue and removing free-floating material from the joint using arthroscopic surgery.While the objective of this procedure is to reduce pain and restore mobility,the long-term result of this procedure often is permanent red
77、uction of joint mobility and an increased risk of developing osteoarthritis.The Companys objective in developing its cartilage-specific technology is to produce a product that provides the proper matrix system to allow the natural regeneration of the patients cartilage,with full restoration of funct
78、ion and diminished risk of osteoarthritis.The product under development would use the Companys peptide technology to create an enhanced template that would encourage cells to grow into the template once implanted into the patient.The Companys peptide portfolio includes bio-active agents designed to
79、mimic natural ECM proteins to promote chondrocyte cell adhesion,cell survival and other important cellular functions.The product under development will use this peptide technology to create an enhanced template that would recruit chondrocyte cells to the template once implanted.The template itself w
80、ould employ proprietary designs based on multiple layers of collagen material of varying but tightly controlled densities and pore sizes to provide a scaffold for chondrocyte proliferation and hyaline cartilage formation.Simultaneously it would prevent the in-growth of unwanted cells that could lead
81、 to scar tissue formation.The Company anticipates that the device will be absorbed into the body over a period of several weeks.Pre-clinical studies involving several variations of the above protocols are in progress.6 In February 1998,the Company announced the signing of a strategic alliance with J
82、JPI to develop and market a new product to regenerate joint cartilage.Integra has agreed to develop an absorbable,collagen-based implant,designed in combination with its proprietary RGD peptide technology,that will allow the body to repair and regenerate articular cartilage found in the knee and oth
83、er joints.JJPI will market the product worldwide.Under the terms of the agreement,JJPI will make payments up to$13 million as Integra meets various milestones,and will fund all necessary development costs beyond the pre-clinical phase.Following successful development,Integra will be responsible for
84、manufacturing the product and for future product development.JJPI is developing the arthroscopic instrumentation to be used in the surgeries.The Company believes the products sales potential,combined with the commitment from J&Js worldwide marketing and sales force,is a strong validation of the pote
85、ntial significance of the Telios RGD peptides.The product is being designed to help overcome the bodys inherent deficiencies in regenerating articular cartilage by promoting the adhesion and function of cells in a manner that will have much wider clinical use.The Company believes that the combinatio
86、n of its collagen matrix technology with Telios RGD peptide technology gives the Company a unique approach to accelerated cartilage repair.The product is being designed to be readily available and sterile off-the-shelf.The products acellular technique does not require cell cultures.The Company expec
87、ts these features to prove substantially more cost-effective than current options.Tyrosine Polycarbonates Program The Company is continuing the development of additional ECM technologies.The goal is to enhance the rate and quality of healing and tissue regeneration with synthetic biodegradable scaff
88、olds to support cell attachment and growth.To this end,the Company is developing a new class of resorbable polycarbonates created through the polymerization of tyrosine,a naturally occurring amino acid.A well-defined and commercially scaleable manufacturing process is employed to prepare these mater
89、ials.Device fabrication by traditional techniques such as compression molding and extrusion is readily achieved.The Company believes that this new biomaterial will be safe and effective in promoting full bone healing when implanted in damaged sites.The Company has licensed this patented technology f
90、rom Rutgers University for all applications and continues to work in collaboration with the technologys inventor,Joachim Kohn,Ph.D.This material is currently being developed for orthopedic and tissue engineering applications where strength and bone compatibility are critical issues for success of he
91、aling.The polymer when implanted in bone appears to be osteoconductive;it conducts bone onto and through the polymer implant.Further,because of the unique structure of the polymer,the biological breakdown products are non-acidic.Highly acidic by-products,which are typical of current commercial ortho
92、pedic implants,are a primary cause of sterile abscess which can lead to pain and even implant failure.In 1997,the Company completed a pre-clinical animal study,funded by NIST and the Company.Toxicity studies completed have shown that the polymer is non-mutagenic and non-cytotoxic.No evidence of syst
93、emic toxicity,irritation,or sensitization was observed.The Companys development activities also include the use of biomaterials for drug delivery applications.In 1997,the Company was awarded a second$2 million research and development grant from NIST for the development of new absorbable and biocomp
94、atible tyrosine-based polymer as a stand alone or in combination with RGD peptides to stimulate in-vivo cartilage regeneration.The Company is also developing the polymers for incorporation into its other manufactured products.The Company has rights to use this material in wound closure and related d
95、rug delivery applications.There is the possibility of delivering growth factors and other biological response modifiers in a controlled manner in conjunction with the Companys skin regeneration,cartilage regeneration and nerve regeneration technologies.In addition,the technology may prove useful in
96、surgical hemostasis and dental surgery applications where the sustained delivery of antibiotics at the surgical site could be beneficial.The Companys strategy is to pursue strategic partnership alliances to assist in the further development and commercialization of this technology.Osteoporosis Nearl
97、y 1.5 million Americans are afflicted with osteoporosis.It is estimated that there are nearly 300,000 new cases of osteoporotic hip fractures each year.The associated costs of osteoporosis approach$10 billion each year.The Company is investigating a new therapeutic approach for the treatment of this
98、 disease based on its proprietary technologies developed at Telios.The approach prevents the attachment of bone dissolving osteoclasts to bone 7 tissue thereby slowing or preventing the disease.Pre-clinical studies have demonstrated the effectiveness of several proprietary peptides in preventing bon
99、e loss.Development efforts are continuing,as are efforts to identify an appropriate strategic partner to assist the Company in commercializing this technology.Decorin for Fibrosis Control The total U.S.market potential for adhesion prevention products is estimated at 4.5 million procedures worth app
100、roximately$900 million.General surgery and gynecology comprise the largest segments with 40%and 38%shares,respectively.Medical Device International reports that there were over 400,000 adhesionolysis procedures performed in 1995,nearly 240,000 of which were for gynecology-related indications.It is e
101、stimated that by the year 2000,overall U.S.revenues for adhesion prevention devices will reach$75-$100 million-growing at a double-digit rate-equivalent to a market penetration of 15%.Although the adhesion prevention market is a potentially lucrative niche,it is unlikely that it will be able to supp
102、ort all the products and technologies currently available or under development.Nevertheless,there is a significant opportunity for a truly effective product.The Companys decorin-based product offers a unique approach to this problem by interrupting the mechanism of adhesion formation,rather than jus
103、t providing a barrier that attempts to prevent tissues from sticking to one another.Decorin,a natural component of the ECM,is the bodys natural regulator of the growth factor TGF-(beta).TGF-(beta)has many functions in the body including regulation of cell death,immune system interactions and wound h
104、ealing.In the case of adhesion formation,a form of uncontrolled wound healing,when a tissue experiences trauma from accident,disease or surgery,the effected cells up-regulate the production of TGF-(beta).This causes a rapid and random deposition of ECM that ultimately results in scarring or fibrosis
105、.When tissues are in close proximity to one another the fibrotic tissue attaches to other nearby tissues and an adhesion is formed.Decorin can bind this excess TGF-(beta)and stop the fibrosis cascade thereby actually preventing adhesions from ever starting.The Company is in early-stage development o
106、f a variety of product forms(sprays,gels,films,solutions).The Company is seeking strategic partners to assist in the development of this technology,and it anticipates that preclinical studies will commence this year.Private Label Medical Products The Company develops and sells,primarily through lice
107、nsing and distribution arrangements,a number of biomaterials-based medical products and devices for infection control,general surgery and dental surgery.These products accounted for approximately$8.0 million,$8.1 million and$8.3 million of product sales for the Company during the years ended Decembe
108、r 31,1997,1996 and 1995,respectively,representing approximately 57%,72%and 100%,respectively,of the Companys product sales for such years.The Company has pursued a strategy of developing new products,obtaining regulatory approvals,and distributing these products through marketing and distribution pa
109、rtnerships.Typically,these partnerships are with leading medical device companies that assist in developing the commercial potential of the Companys medical products.A substantial portion of the Companys medical products is sold to customers under the terms of multiple-year marketing and distributio
110、n agreements that provide for purchase and supply commitments on the part of the customer and the Company,respectively.In many cases,marketing customers have paid license fees to the Company for the marketing and distribution rights.In the absence of a suitable United States marketing partner for th
111、e Companys hemostasis product line,the Company has elected to sell certain portions of the hemostasis product line in the United States through a national network of specialized distributors.Of the Companys total product sales during 1997,1996 and 1995,customers accounting for more than 10%of total
112、product sales included two customers accounting for 24%,three customers accounting for 42%and four customers accounting for 56%,respectively.8 Infection Control Products The Companys patented VitaCuff(TM)product provides protection against infection arising from long-term catheters.VitaCuff(TM)consi
113、sts of a silver nitrate impregnated collagen matrix ring,which is positioned on the catheter before placement.Once in place the collagen forms a seal at the point of entry,mechanically preventing microbial invasion along the catheter while at the same time releasing silver nitrate into the surroundi
114、ng area.In this application,silver-nitrate functions as a highly effective,broad-spectrum anti-microbial agent.VitaCuff(TM)and related products are manufactured by the Company and marketed through Arrow International,Inc.,Bard Access Systems,Inc.and Quinton Instruments.The Company manufactures a pat
115、ented wound dressing composed of a synthetic and biopolymer composite foam impregnated with an anti-microbial compound which is marketed by Ethicon,Inc.,a Johnson&Johnson subsidiary,under the trade name BioPatch(TM).The product is applied over the entry point of any percutaneous device,such as ortho
116、pedic traction pins and epidural catheters,and serves to protect the area from bacterial growth for an extended period.In 1997,the Company extended its licensing and distribution agreement with Ethicon,Inc.for BioPatch(TM)and agreed to provide them with an exclusive license to its patents in this fi
117、eld.The Company has also developed a silver impregnated foam wound dressing which provides anti-microbial protection to prevent bacterial colonization leading to infection.Dental Surgery Products The Companys dental surgery products are extensions of the Companys absorbable collagen hemostatic spong
118、e technology(see below).Each of the three products,CollaCote(TM),CollaPlug(TM)and CollaTape(TM),has a unique dimension,shape and density and provides most of the hemostasis requirements encountered in dental surgery.Calcitek markets the Companys dental surgery products.The Company has also developed
119、 BioMend(TM)Absorbable Collagen Membrane(BioMend(TM)for use in guided tissue regeneration in periodontal surgery.BioMend(TM)is inserted between the gum and the tooth after surgical treatment of periodontal disease.BioMend(TM)prevents the gum tissue from interfering with the regeneration of the perio
120、dontal ligament that holds the tooth in place.BioMend(TM)is intended to be absorbed into the patient after approximately four to seven weeks,avoiding the requirement for additional surgical procedures to remove a non-absorbable membrane.Calcitek also markets BioMend(TM).Surgical and Hemostasis Produ
121、cts The Companys hemostasis products are used in surgical procedures to help control bleeding.The Companys absorbable collagen hemostatic sponge products consist of Helistat(TM)(Absorbable Collagen Hemostatic Sponge),Helitene(TM)(Absorbable Collagen Hemostatic Agent-Fibrillar Form),Collastat(TM)and
122、related products.The Companys products have been manufactured for more than 15 years and are estimated to have been used in several hundred thousand patients.These products are manufactured by Integra and marketed in the United States through a network of specialized distributors.Outside of the Unit
123、ed States,various international distributors sell the products.The Company introduced a new product under its Helistat(TM)line in 1997,a 1 x 9 collagen sponge strip for sternal hemostasis.The Companys Instat(TM)Products(absorbable collagen hemostatic agent in fibrillar form)are manufactured by the C
124、ompany and marketed in the United States by Ethicon,Inc.In January 1998,the Company announced that it had signed an agreement with CMI for supply and distribution of the Companys Helistat(TM)and Helitene(TM)products in Japan.One variant of the Companys hemostasis product line is a collagen sponge so
125、ld by JJPI under the brand name Bicol(TM)that acts as a moistening agent to prevent drying of brain tissue and as a protective device to buffer the pressure of retractors in neuro-surgery.The domestic market for hemostasis products is dominated by long standing,traditional products based on gelatin
126、or cellulose technology.The Companys collagen technologies provide an effective control of surgical bleeding and are approved to be left in the body following completion of a surgical procedure.9 Biocompatible Coatings As an extension of its surgical product line,the Company has developed a collagen
127、 vascular graft coating in conjunction with Sorin.This proprietary collagen coating provides an alternative to fabric vascular graft products,which require pre-clotting before use.The Companys product is easier to use because it eliminates the need for pre-clotting.The Company transferred the coatin
128、g technology and pilot plant equipment to Sorin.Integra derives ongoing revenues from royalties and the sale of materials to Sorin.The use of prosthetic device implants creates a variety of clinical problems,including inflammation,encapsulation,thrombosis and infection.These problems may be overcome
129、 by coating the surface of implanted materials with cell attachment sites which enable the natural development of tissue structure at the material-tissue interface providing for long-term,stable tissue integration.The Company is developing PepTite(TM)Biocompatible Coating(PepTite(TM)designed to impr
130、ove the biocompatibility of implantable materials.The coating contains the proprietary RGD peptide.The Company is conducting a number of pre-clinical in-vivo effectiveness studies in collaboration with various implant manufacturers.The Company has coated and is studying:(a)percutaneous access cathet
131、ers to reduce thrombus formation;(b)polyester mesh to enhance endothelialization of arterial wall defect repairs and reduce inflammation inhernia and other fascial defects;(c)metal stents;(d)silicone implants to reduce or eliminate encapsulation of the implant;and(e)certain polymers utilized in card
132、iovascular devices to reduce thrombogenicity and enhance tissue in-growth.The Companys strategy is to develop PepTite(TM)in collaboration with other medical device manufacturers.Developing Businesses and Ventures The company has a number of developing businesses and ventures.These include a womens h
133、ealth initiative,an Artecor vascular graft,a variety of Matrix Medicine(TM)products developed at Telios,including Decorin,and a project surrounding the regeneration of pancreatic islets.Womens Health Initiative The Company is working with the Agency for Contraceptive Research and Development and the
134、 Population Council in the development of topical,trans-dermal and implantable drug delivery systems.These systems are intended to deliver steroids and other pharmaceuticals for reproductive health applications such as contraception,fertility enhancement and topical control of sexually transmitted d
135、isease.Products developed through these relationships are intended to be manufactured exclusively by the Company for worldwide distribution.Artecor Vascular Graft In 1996,the Company formed Medicol Sciences,Ltd.,a wholly-owned subsidiary in the Czech Republic(Medicol),and acquired rights to several
136、patented processes relating to the development and manufacture of small diameter(less than 6 mm)vascular grafts.The technology employs a collagen-based matrix in conjunction with an open mesh Dacron fabric.Following sterilization,the resulting product can be implanted as a vascular graft.The Company
137、 also entered into a consulting agreement with Dr.Milan Krajicek,who is the inventor of the technology.The Company will be funding continued pre-clinical studies to determine the effectiveness of the graft in coronary artery by-pass surgery and for use in peripheral reconstruction procedures.Matrix
138、Medicine:The Telios Product Pipeline Integra acquired Telios in 1995 to commercialize Telios technologies relating to extracellular matrices and integrin-mediated activity,and in particular,their applications to tissue regeneration.Integra is developing Telios findings and methodologies to enhance a
139、nd accelerate development and commercialization of its products.10 Telioss RGD peptide technology is a direct result of the pioneering work begun in the early 1980s by co-inventors Michael D.Pierschbacher,Ph.D.,Integras Senior Vice President and General Manager of Telios,and Erkki Ruoslahti,MD,Presi
140、dent and CEO of The Burnham Institute.The patented RGD technology has been shown to have potential utility in a number of important and rapidly growing medical therapies.These include tissue regeneration,biocompatible coatings for implantable medical devices,thrombosis(blood clotting),cancer treatme
141、nt,immune system regulation,inflammation,and control of angiogenesis.Peptides are small synthetic chains of amino acids that are designed to perform specific functions on cells.Peptides can be engineered to mimic very large natural matrix proteins that are found within tissues of the body.Peptides b
142、ind integrin receptors found on the surface of virtually all cells of the body.There are more than 20 such integrin types within this family of cell receptors.Integrins control cell attachment,growth,migration and differentiation.Cells present within tissues rely on specific integrin types during ti
143、ssue regeneration.Small synthetic peptides can be designed to interact selectively with certain integrins to achieve differing outcomes by enhancing certain interactions between cells and matrix.When used in combination with a collagen scaffold,these peptides signal the appropriate cell-matrix funct
144、ions through integrins and promote the formation of new tissue by guiding the attachment and growth of cells.The Companys proprietary pharmacological applications of its technologies are intended to target and control the behavior of human cells through their interactions with the extracellular matr
145、ix.The Company refers to the clinical applications of these technologies as Matrix Medicine(TM),and is developing applications for the pharmacological treatment of serious human disease conditions,including diseases involving thrombosis,fibrosis and angiogenesis.The Companys Matrix Medicine(TM)techn
146、ologies are based on the interaction between a family of cell surface proteins called integrins and the arginine-glycine-aspartic acid(RGD)peptide sequence found in the majority of extracellular matrix proteins,including structural molecules and adhesion molecules that provide binding sites,structur
147、al support,and physiological information for the maintenance of normal cell function in the body.In 1997 additional significant patents that strengthen the Companys proprietary position in this technology were issued to The Burnham Institute.These patents are exclusively licensed to Integra through
148、its Telios subsidiary.The Company has in development new pharmacological products based on the interaction between the extracellular matrix and the integrin family of receptors that are present on virtually all cells in the body.The Company believes that many major diseases and disorders throughout
149、the body,including many that are debilitating,life-threatening,costly and difficult or impossible to treat satisfactorily with existing therapies,involve the disruption or abnormality of the interaction of cells with the extracellular matrix.The Companys Matrix Medicine(TM)technologies are intended
150、to modify the interaction of cells with the matrix in such a way as to provide new treatment strategies for a range of disorders.The Company is pursuing a strategy to identify clinical and market leaders in pharmacological areas to co-develop and license the Companys proprietary technologies and app
151、lications.The Company believes that such development and marketing relationships could result in a greater likelihood of commercialization of these opportunities by utilizing the skills of partners to complete clinical trials and market introduction,while allowing the Company to focus on pre-clinica
152、l development.Many of the Companys technologies are in the early stages of development and will require the commitment of substantial additional resources by the Company and its potential strategic partners prior to commercialization.There can be no assurance that the Company will be able to form st
153、rategic alliances or successfully develop commercial products.TP-9201 Platelet Aggregation Inhibitor for the Treatment of Stroke The Company has developed a platelet aggregation inhibitor which has been demonstrated to be safe in a Phase I clinical trial and is now ready for Phase II dose ranging tr
154、ials in patients.Platelets are small cells that circulate in the blood and have many important functions,one of which is related to the control of bleeding.Platelets prevent bleeding by first adhering to the vessel wall in a process called platelet adhesion and spreading.In a secondary process of pl
155、atelet aggregation,platelets aggregate to form clumps.Without properly functioning platelets,dangerous bleeding can occur.In diseased or surgically damaged blood vessels,platelets can aggregate and restrict the vital supply of blood to the heart,brain and other organs and tissues.This condition,term
156、ed thrombosis,is a common hallmark of cardiovascular diseases such as heart attack and stroke,and can cause serious complications during and after surgical procedures.Two kinds of drugs currently available for the treatment of thrombotic diseases and conditions are anticoagulants and thrombolytics.A
157、nticoagulants inhibit formation of clots and have both 11 preventive and therapeutic applications.Thrombolytics function by dissolving already existing clots.However,when the consequences of bleeding are severe,neither of these agents are generally recommended.Current approaches to thrombosis preven
158、tion that involve inhibition of platelet aggregation carry the risk of compromising the bodys ability to control bleeding.Even minor bleeding,if allowed to go unchecked,can lead to life-threatening events such as stroke and other forms of internal hemorrhage.The Company is developing a selective pla
159、telet aggregation inhibitor targeting the(alpha)IIb(beta)3 integrin receptor that appears on the surface of activated platelets and mediates their aggregation.A key technical challenge in the development of a(alpha)IIb(beta)3 inhibitor is to provide a molecule specific enough to allow the beneficial
160、 functions of(alpha)IIb(beta)3,such as those responsible for the primary event of platelet adhesion and spreading while at the same time inhibiting the negative effects caused by platelet aggregation.Anti-platelet agents without such characteristics prevent thrombosis but promote bleeding.ReoPro,an
161、antibody that blocks the function of(alpha)IIb(beta)3 was approved by the FDA in 1996 for use to prevent thrombosis after angioplasty procedures.Eli Lilly,who markets this product,claims that the initial bleeding problems associated with this product can be controlled by carefully controlling the do
162、sage.The Company has conducted pre-clinical studies that demonstrate TP-9201 doses that prevent unwanted platelet aggregation without reducing the platelets ability to control capillary bleeding.The unique properties of this molecule are being developed for application in therapeutic areas where the
163、 separation of bleeding from anti-thrombotic effect is crucial.The potential markets that could benefit from TP-9201 include:(a)unstable angina,as transient blockage of coronary arteries by blood clots,often preceding complete myocardial infarction;(b)restenosis,as reclosure of arteries,typically af
164、ter angioplasty;(c)reocclusion,as reclosure of arteries,typically after angioplasty or treatment of mild myocardial infarction with thrombolytics;and(d)ischemic stroke,as blockage of blood vessels supplying the brain,often resulting in permanent brain damage.Additionally,vascular synthetic grafts ca
165、n cause thrombosis and have a tendency to leak blood.TP-9201 may be able to prevent thrombosis without increasing risk of bleeding associated with these grafts.Finally,problems associated with organ transplantation thrombosis,which occurs after reestablishing blood flow to the organ and results in b
166、lockage of the microvascular bed and organ failure,could be reduced with the use of TP-9201.The Company believes that there are many procedures that may be addressed with the use of TP-9201 or future products developed from this technology.The Company intends to seek strategic alliances to further d
167、evelop this technology.There can be no assurance that the Company will be able to form strategic alliances or successfully develop commercial products.TGF-(Beta)Antagonists to Target Fibrosis and Cancer Transforming Growth Factor Beta(TGF-(beta)is a class of growth factors(cytokines)that has widespr
168、ead regulatory effects on many processes that are essential for normal health.Such processes include cell growth and differentiation,fetal development,immune regulation,inflammation and tissue repair.The Company believes that the importance of TGF-(beta)for human medicine is that an imbalance of TGF
169、-(beta)underlies chronic inflammatory and fibrotic diseases,and contributes to tumor progression.The Company intends to develop TGF-(beta)antagonists that correct such TGF-(beta)imbalances.The Company has licensed from the Burnham Institute,as well as from the University of Utah,patents and patent a
170、pplications relating to the control of TGF-(beta)activity.Potential medical applications of this technology include prevention of scarring following surgery or trauma and prevention or limitation of fibrosis of the kidney,lung,liver,skin,arteries and the central nervous system as well as potentially
171、 preventing drug resistance in tumors.The Company has identified two primary therapeutic approaches to the control of TGF-(beta):human antibodies directed against TGF-(beta)and recombinant human decorin.Decorin is a natural regulator of TGF-(beta)activity and suppresses the production of TGF-(beta)i
172、n injured tissues.The Companys human antibody development program is being carried out under an agreement with Cambridge Antibody Technology Limited(CAT),under which CAT has already developed several human anti-TGF-(beta)antibodies that are presently under pre-clinical or clinical investigation.The
173、Company has the right to market all dermal applications of these antibodies,including the treatment of dermal scarring.The Company has also developed cell lines expressing recombinant human decorin and is developing production procedures for decorin.12 Drug Discovery Capability for Integrin Specific
174、 Compounds The Company has developed integrin receptor and cell based assay systems which have been used to screen for and discover integrin specific drug candidates for clinical development.This capability has enabled the successful discovery of the clinical development candidate TP-9201(an anti-th
175、rombotic compound that may be uniquely applicable to the treatment of stroke),an antagonist that effectively inhibited bone resorption in animal models of osteoporosis and a compound that effectively inhibits angiogenesis.Based on this experience,the Company is in a position to expand its drug disco
176、very and screening programs and is seeking corporate partnerships for collaboration in this effort.The following integrins are being studied as potentially useful therapeutic targets in pre-clinical research:The Company has developed lead compounds targeting(alpha)IIb(beta)3,(alpha)v(beta)5,(alpha)v
177、(beta)3 and(alpha)v(beta)1,and is carrying out continuing pre-clinical research on these compounds through collaborative arrangements with academic laboratories experienced in the appropriate disease models.The Company intends to seek strategic alliances to develop further the application of these c
178、ompounds.There can be no assurance that the Company will be able to form strategic alliances or successfully develop commercial products.Pancreatic Islet Regeneration The Company has an ongoing collaboration with Drs.Daniel Salomon and Bruce Torbet at The Scripps Research Institute for the developme
179、nt of Integras proprietary technology to support the regeneration and long term survival of functioning pancreatic islets for the treatment of diabetes.By providing a synthetic extracellular matrix that supports the function of appropriate integrins,these researchers have shown in animal models that
180、 islet engraftment and vascularization can be achieved and that long term viability and glucose sensitivity can be maintained.Research Strategy The Company has either acquired or secured the proprietary rights to several important scientific platforms.These platforms can be organized into four disti
181、nct but complementary technological categories:a)bioabsorbable and other materials;b)ECM and other specialized materials structures;c)materials as delivery vehicles for peptides,13 Target Integrin Clinical Indications Suggested Mechanism-(alpha)IIb(beta)3 Thrombosis Platelet aggregation(alpha)v(beta
182、)3 Angiogenesis Endothelial cell migration(alpha)v(beta)3 Vascular grafts Endothelial cell migration(alpha)v(beta)3 Osteoporosis Bone cell adhesion(alpha)v(beta)3 and/or(alpha)IIb(beta)3 Restenosis Smooth muscle cell proliferation(alpha)v(beta)3 and/or(alpha)5(beta)1 Metastasis Migration of cancer c
183、ells(alpha)v(beta)3 and/or(alpha)v(beta)5 Bone formation Adhesion of bone-producing cells to bone(alpha)5(beta)1 Cell survival Control of apoptosis cells,growth factors,drugs and other actives;and d)actives.These technologies provide support for the Companys critical applications in tissue regenerat
184、ion,developing pharmacological applications,and additional opportunities for generating near-term and mid-term revenues from medical applications.The Company has been able to identify and bring together critical platform technology components from which it wants to develop solutions to the problem o
185、f targeting and controlling selected cell behavior in the patients body for both tissue regeneration and pharmacological application.The Company focuses its efforts on the convergence of these technology categories into a type of basic operating system solution for technology development and product
186、 performance.Just as a computers basic operating system interfaces with its electronic hardware to direct and control the performance of the computer,specialized absorbable products developed by the Company are intended to function in the patients body by directing and controlling targeted cell beha
187、vior to achieve a specified desired medical result.The Companys research focus is on technology development as opposed to early stage basic research.Toward that end,Integra focuses on the commercial and clinical utility of its products by encouraging early and close collaboration with clinicians.As
188、an example,INTEGRA(TM)Artificial Skin is the result of a close collaboration between a surgeon and a materials scientist.The surgeons ability to define the critical specifications of the product were essential prerequisites to the product development and demonstration of clinical utility in human cl
189、inical trials.Particularly critical were that the product be readily available off the shelf at the time of early wound excision for patients with life-threatening injury and that it be a permanent wound cover.The Companys research implementation is to supplement a relatively small group of in-house
190、 scientists and researchers with collaborative links with a network of various hospitals and medical organizations which are centers of research in the Companys technologies.The Company believes this is a cost-effective way to obtain knowledge and expertise in the Companys technologies while maintai
191、ning an ability to respond quickly and effectively to technological change.To assist the Company in achieving its objectives,Integra has entered into collaborations,research and/or licensing arrangements with the following institutions:(a)Brigham&Womens Hospital,Inc.,Boston,MA for INTEGRA(TM)Artific
192、ial Skin;(b)Cambridge Antibody Technology Limited,Cambridge,England,for product development of human TGF-(beta)antibodies;(c)Duke University Medical Center,Durham,NC for pre-clinical studies of collagen nerve graft tubes;(d)Eastern Virginia Medical School,Norfolk,VA for pre-clinical studies on polym
193、ers;(e)Agency for Contraceptive Research and Development,Norfolk,VA for topical fertility and sexually transmitted disease control;(f)Hospital for Joint Diseases Orthopedic Institute,New York,NY for pre-clinical studies on cartilage regeneration;(g)National Institute of Standards and Technology for
194、resorbable polymers for orthopedic indications and tissue engineering;(h)The Burnham Institute,La Jolla,CA(formerly La Jolla Cancer Research Foundation)for basic research on integrin signaling pathways;(i)Massachusetts General Hospital,Boston,MA for INTEGRA(TM)Artificial Skin studies;(j)Massachusett
195、s Institute of Technology,Cambridge,MA for INTEGRA(TM)Artificial Skin studies;(k)Robert Wood Johnson Medical School,Piscataway,NJ for quality control methodology;(l)Rutgers University,Piscataway,NJ for tyrosine polycarbonate polymers for orthopedic applications and tissue engineering;(m)University H
196、ospital Copenhagen,Denmark for clinical studies of collagen nerve graft tubes and resorbable polymers for tissue engineering;(n)J&J Professional,Inc.for articular cartilage regeneration;(o)Century Medical Inc.,Japan for INTEGRA(TM)Artificial Skin and neuro-surgical product clinical trials in Japan;(
197、p)The Scripps Research Institute in the areas of regenerating pancreas and stroke;and(q)University of Washington Engineered Biomaterials for bioengineering.The Company spent approximately$6.4 million,$6.3 million and$5.2 million during 1997,1996 and 1995,respectively,on research and development acti
198、vities.Research and development activities funded by government grants and contract development revenues amounted to$500,000,$1.1 million and$1.1 million during 1997,1996,and 1995,respectively.Patents and Proprietary Rights The Companys ability to compete effectively will depend,in part,on the clini
199、cal and commercial success of its development efforts and its ability to maintain the proprietary nature of its technologies and manufacturing processes.The Company pursues a policy of seeking patent protection for certain of its technology,products and product improvements both in the United States
200、 and in selected foreign countries.When appropriate,the Company has and plans to continue to enforce and defend its patent rights.The Company also relies upon trade 14 secrets,continuing technological innovations and licensing opportunities to develop and maintain its competitive position.As of Dece
201、mber 31,1997,the Company owned or had exclusive license rights to 134 issued or allowed United States patents and 107 issued or allowed foreign patents,with pending United States patent applications and related foreign patent applications describing approximately 250 additional inventions.These pate
202、nts and patent applications contain composition of matter,process and method of use claims for various fields of use,primarily involving regenerative medicine and related technologies.The Company files patent applications both in the United States and in foreign countries in order to protect both it
203、s products and technologies.In addition,the Company has various licenses to technologies patented by others.The patent position of biotechnology and pharmaceutical firms is highly uncertain,involves many complex legal,factual and technical issues and has recently been the subject of much litigation.
204、There is no clear policy involving the breadth of claims allowed in such cases or the degree of protection afforded under such patents.As a result,there can be no assurance that patent applications relating to the Companys products or technologies will result in patents being issued,that patents iss
205、ued or licensed to the Company will provide protection against competitors or that the Company will enjoy patent protection for any significant period of time.It is possible that patents issued or licensed to the Company will be successfully challenged,or that patents issued to others may preclude t
206、he Company from commercializing its products under development.Certain of the patents licensed by the Company for specific uses are licensed to other parties for use in certain fields or are sublicensed to other parties.Litigation to establish the validity of patents,to defend against infringement c
207、laims or to assert infringement claims against others,if required,can be lengthy and expensive.There can be no assurance that the products currently marketed or under development by the Company will not be found to infringe patents issued or licensed to others.The Companys competitive position is al
208、so dependent upon unpatented trade secrets.The Company continues to develop a substantial database of information concerning its research and development.The Company has taken security measures to protect its data and is in the process of exploring ways to enhance further the security of its data.Ho
209、wever,trade secrets are difficult to protect.There can be no assurance that others will not independently develop substantially equivalent proprietary information and techniques or otherwise gain access to the Companys trade secrets,that such trade secrets will not be disclosed,or that the Company c
210、an effectively protect its rights to unpatented trade secrets.In an effort to protect its trade secrets,the Company has a policy of requiring its employees,consultants and advisors to execute proprietary information and invention assignment agreements upon commencement of employment or consulting re
211、lationships with the Company.These agreements provide that all confidential information developed or made known to the individual during the course of their relationship with the Company must be kept confidential,except in specified circumstances.There can be no assurance,however,that these agreemen
212、ts will provide meaningful protection for the Companys trade secrets or other proprietary information in the event of the unauthorized use or disclosure of confidential information.Government Regulation The Companys research and development activities and the manufacturing and marketing of the Compa
213、nys existing and future products are subject to regulation by numerous governmental agencies in the United States and in other countries.The FDA and comparable agencies in other countries impose mandatory procedures and standards for the conduct of clinical trials and the production and marketing of
214、 products for diagnostic and human therapeutic use.The FDA product approval process has different regulations for drugs,biologics,and medical devices.The FDA currently classifies the Companys proposed regenerative medicine products as medical devices.Review Process for Medical Devices There are two
215、types of FDA review/approval procedures for medical devices:a Premarket Notification Section 510(k)(510(k)and a Premarket Approval(PMA)application.A 510(k)requires submission of 15 sufficient data to demonstrate substantial equivalence to a device marketed prior to May 28,1976,or to a device markete
216、d after that date which has been classified into Class I or Class II.Although the mandated period for FDA review is 90 days,actual review times can be substantially longer,and the sponsor cannot market the device until FDA clearance is obtained.For those devices that involve new technology and/or th
217、at present significant safety and effectiveness issues,510(k)submissions may require significantly more time for FDA review and may require submission of more extensive safety and effectiveness data,including clinical trial data.Among the conditions for clearance to market of a 510(k)submission is t
218、he requirement that the prospective manufacturers quality control and manufacturing procedures conform to the FDAs current Quality System Regulations.In complying with standards set forth in these regulations,manufacturers must expend time,money and effort for production and quality control to ensur
219、e full technical compliance at all times.Manufacturing establishments,both international and domestic,are also subject to inspections by or under the authority of the FDA.Although,at present,the FDA generally does not inspect such establishments prior to clearance of a 510(k)submission,it is establi
220、shing a program of conducting quality system inspections for new devices in the future as a standard practice.The Medical Device Amendments of 1976 amended the Federal Food,Drug and Cosmetics Act to establish three regulatory classes for medical devices,based on the level of control required to assu
221、re safety and effectiveness.Class III Devices are defined as life-supporting and life-sustaining devices,devices of substantial importance in preventing impairment of human health or devices that present potentially unreasonable risk of illness or injury.Class III devices are those for which there i
222、s insufficient information to show that Class I or Class II controls can provide a reasonable assurance of safety or effectiveness.The PMA application review process for Class III devices was established to evaluate the safety and effectiveness of these devices on a product by product basis.Manufact
223、urers that wish to market Class III devices must submit and receive approval of a PMA application from the FDA.The FDA has substantial content and format requirements for PMA applications,which include clinical and non-clinical safety and effectiveness data,labeling,manufacturing processes and quali
224、ty assurance programs.As part of the PMA application process,the PMA application may be referred to an FDA Advisory Panel for review.Additionally,final approval of the product is dependent on an inspection of the manufacturing facility for compliance with FDA Quality System Regulations.All studies i
225、n humans for the purpose of investigating the safety and effectiveness of an investigational medical device must be conducted under the Investigational Device Exemption(IDE)regulations.An IDE application to the FDA includes all preclinical biocompatibility testing,investigational protocols,patient i
226、nformed consents,reports of all prior investigations,manufacturing and quality control information.It takes a number of years from initiation of the project until submission of a PMA application to the FDA,and requires the expenditure of substantial resources.If a PMA application is submitted,howeve
227、r,there can be no assurance on the length of time for the review process at the FDA or that the FDA will approve the PMA application.Under either the 510(k)submission or PMA application process,manufacturing establishments,foreign and domestic,are subject to periodic inspections by the FDA for compl
228、iance with Quality System Regulations.The Company and each of its operating subsidiaries are subject to such inspections.To gain approval for the use of a product for clinical indications other than those for which the product was initially evaluated or for significant changes to the product,further
229、 studies,including clinical trials and FDA approvals are required.In addition,for products with an approved PMA application,the FDA requires post-approval reporting and may require post approval surveillance programs to monitor the products safety and effectiveness.Results of post approval programs
230、may limit or expand the further marketing of the product.16 International Regulatory Requirements The Company is preparing for the changing international regulatory environment.ISO 9000 is an international recognized set of guidelines that are aimed at ensuring the manufacture and development of qua
231、lity products.The Company was audited under ISO standards in 1997,and received certification to ISO9001,a full quality system.The Company is required to be audited on an annual basis by a recognized notified body to maintain certification.Companies that meet ISO standards are internationally recogni
232、zed as functioning under a quality system.Approval of a product by regulatory authorities in international countries must be obtained prior to the commencement of marketing of the product in such countries.The requirements governing the conduct of clinical trials and product approvals vary widely fr
233、om country to country,and the time required for approval may be longer or shorter than that required for FDA approval of the PMA application.In June 1998,the European Union Medical Device Directive becomes effective,and all medical devices must meet the Medical Device Directive standards and receive
234、 CE mark certification.CE mark certification involves a comprehensive quality system program,and may require submission of data on a product to the notified body in Europe.Other United States Regulatory Requirements In addition to the regulatory framework for product approvals,the Company is and may
235、 be subject to regulation under federal and state laws,including requirements regarding occupational health and safety;laboratory practices;and the use,handling and disposal of toxic or hazardous substances.The Company may also be subject to other present and possible future local,state,federal and
236、foreign regulations.The Companys research,development and manufacturing processes involve the controlled use of certain hazardous materials.The Company is subject to federal,state and local laws and regulations governing the use,manufacture,storage,handling and disposal of such materials and certain
237、 waste products.Although the Company believes that its safety procedures for handling and disposing of such materials comply with the standards prescribed by such laws and regulations,the risk of accidental contamination or injury from these materials cannot be completely eliminated.In the event of
238、such an accident,the Company could be held liable for any damages that result and any such liability could exceed the resources of the Company.Although the Company believes that it is in compliance in all material respects with applicable environmental laws and regulations,there can be no assurance
239、that the Company will not incur significant costs to comply with environmental laws and regulations in the future,nor that the operations,business or assets of the Company will not be materially adversely affected by current or future environmental laws or regulations.Manufacturing The Companys prim
240、ary manufacturing facility is located in Plainsboro,New Jersey.The Company manufactures the majority of its medical products at this approximately 35,000 square foot FDA-registered and inspected facility which also serves as the Companys executive offices.The Companys commercial-scale manufacturing
241、facility for INTEGRA(TM)Artificial Skin is at this location.The basic material for many of the Companys medical and regenerative medicine products is principally purified collagen prepared from bovine tendon in a four-step process:(i)the raw material is processed with various enzymes and solvents to
242、 purify and render it non-immunogenic;(ii)the purified material is dispersed into suspensions appropriate for the manufacture of the different forms of collagen material and then dried using freeze drying techniques;(iii)the fibrous material yielded from the drying step is cross-linked through chemi
243、cal bonding of overlying fibers,with different types and degrees of cross-linking being used for different products;and(iv)the bonded material is sized and packaged.The Company has installed equipment for the manufacture of bovine collagen-based products at its Plainsboro facility.17 The Company als
244、o has a lease agreement for a four-building site consisting of approximately 25,000 square feet in West Chester,Pennsylvania.The West Chester facility and manufacturing assets were under renovation from 1994 through 1996.The Company has decided to reduce costs by shutting down the West Chester facil
245、ity and consolidating the operations at the Plainsboro site.Through improved efficiencies,the Plainsboro facility is capable of handling these additional operations,as well as requirements from increased sales in the foreseeable future.The West Chester facility transition will occur during the early
246、 part of 1998,and the Company plans on transferring some associates to the Plainsboro facility.The Company believes that its existing and renovated manufacturing facilities are adequate for the foreseeable future and,depending on product mix and pricing,can support the manufacturing for significant
247、product sales.Further,the Company believes that suitable additional or alternative space will be available on commercially reasonable terms when needed in the future.Competition In general,the medical technology industry is subject to rapid,unpredictable and significant technological change.Competit
248、ion from established pharmaceutical and medical technology companies is intense.Competition also comes from early stage companies that have alternative technological solutions for the Companys primary clinical targets.New technologies are constantly being developed at universities and research insti
249、tutions.The Companys competitive position will depend on its ability to secure regulatory approval for its products,implement production and marketing plans,obtain patent protection and secure adequate capital resources.The Company is aware of several companies seeking to develop dermal replacement
250、and other products that could,if successfully developed,potentially compete with the regenerative medicine technologies under development by the Company.A number of biotechnology,pharmaceutical and chemical companies are developing various types of wound healing treatments which are alternatives to
251、tissue regeneration for some conditions,including chronic skin ulcers.These treatments employ a variety of approaches such as growth factors,tripeptides and wound dressings.The Company believes that some of these alternatives could be used in conjunction with the Companys products.The Company compet
252、es primarily on the uniqueness of its technology and product features and on the quality and cost-effectiveness of its products.Many competitors or potential competitors have greater financial resources,research and development capabilities,and marketing and manufacturing experience than the Company
253、.While there can be no assurance that the Companys products and technology will not become obsolete,the Company believes that it occupies a unique position in its industry because INTEGRA(TM)Artificial Skin was the first regenerative product approved by the FDA and due to the Companys strong patent
254、portfolio covering the field of regeneration.The Company is aware of several companies seeking to develop products that could,if successful and approved,compete with the regenerative medicine technologies under development by the Company.Several of these companies have products that may compete with
255、 INTEGRA(TM)Artificial Skin,including LifeCell Corporation(see Item 3.Legal Proceedings below),Genzyme Tissue Repair(a division of Genzyme Corporation),Advanced Tissue Sciences,Inc.,Organogenesis,Inc.and Ortec International,Inc.LifeCell Corporation and Genzyme Tissue Repair are currently not subject
256、 to FDA regulation because they involve the processing of human cells and tissues and,therefore,are not currently subject to the costs and expenses and the potential delays associated with the FDA approval process.The Company believes that expansion of its markets will be enhanced by the entry of ad
257、ditional competitors.During the last year several new products have been approved by the FDA or have moved closer to final approval.These include products by Johnson&Johnson(Regranex),Advanced Tissue Sciences,Inc.(Dermagraft)and Organogenesis,Inc.(Apligraf),Regranex is a growth factor based wound he
258、aling compound which competes with the Companys technologies at Telios.Dermagraft and Apligraf are dermal replacement products targeted primariliy at chronic wounds.Dermagraft received a recommendation for approval from the FDA Advisory Panel on January 29,1998 for treatment of diabetic ulcers.Graft
259、skin is composed of donor human cells,bovine collagen and other ingredients and received a recommendation for approval from a FDA Advisory Panel on January 29,1998 for treatment of venous stasis ulcers.The Company believes that success of these products in the market will offer an opportunity for In
260、tegras technologies in the future.Ultimately,therefore,the Companys competitive position will depend both on the size of the market for its products and on the sales and marketing strength established by the 18 Company and its corporate partners.The breadth of the Companys technologies allows it to
261、compete in a wide range of possible solutions to the problem of repair of damaged tissue.Employees The Company regards its employees as one of its most important assets.The competitive advantage of life sciences companies depends on a committed workforce,sound management processes and systems that m
262、aximize utilization of each employees technical knowledge.The Company has developed such systems and processes in order to allow it to manage and market effectively its intellectual capital.To foster employee commitment the Company has implemented incentive plans that provide its employees the oppor
263、tunity to invest and benefit from the Companys success.The Company is dedicated to building on these principles as it moves forward.At December 31,1997,the Company employed 166 full-time people(including temporary and part-time employees)of which 58 are engaged in production and production support(i
264、ncluding warehouse,engineering,and facilities personnel),15 in quality assurance/quality control,35 in research and development,10 in regulatory and clinical affairs,21 in sales/marketing and 27 in administration and finance.None of the Companys employees is subject to a collective bargaining agreem
265、ent.Forward Looking Statements This report contains trend information and other forward-looking statements related to the future use and sales of the Companys products,potential markets for the Companys products,anticipated expenditure levels compared to historical amounts and the Companys plans for
266、 its research and development efforts.Such statements are made pursuant to the safe harbor provisions of the Securities Litigation Reform Act of 1995 and involve risks and uncertainties which may cause results to differ materially from those set forth in these statements.Potential risks and uncertai
267、nties include,without limitation,those mentioned in this report and,in particular,those mentioned under Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations-Factors That May Affect Future Results of Operations.ITEM 2.PROPERTIES The Company has a lease for appro
268、ximately 35,000 square feet for its principal administrative,marketing,manufacturing and product development activities in Plainsboro,New Jersey that expires in October 2012.It also holds a lease for approximately 25,000 square feet of production,administration and warehouse space in West Chester,Pe
269、nnsylvania that expires in April 1999,with three five-year renewal options.The Company has decided to suspend its operations at the West Chester,Pennsylvania facility.The Companys Telios Pharmaceutical,Inc.subsidiary leases approximately 18,600 square feet of administrative and laboratory space loca
270、ted in San Diego,California under a lease that expires in October 2004.The Company also leases several smaller facilities to support additional administrative and storage operations.ITEM 3.LEGAL PROCEEDINGS In January 1994,ABS LifeSciences,Inc.,a wholly-owned subsidiary of the Company,entered into a
271、 five-year distribution agreement with the distributor of the Companys Chronicure product pursuant to which the distributor is obligated to purchase certain minimum quantities of wound care products.In October 1995,the Companys subsidiary filed a complaint in the United States District Court for the
272、 District of New Jersey claiming the distributor breached the distribution agreement by,among other things,not paying the subsidiary for certain products delivered.In November 1995,the distributor filed an affirmative defense and counterclaim alleging,among other things,fraudulent misrepresentation
273、and breach of contract and seeking damages of approximately$1.2 million plus unspecified punitive damages.During 1997,the case was inactive and dismissed by the court based on a tentative settlement with leave to reinstate on the request of either party.However,the Company has not been able to consu
274、mmate an acceptable settlement and has submitted a request to reinstate the case.The Company intends to continue to defend the counterclaim.On or about July 18,1996,Telios filed a patent infringement lawsuit against three parties:Merck KGaA,a German corporation,Scripps Research Institute,a Californi
275、a nonprofit corporation,and David A.Cheresh,Ph.D.,a research scientist with Scripps.The lawsuit was filed in the U.S.District Court for the Southern District of California.The complaint charges,among other things,that the defendant Merck KGaA willfully and deliberately induced,and continues to willf
276、ully and deliberately induce,defendants Scripps Research Institute and Dr.David A.Cheresh to infringe United States Letters Patent No.4,729,255.This patent is one of a group of five patents granted to Burnham and licensed by Telios that are based on the interaction between a family of cell surface p
277、roteins called integrins and the arginine-glycine-aspartic acid(known as RGD)peptide sequence found in many extracellular matrix proteins.The Company is pursuing numerous medical applications of the RGD technology in the fields of anti-thrombic agents,cancer,osteoporosis,and a cell adhesive coating
278、designed to improve the performance of 19 implantable devices and their acceptance by the body.The defendants have filed a countersuit asking for an award of defendants reasonable attorney fees.In August 1995,Telios received confirmation of its Chapter 11 plan of reorganization in the United States
279、Bankruptcy Court for the Southern District of California.Under the plan,Telios assumed a certain License Agreement and a certain Research Agreement entered into with the University of Utah and the University of Utah Research Foundation(University)in 1991.On March 27,1996,Telios filed a motion with t
280、he bankruptcy court for a determination as to whether there were any cure requirements for the assumed contracts with the University(the Motion).In the meantime,on March 22,1996,the University filed a complaint against Telios in the United States District Court for the District of Utah seeking a dec
281、laration that the License Agreement and Research Agreement were terminated or terminable.The District Court case was subsequently dismissed in light of the pending Motion in the bankruptcy court.In November 1997,the bankruptcy court entered an order decreeing that Telios license to certain of the pa
282、tents and technology rights under the License Agreement had been reduced to a non-exclusive license.However,the court did not terminate the license.In addition,Telios still retains an exclusive license to certain patents,technology and rights to make,use and sell licensed products thereunder,which h
283、ave been exclusively sublicensed by Telios to Cambridge Antibody Technology,Limited.A hearing has been set for May 27,1998 to determine whether Telios has licensing rights to a certain new invention disclosed by the University under the License Agreement and/or the Research Agreement.On or about Nov
284、ember 4,1997,Integra(Artificial Skin)Corporation(IASC),a wholly-owned subsidiary of the Company,and the Massachusetts Institute of Technology(MIT)filed a patent infringement lawsuit against LifeCell Corporation(LifeCell)alleging that LifeCell infringed United States Patent Nos.4,458,678 and 4,505,26
285、6 through the making,using and selling of its AlloDerm(R)and/or XenoDerm(TM)products.The suit was filed in the United States District Court for the District of Massachusetts.The patents in suit are licensed by MIT to IASC and relate to treating wounds with products which encourage tissue regeneratio
286、n.LifeCell has filed counterclaims seeking declaratory judgments of non-infringement and patent invalidity and also claims that MIT and IASC are barred from recovery under the doctrines of laches,patent misuse and unclean hands alleging,among other things,that MIT and IASC filed this suit solely to
287、disrupt LifeCells November 1997 stock offering.LifeCell has filed a motion to transfer this action to the United States District Court for the Southern District of Texas which motion MIT and IASC are opposing.The Company intends to vigorously pursue its claims and vigorously defend against LifeCells
288、 counterclaims and affirmative defenses.On or about December 10,1997,LifeCell filed a complaint against MIT and IASC in Texas state court claiming tortious interference,business and product disparagement,unfair competition,civil conspiracy and violation of the Texas Free Enterprise and Antitrust Act
289、 based upon the contention that MIT and IASC filed the patent infringement suit in Massachusetts in order to interfere with LifeCells November 1997 stock offering.LifeCell is seeking unspecified actual monetary damages in an amount not less than$12 million together with treble damages,unspecified pu
290、nitive damages,and other relief.MIT and IASC removed this case to the United States District Court for the Southern District of Texas and have filed a motion to transfer it to United States District Court in Massachusetts.LifeCell filed a motion to remand the case back to Texas state court which mot
291、ion MIT and IASC are opposing.MIT and IASC have also filed motions to dismiss the case for lack of personal jurisdiction and to stay discovery.The Company also intends to vigorously defend against this suit.The ultimate liability of the cases disclosed above cannot now be determined because of the c
292、onsiderable uncertainties that exist.The Companys financial statements do not reflect any significant amounts related to possible unfavorable outcomes of these matters.The Company intends to continue its vigorous defense of these matters.However,it is possible that the Companys results of operations
293、,financial position and cash flows in a particular period could be materially affected by these contingencies.ITEM 4.SUBMISSION OF MATTERS TO A VOTE OF SECURITY HOLDERS Pursuant to a written consent dated December 27,1997,the holders of 18,428,836 shares,or approximately 61.6%,of the Companys issued
294、 and outstanding shares of Common Stock approved the following:(i)an amendment to the Companys 1996 Incentive Stock Option and Non-Qualified Stock Option Plan(the Plan)increasing the maximum number of options that may be issued under the Plan to an individual over any one-year period from 300,000 to
295、 1,000,000;(ii)the grant to Stuart M.Essig,the Companys President and Chief Executive Officer,of an option under the Plan to purchase 20 1,000,000 shares of Common Stock;and(iii)the grant to Mr.Essig of restricted units pursuant to which he is to acquire an additional 2,000,000 shares of Common Stoc
296、k.These approvals were obtained pursuant to Section 228 of the Delaware General Corporation Law,subject to the expiration of twenty(20)days following the mailing on February 24,1998 of an Information Statement to the Companys stockholders as required under the Securities Exchange Act of 1934,as amen
297、ded.Additional Information The following information is furnished in this Part I pursuant to Instruction 3 to Item 401(b)of Regulation S-K:Executive Officers of the Company.The executive officers of the Company serve at the discretion of the Board of Directors.The only family relationship between an
298、y of the executive officers of the Company is between Dr.Caruso and Mr.Holtz,who is the nephew of Dr.Caruso.The following information indicates the position and age of the Companys executive officers as of the date of this report and their previous business experience.Executive Officers Richard E.Ca
299、ruso,Ph.D.founded the Company and is the Chairman of the Board of Directors.Until December 1997,Mr.Caruso also served as President and Chief Executive Officer.From 1969 to 1992,Dr.Caruso was a principal of LFC Financial Corporation,a major entrepreneurial financing company located in Radnor,Pennsylv
300、ania.When he left in 1992,he was a director of the company and held the position of Executive Vice President.He has 25 years experience in finance and entrepreneurial ventures.Before joining LFC Financial Corporation,Dr.Caruso was associated with Price Waterhouse&Co.in Philadelphia,Pa.Dr.Caruso has
301、served as a director or trustee of the following organizations:American Capital Open End Mutual Funds,LFC Financial Corporation,202 Data Systems,Tenley Enterprises,Inc.,and London School of Economics Business Performance Group.He is currently a director of Susquehanna University,The Baum School of A
302、rt,Uncommon Individual Foundation(Founder)and the Company.He received a BS degree from Susquehanna University,an MSBA degree from Bucknell University,and a Ph.D.degree from the London School of Economics,University of London(UK).Dr.Caruso is also a certified public accountant.21 Name Age Position Ri
303、chard E.Caruso,Ph.D.54 Chairman Stuart M.Essig,Ph.D.36 President and Chief Executive Officer George W.McKinney,Ph.D.54 Vice Chairman,Executive Vice President and Chief Operating Officer Frederick Cahn,Ph.D.55 Senior Vice President,Technology Andre P.Decarie 52 Senior Vice President,Corporate Develop
304、ment Michael D.Pierschbacher,Ph.D.46 Senior Vice President and General Manager,Telios Surendra P.Batra,Ph.D.51 Vice President,Product Research Carlos Blanco,M.D.62 Vice President,Medical Director David B.Holtz 31 Vice President,Treasurer Donald Nociolo 35 Vice President,Operations Judith E.OGrady 47
305、 Vice President,Regulatory Affairs Robert D.Paltridge 40 Vice President,North American Sales Robert G.Runckel 52 Vice President,Marketing and International Sales Stuart M.Essig,Ph.D.has served the Company as President and Chief Executive Officer since December 1997.Mr.Essig was elected by the Board
306、of Directors as the Companys President and Chief Executive Officer and appointed to the Board in December 1997.Before joining the Company,Mr.Essig supervised the medical technology practice at Goldman,Sachs&Co.as a managing director.Mr.Essig has ten years of broad health care experience at Goldman S
307、achs serving as a senior merger and acquisitions advisor to a broad range of domestic and international medical technology,pharmaceutical and biotechnology clients.Mr.Essig received an A.B.degree from the Woodrow Wilson School of Public and International Affairs at Princeton University,and an MBA an
308、d a Ph.D.degree in Financial Economics from the University of Chicago,Graduate School of Business.Mr.Essig also serves on the Board of Directors of Neuromedical Systems,Inc.,a Medical diagnostics products company.George W.McKinney,Ph.D.has served the Company as Vice Chairman,Executive Vice President
309、 and Chief Operating Officer since May 1997 and as a member of the Board of Directors since December 1992.Between 1990 and 1997,Dr.McKinney was Managing Director of Beacon Venture Management Corporation,a venture capital firm.Between 1992 and 1997,Dr.McKinney also served as President and Chief Execu
310、tive Officer of Gel Sciences,Inc.and GelMed,Inc.,a privately held specialty materials firm with development programs in both the industrial and Medical products field.From 1983 to 1989,Dr.McKinney was a Managing Director at American Research&Development,a venture capital firm.Between 1986 and 1989,h
311、e also served as President and Chief Executive Officer of American Superconductor,Inc.(NASDAQ:AMSC),a development stage firm in the specialty materials field.From 1965 to 1983,Dr.McKinney worked for Corning Glass Works(now Corning,Inc.),a specialty materials firm,in a variety of manufacturing,engine
312、ering,and financial positions.At Corning,he served as President of Corning Designs,a subsidiary which he founded,as Secretary to the Management Committee,as Director of Business Development and Planning,as Treasurer,International,as Assistant Treasurer,Domestic,and as Financial and Control Manager f
313、or the Engineering Division.Dr.McKinney holds a S.B.from MIT in Management and a Ph.D.from Stanford University in Strategic Planning.Frederick Cahn,Ph.D.has served the Company as Vice President for Technology from 1993 to September 1995 and as Senior Vice President of Technology since September 1995
314、.Between 1987 and 1993,Dr.Cahn was President and Founder of Biomat Corporation.The Company appointed him to his current position after the acquisition of Biomat in April 1993.Before founding Biomat,Dr.Cahn served as Senior Scientist at Digilab Division of Bio-Rad Laboratories developing software and
315、 methods for chemical analysis and quality control for semiconductor and medical diagnostic applications.From 1980 to 1984,Dr.Cahn was Senior Scientist for New England Digital Corporation developing acoustic research and digital signal processing products.From 1988 to the present,he carried out vari
316、ous research duties as a Research Affiliate with the Massachusetts Institute of Technology,including a project to demonstrate the feasibility of porous microcarriers for mass culture of mammalian cells.Dr.Cahn received a BA degree in Physics and Biology from the University of California at Berkeley,
317、and a Ph.D.degree in Biophysics from the Massachusetts Institute of Technology.Andre P.Decarie,Senior Vice President,Corporate Development,joined the Company as Vice President of Marketing in 1993.Mr.Decarie has been active in the medical industry for over 20 years,both in senior management position
318、s and in private consulting.He was Vice President of Sales for Surgical Laser Technologies and Vice President of Marketing for Hemostatic Surgery Corporation.He spent over 14 years at United States Surgical Corporation in a variety of national and international assignments,including sales,marketing
319、and product development.In 1990,as Director of Continuing Medical Education for USSC,he led the group which guided the training of over 15,000 surgeons in the US and hundreds of international surgeons,in techniques of Minimally Invasive Surgery.He is a member of the ASCRS Research Foundation,and a m
320、ember of their Gold Eagle Society.Mr.Decarie holds a BBA degree in Marketing from the University of Miami.Michael D.Pierschbacher,Ph.D.joined the Company in October 1995 as Senior Vice President,Research and Development.Dr.Pierschbacher served Telios,which was acquired by the Company in connection w
321、ith the reorganization of Telios under Chapter 11 of the Bankruptcy Code,as Senior Vice President and Scientific Director from June 1987 to September 1995.He was a co-founder of Telios in May 1987 and is the co-discoverer and developer of Telios matrix peptide technology.Before joining Telios as a f
322、ull-time employee in October 1988,he was a staff scientist at the Burnham Institute for five years and remained on staff there in an adjunct capacity until the end of 1997.He received his post-doctoral training at Scripps Clinical and Research Foundation and at the Burnham Institute.Dr.Pierschbacher
323、 received his Ph.D.in Biochemistry from the University of Missouri.22 Surendra P.Batra,Ph.D.has served the Company as Vice President for Product Research since January 1992.Between 1991-1992 Dr.Batra was a Research and Development Manager at ABS LifeSciences,a subsidiary of Integra LifeSciences.Dr.B
324、atra has worked in the field of protein biochemistry,enzymology,biomaterials,tissue regeneration and implantable materials,for 15 years and has published ten(10)research articles.Prior to joining Integra LifeSciences,Dr.Batra served with Semex Medical,Inc.as a Senior Scientist Group Leader in biomat
325、erials development,specializing in wound care,ophthalmology,drug delivery and implantables.Before coming to the United States,Dr.Batra taught medical biochemistry for eight(8)years in a reputable medical school in New Delhi,India.Dr.Batra received an MS Chemistry degree from the University of Meerut
326、,India;an MS in Medical Biochemistry from Delhi University,India and a Ph.D.in Physiology and Biochemistry from the Reading University in the U.K.Carlos Blanco,M.D.joined the Company full time in May 1997 and serves as the Companys Vice President,Medical Director.He had previously served as a consul
327、tant and senior advisor to the Company.From 1985 to 1996,Dr.Blanco was employed by Marion Laboratories and its successor companies Marion Merrell Dow,Inc.and Hoechst Marion Roussel,holding positions as Director,International Marketing;Director,Medical Marketing;Director,Marketing Relations for Wound
328、 Care;and Medical Director,Wound Care.While at Marion,Dr.Blanco was instrumental in the development of INTEGRA(TM)Artificial Skin.Prior to working for Marion,Dr.Blanco served in several companies in the wound care business,most notably for 15 years with The Purdue Frederick Company,where he served a
329、s Director,Clinical Research and Director,Burn/Wound Programs.Dr.Blanco is on the Board of Directors for the Wound Healing Society,Chairman of Ad hoc Committee of the International Society of Burn Injuries,Chairman of the Industry Relations Committee Wound Healing Society and the Board of Trustees o
330、f the American Burn Association.Dr.Blanco received his medical degree from Seville Medical School in Seville,Spain and his BS degree from Colegio del Carmen,Melila,Spain.David B.Holtz joined the Company as the Controller in 1993 and has served as Vice President,Treasurer since March 1997.His respons
331、ibilities include managing all accounting and information systems functions.He is also responsible for the preparation of the Companys Securities and Exchange Commission filings and federal and state tax returns.Before joining the Company,Mr.Holtz was an associate with Coopers&Lybrand,L.L.P.in Phila
332、delphia and Cono Leasing Corporation,a private leasing company.He received a BS degree in Business Administration from Susquehanna University in 1989 and is a certified public accountant.Donald Nociolo joined the Company as Director,Manufacturing in 1994 and has served as Vice President,Operations s
333、ince March 1997.His responsibilities include managing all manufacturing operations to ensure on-time shipment of GMP produced and high quality product to all customers.Mr.Nociolo has over ten years experience working in engineering and manufacturing management in the Medical device industry.Six of those years were spent working at Ethicon,Inc.,Johnson&Johnsons suture division.Mr.Nociolo received a
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