sector landscapes: tissue & biologics

SECTORLANDSCAPES

Leading the conversation

TISSUE & BIOLOGICS2015

About LifeScience AlleyLifeScience Alley is a global leader in enabling health technology and care organizations to innovate, succeed, and influence the evolution of healthcare. By influencing policy, delivering actionable information and intelligence and connecting members with critical resources, we work to ensure that Minnesota's Medical Alley remains the world's strongest health technology community.

SECTOR LANDSCAPES: TISSUE & BIOLOGICSCopyright © 2015 by LifeScience Alley. All rights reserved.

About Sector Landscapes PublicationsThe Sector Landscapes provide in depth analysis of emerging and established industry sectors in Minnesota. The reports highlight global industry insights, Minnesota core and supporting assets, unique positioning, company lists, and industry trends. Identified sector areas include: neuromodulation, cardiac active implantables, tissue based products, research tools, animal health, diagnostics, vascular technologies, and digital health.

List of Contributors

PLEASE DIRECT CORRESPONDENCE TO:

Cheryl Matter, PhD, Vice President of Intelligence & Research, LifeScience [email protected] | 952.746.3817

Bridget Wallm, PhD, LifeScience Alley ConsultantContributing Author

Elly Liao, PhD, University of Minnesota Postdoctoral FellowResearch Lead

Amanda K. Weber, LifeScience Alley Design ConsultantVisualization + Design

LifeScience Alley's intelligence and research work is generously supported by our Foundational and Sustaining Members.

Foundational Members

Sustaining Members

Tissue & Biologics is a rapidly growing sector in the thriving regenerative med-icine industry. Historically, Minnesota has been a pioneer in tissue-based products and biologics. In fact, the first pre-market approvals issued in the state were to Coloplast and Synovis Surgical Innovations for vocal cord augmentation and vascular reconstruc-tion respectively.

There has been continued growth in the sector since the 1970s, which has led to a burgeoning cluster of biologics companies developing novel therapies using cell or tissue-based approaches to repair or replace organs and tissues.

Using core community competencies in cardiovascular diseases, unique tissue and biomaterial processing technolo-gies, and tissue transplantation capa-bilities; the Tissue & Biologics sector in Minnesota is developing unique products that are advancing the field of regenerative medicine.

The companies in this industry are succeeding by taking advantage of the strong ecosystem created by the medical device companies, support-ive infrastructure at the University of Minnesota and Mayo Clinic and a highly educated workforce with a history of innovation. The primarily small com-panies and startups in this industry have been able to garner support from

the investment community. In 2014, life science investment in the region set a five-year high; investments in both pharma and biotech companies increased ten-fold over 2013 levels.

EXECUTIVE SUMMARY

1955

2014

1925

1985

1895

CUMULATIVE GROWTH OF INDUSTRY IN MINNESOTA

one line = one company

[1] INSIDE THE TISSUE & BIOLOGICS INDUSTRY 1

Minnesota’s Tissue & Biologics sector is developing unique products that are advancing the field of regenerative medicine by using core community competencies in cardiovascular diseases, unique biomaterial & tissue processing technologies, and tissue transplantation capabilities.

MINNESOTA INDUSTRY BY SECTOR 2

[2] THE GLOBAL - LOCAL COMPARISON 4

Of all the companies representing the Tissue & Biologics industry across the world, more than ten-percent are based out of Minnesota.

GLOBAL INDUSTRY 5

[3] CORE CAPABILITIES IN MINNESOTA 7

The Therapeutics Sector and Support & Services Sector are among the most developed of the four represented core capabilities in Minnesota.

THERAPEUTICS 10

+ Orthopedics 11

+ Scaffold & Matrix 12

+ Emerging Technologies 14

+ Cardiovascular Disease 16

BIOBANKS 17

TOOLS & DIAGNOSTICS 19

SUPPORT & SERVICES 20

[4] TISSUE & BIOLOGICS RESOURCE DIRECTORY 26

APPENDIX: LISTING OF RECENT ACQUISITIONS 38

LIST OF FIGURES

FIGURE 1. Breakdown Of MN Tissue & Biologics Sector by Specialty 3

FIGURE 2. Global Breakdown of Sectors 6

FIGURE 3. Global Companies with Tissue & Biologics Products on Market 6

FIGURE 4. Cumulative Growth Of Industry Segments In Minnesota 9

FIGURE 5. Breakdown of Therapeutics Sector in Minnesota 10

1Sector Landscapes: Tissue & Biologics | Text

INSIDE THETISSUE &BIOLOGICSSECTOR

1.

2Sector Landscapes: Tissue & Biologics | Inside the Tissue & Biologics Sector

The regenerative medicine industry has caused a paradigm shift in healthcare therapies. Scientific advances and discoveries have allowed the shift from traditional methods that treat the symptoms of the disease to a focus on ameliorating the underlying causes of the disease. Some of the factors driving this change are: the growing elderly population which is putting a strain on the healthcare industry; increase in chronic diseases like diabetes, obesity and neurodegenerative diseases; change in reimbursement policies; and the increasing prevalence of private insurance which is willing to pay for these new treatments.

This brief focuses on tissue-based products and cellular biologics, which are large sectors within the regenerative medicine industry. There is a significant potential to resolve many unmet medical needs using cell or tissue-based therapies and natural and synthetic scaffolds to replace, repair or aid in the regeneration of organs and tissues.

114 Minnesota companies are dedicated to discovering new ways to innovate across the Tissue & Biologics sector.

3Sector Landscapes: Tissue & Biologics | Inside the Tissue & Biologics Sector

FIGURE 1. BREAKDOWN OF MN TISSUE & BIOLOGICS SECTOR BY SPECIALTY

37%

23%

08%

32%

114

MIN

NES

OTA

CO

MPA

NIE

S IN

TIS

SUE

& B

IOLO

GIC

S SE

CTO

R

THE GLOBAL - LOCALCOMPARISON

2.

5Sector Landscapes: Tissue & Biologics | The Global - Local Comparison

Principal players in the Pharmaceutical and Biotech industry believe that the Tissue & Biologics sector is key to developing the next generation of breakthrough medicines.1 Although these companies have already invested $92 billion in research and development of cellular-based therapies, many are still actively pursuing new opportunities. Some of these investments are now coming to fruition and are generating approximately $1 billion in revenue. Since 2008, the FDA has approved six biologics products for the market.2

In 2014, these companies acquired $2.9 billion in funding for 466 unique products and about 700 on-going preclinical and clinical trials.1 Due to this investment, the tissue biologics sector had an annual growth of 28.7% from 2008 to 2013 and is anticipated to grow 18% over the next five years.2

There are approximately 700 companies worldwide pursuing therapeutics classified as regenerative medicine therapies, 418 of which are being actively tracked by Alliance Regenerative Medicine as leading in the sector.1

1 SOURCE: Alliance for Regenerative Medicine Annual Report 2014.2 SOURCE: IBISWorld Industry Report Cell Therapy, OD4040, May 2013.

6Sector Landscapes: Tissue & Biologics | The Global - Local Comparison

FIGURE 2. GLOBAL BREAKDOWN OF SECTORS

FIGURE 3. GLOBAL COMPANIES WITH TISSUE & BIOLOGICS PRODUCTS ON MARKET

COMPANY &HQ LOCATION

MARKETED PRODUCT* FDA APPROVED

ANNUAL REVENUE

PRODUCT APPLICATION

3M Critical & Chronic Care, Minnesota Multiple Products $700M Various wound care products

Dendreon (Valeant),Washington * Provenge™ $320M Vaccine for prostate cancer

Organogenesis,Massachusetts

Dermagraft™, Apligraf™, * Gintuit™ $310M Skin grafts / wound healing

Gum-line restoration

Baxter International,Illinois (presence in MN) TISSEEL™, FLOSEAL™ $162M Medical adhesives / sealants

NuVasive, California Osteocel™ $74M Osteochondral defects

Aastrom, Massachusetts * Carticel™ $35.2M Chondral defects

Fibrocell Technologies,Pennsylvania * LAVIV™ $0.1M Wrinkles in nasolabial folds

Sanofi Pasteur Limited,France * Theracys™ - Bladder cancer vaccine

Multiple Centers * HPC Cord Blood - Bone marrow transplantation

56%19%

13%

12%


CORE CAPABILITIESIN MINNESOTA

3.

8Sector Landscapes: Tissue & Biologics | Core Capabilities in Minnesota

The Tissue & Biologics sector in Minnesota has been a leader of innovative Tissue & Biologics products since the first premarket approvals (PMA) were issued for the state. In 1972, Coloplast was granted a PMA for Polytef Injection for Vocal Cord Augmentation. Synovis Surgical Innovations was granted a PMA in 1979 for a vein biograft derived from umbilical cords. The industry has continued to progress, and as a result there are currently 114 companies and organizations in Minnesota that are developing tissue-based products and cellular biologics. These companies are distributed across four sectors, some contributing to more than one sector:3

+ Therapeutics | 37 companies + Biobanks | 28 establishments + Tools & Diagnostics | 9 companies + Support & Services | 43 companies

These companies secured approximately $80 million in funding in 2014. Most of the funding came from venture capital firms, but locally sponsored programs from DEED, like the Angel Investor Tax Credit, R&D Tax Credit and other business financing initiatives have also helped attract capital. Furthermore, there have been many acquisitions by larger biotechnology firms in this sector, such as the Wright Medical merger with Tornier in 2014 and the Baxter International acquisition of Synovis Surgical Innovations in 2011.4

3 See Tissue & Biologics Company Directory for list of MN Companies and their products within each category (p 27).4 See Appendix I for list of aquisitions (p 39).

THERAPEUTICS


FIGURE 4. CUMULATIVE GROWTH OF INDUSTRY SEGMENTS IN MINNESOTA

ten existing companies

twenty existing companies

thirty existing companies

forty existing companies

THERAPEUTICS

BIOBANKS

TOOLS & DIAGNOSTICS

SUPPORT & SERVICES

19701955194019251910189518801865 1985 2000 2015


FIGURE 5. BREAKDOWN OF THERAPEUTICS SECTOR IN MINNESOTA5

5 See Tissue & Biologics Resource Directory for list of MN Companies and their products within each category (p 27).

eleven companiesfo

urte

en c

ompa

nies

nine

com

pani

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f fteen companies

OrthopedicsThe field of Orthopedics is one of the most established areas of technological expertise in the

Minnesota region, comprised of fifteen companies.

CardiovascularWith internationally-recognized

cardiovascular research centers, the Tissue & Biologics sector has

been able to collaborate with strong MN assets, creating nine companies.

Scaffold & MatrixFourteen Minnesota companies have been reacting to demand for biodegradable scaffold

matrices, keeping them ahead in national comparisons.

Emerging TechnologiesTechnological advances in stem cell

research and immunotherapy are steadily becoming more prevalent

among eleven companies in the Therapeutics Sector.


Therapeutics in the orthopedics field (bone and cartilage defects) is one of the most established sectors in regenerative medicine, comprising approximately 30% of the products on the global market.6 There is also a strong presence of orthopedic companies in Minnesota, accounting for over a third of all companies in the Therapeutics sector. Many of the emerging companies in the orthopedic space are utilizing the technical expertise of the device manufacturers in the region to develop minimally invasive approaches to treat orthopedic defects.

Tornier/Wright Medical

NordsonMicromedics

SignusMedical

ConventusOrthopedics

Liventa Bioscience

LifecoreBiomedical

Baxter Intl.

Rotation Medical

Zyga Tech.

KEY PLAYERS

EMERGING PLAYERS

Medtronic,Spine

KEY

PLA

YER

S Medtronic Spine Division generates $3 million annually with numerous products such as biologic infusion systems and minimally invasive surgical technologies.

Tornier/Wright Biologics has many osteoconductive scaffolds and also resorbable scaffolds to be used in conjunction with biologics. Tornier recently merged with Wright Medical to form a $3.3 billion ortho-biologics company.

EMER

GIN

G

PLAY

ERS

Rotation Medical is developing a minimally invasive, bio-inductive implant for rotator cuff repair using a novel arthroscopic delivery system.

Zyga Technologies is also developing a minimally invasive procedure for sacroiliac spine fusion.

THERAPEUTICS // ORTHOPEDICS

6 SOURCE: Alliance for Regenerative Medicine Annual Report 2014.


A great resource in the orthopedic field is Excelen, Center for Bone and Joint Research and Education. It is a non-profit orthopedic research and training facility located in Minneapolis with 10,000 square feet of space dedicated for developing innovative surgical and rehabilitative techniques. The facilities include the surgical skills lab for training or testing new protocols and a biomechanics lab with the ability to test cadaveric biomechanics.

Scaffolds and matrices made from natural or synthetic biomaterials have wide applications from wound healing to fixation of tissue, for hernias to the replacement of whole organs. Wound healing products, such as biological dressings and active wound care products, are another well-established segment of the market. The largest percentage (~38%) of all approved marketed products are for dermatological purposes.6 In addition to wound healing products, some of these companies also manufacture medical adhesives and sealants made from natural or synthetic materials for surgical operations, dental reconstruction, and orthopedic fixation.

Furthermore, technology for the development of biodegradable scaffolds and biomaterials has evolved in the last decade resulting in applications beyond wound healing and surgical adhesives. Due to shortages in donor tissue or complications with donor and recipient histocompatibility, the need for natural or synthetic scaffold matrices has expanded. Many emerging companies in Minnesota are developing new processing technologies for producing unique natural scaffolds and biomaterials. In the future, these new technologies may revolutionize the regenerative medicine space by reducing the need for donor tissue.

THERAPEUTICS // SCAFFOLD & MATRIX


7 SOURCE: IBISWorld Industry Report Wound Care Product Manufacturing, OD4099, April 2014 and IBISWorld Industry Report Medical Adhesives & Sealants Manufacturing, OD4095, June 2014.

Gel-DelTechnologies

LiventaBioscience

BRTILife Sciences

Miromatrix

RotationMedical Baxter

Intl. SignusMedical

3M

Endo Pharma - AMS, Inc.

ColoplastAdmedus

Tornier/Wright MedicalKips BayMedical

NATURAL

BIOMATERIAL

THERAPEUTICS // SCAFFOLD & MATRIX

KEY

PLA

YER

S

3M, Critical and Chronic Care Division holds 12% global market share of both wound healing and medical adhesive products ($700 million annually).7

Baxter International holds 9.4% global market share in medical adhesives ($163 million annually).7

Coloplast has both natural and synthetic wound healing products, as well as naturally derived products for urologic indications and surgical procedures.

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Miromatrix’s tissue decellularization technology produces a natural tissue scaffold that currently is used for treatment of hernias, but the decellularization process is transferrable to whole organs. Miromatrix is working with Mayo Clinic to develop a decellularized whole liver transplant.

Admedus’ cardiocel technology uses a decellularized bovine graft for congenital heart defects and other complex cardiovascular defects.

Liventa Bioscience develops novel products for both wound dressing and orthopedic use from placental tissue and amniotic fluid.


Approximately a quarter of Minnesota companies in the Tissue & Biologics space are working on emerging technologies. These companies can be categorized into three groups:

+

+

+

Cell-based immunotherapy is the youngest category in regenerative medicine, but it is one of the hottest areas in regenerative medicine. These companies produce a variety of immune products from interleukins, antibodies, lymphocytes, T-cells, and natural killer cells.8 Most of the companies are using the body’s own immune cells to target various forms of cancer.

Stem cell and progenitor therapies are the largest category in regenerative medicine. These therapies have garnered the most investment and have the greatest potential to produce breakthrough therapeutics for the regeneration of tissues and treatment of diseases.8

Other novel technologies include products for optometric purposes and new biologic drugs.

Biovest Intl.

Cardio3 Biosciences(Celyad Subsidiary)

OmnisPharmaceuticals

Altravax

BiotheraBioMatRx

Liver CellTherapies

Silk Tears

Lifecore Biomedical

Rebiotix

IMMUNOTHERAPY

STEM CELL THERAPIES

OTHER

BioE -CytoMedical

Design Group

THERAPEUTICS // EMERGING TECHNOLOGIES

8 SOURCE: Alliance for Regenerative Medicine Annual Report 2014.


THERAPEUTICS // EMERGING TECHNOLOGIES

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Biovest International is leading the field of personalized medicines by creating vaccines targeting non-Hodgkin’s lymphoma using the patient’s own immune cells.

Omnis Pharmaceuticals recently received a licensing agreement with MedImmune / AstraZeneca for its genetically engineered virus targeting cancer cells.

BioMatRx is developing a root canal alternative using dental pulp stem cells and a mixture of growth factors to stimulate new growth.

Liver Cell Therapies is constructing an artificial liver bioreactor using pig islets.

Rebiotix is generating a first-in-class biologic drug using live human-derived organisms to treat Clostridium difficile infections. They are currently testing the novel microbiota suspension in Phase 2 clinical trials.


THERAPEUTICS // CARDIOVASCULAR

Minnesota is a pioneer in open heart surgery and continues to be a leader in cardiovascular disease management. The heavy concentration of medical device companies and the presence of the Lillehei Heart Institute form a large knowledge base around the cardiovascular sciences. By combining tissue engineering principles with this technical expertise in cardiology, these companies have expanded beyond heart valve implants and are developing the next generation of cardiovascular products.

Heart LeafletTechnologies

St. JudeMedical

TissX

Tendyne HoldingsAdmedus

Baxter Intl.(Synovis Surgical)


Kips BayMedical

Gel-DelTechnologies

HEART VALVES NEW TECHNOLOGIES

EMER

GIN

G P

LAYE

RS Heart Leaflet Technologies has a transcatheter delivery system for a por-

cine heart valve with mesh support system.

Tendyne (recent acquisition by Abbott Laboratories) developed a mitral valve replacement using a transcatheter delivery system without the need for coronary bypass.

Cardio3 Biosciences (Celyad Subsidiary) is collaborating with the Mayo Clinic to use cardiopoietic stem cells for treating patients with congestive heart failure. They received FDA approval to start Phase III trials in late 2014.


With the first successful allogeneic bone marrow transplantation in 1968, Minnesota has been a leader in tissue and organ transplantation, and continues to advance the field of transplantation research. Both the University of Minnesota Medical Center and the Mayo Clinic in Rochester are consistently ranked among the “Top Hospitals” in the nation by U.S. News and World Report. In fact the Mayo Clinic, Rochester, was ranked the Number One hospital in 2014 due to its fifteen top-ranked adult specialties and nine pediatric programs.9

MusculoskeletalTransplant

Foundation

LifeSource

LifeStorCordblood Services

Mayo Clinic

U of M Medical CenterRegions Hospital

CyrogenicLaboratories

AmericanRed Cross

AmericanDonor Services

MinnesotaLions

Eye Bank

U of M,Liver Tissue Cell

Distribution System

Mayo Clinic, Mitochondrial Disease Biobank

Mayo Clinic, Bipolar Disorder Biobank

Hennepin CountyMedical Center

National Marrow Donor Program

BIOBANKS HOSPITALS

BIOBANKS

9 SOURCE: U.S. News and World Report Best Hospitals 2014 - 2015 Honor Roll.


KEY

PLA

YER

S

National Marrow Donor Program (NMDP) is a nonprofit organization that manages the largest and most diverse bone marrow registry in the world. NMDP is also an expert in bioinformatics.

American Donor Services is a nonprofit organization that facilitates tissue donations and it will be one of the first organizations in the area with the capability to process human tissue.

Minnesota Lions Eye Bank is one of the largest eye banks in the world and has contributed many innovations in corneal preservation and transplantation research.

Mayo Clinic, Rochester is not only one of the top hospitals in the nation, but also has three biobanks for scientific research.

University of Minnesota Medical Center has the second largest unrelated-donor transplant program in the nation and one of the largest umbilical cord transplant centers worldwide, due to collaboration with NMDP. The University of Minnesota also has many institutes and biobanks that rely on UMMC to support scientific research and collaboration.

BIOBANKS

The National Marrow Donor Program (NMDP) is headquartered in Minneapolis and has the largest hematopoietic registry in the nation with over 10 million donors and 185,000 cord blood units. The NMDP helps coordinate over 6000 donor-recipient transplants per year. It also holds the highest number of biologics license applications (BLA) and investigational new drug (IND) applications in the region.

Furthermore, the NMDP has advanced knowledge of complex histocompatibility algorithms and is vested in advancing the field of bioinformatics. NMDP, along with the University of Minnesota Rochester, the Hormel Institute, the University of Minnesota Twin Cities, the Mayo Clinic, IBM, and Cray Inc., launched the Biomedical Informatics and Computational Biology Program. The vision of this bioinformatics research program is to advance translational medicine by applying immunobiology, histocompatibility, and population genetics.

NMDP collaborates with the Medical College of Wisconsin to fund the Center for International Blood and Transplant Research (CIBTR). The purpose of CIBTR is to enhance collaborations with the global scientific community to advance hematopoietic cell transplantation and cellular therapy research.


Minnesota also has a significant presence in the tools and diagnostics field with several large players headquartered in the area.10 A small number of the small and/or emerging companies in this space are working specifically on cell-based assays for drug or toxicity screening, and creative technology platforms for processing tissue products.

CircleBiologics

Altravax

Mill Creek Life Sciences

Imanis LifeSciences StemoniX

BioE-CytoMedicalDesign Group Celcuity

CellProLabs

TOOLSDIAGNOSTICS

Nordson Micromedics

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Circle Biologics developed a device for sorting and collecting blood and peripheral cells.

BioE -CytoMedical Design Group has a FDA approved system for improved cord blood processing and multi-lineage progenitor cells available for diagnostics.

StemoniX is creating low-cost drug discovery assay plates using regenerative medicine.

CellPro Labs has both cell lines and cell culture products for viral diagnosis and detection.

TOOLS & DIAGNOSTICS

10 See LifeScience Alley's Diagnostics Capability Brief

Sector Landscapes: Tissue & Biologics | Core Capabilities in

Minnesota


The Tissue & Biologics companies in Minnesota are surrounded by a strong network of supporting organizations. While there is a strong academic presence in the Mayo Clinic and the University of Minnesota, private sector companies in Minnesota also have much to offer, from early stage research through post-market support. These 43 companies are distributed among four different categories, some contributing to more than one category.

SUPPORT & SERVICES

SUPPORT & SERVICES: ACADEMIC & INSTITUTIONAL RESOURCES

+ + + +

Contract manufacturing and development (15)Clinical/quality/regulatory (13)Logistics/distribution (8)Support/testing (22)

Much of the support infrastructure can be found at the University of Minnesota or the Mayo Clinic. Both have strong research laboratories with expertise in biotechnology, core research facilities with state of the art equipment and incubator space for startups. They also have initiatives that help startups and emerging companies create business models based on the Lean Development methodology.

Mayo Clinic

In 2006, Mayo Clinic was one of twelve institutions awarded with a Clinical and Translational Science Award from the National Institutes of Health. This funding provides support for the Center for Clinical and Translational Science (CCaTS), the largest research-related center at Mayo Clinic. CCaTS administrates the support infrastructure for clinical research, patient-oriented research and other development programs that enable the acceleration of translating laboratory discoveries into im-proved patient care.

Due to programs like the Center for Clinical and Translational Science, Mayo Clinic has been particularly successful at the development of translational research for clinical applications. Mayo Clinic also has a few business resources for licensing technology and fostering startups:

Taking a product from a mere idea all the way to the clinic is a challenge that Minnesota companies are skilled at addressing.


+ Mayo Clinic Business Accelerator is a 2,000 square-foot facility that provides collaborative office space for new companies, entrepreneurs and venture capital firms. As a joint venture between Mayo Clinic Ventures, the Rochester Area Economic Development, Inc. and Mayo Clinic Treasury Services, it currently has twenty tenants with plans for expansion in 2015.

+ + + + + + + + +

Imaging CenterBiotechnology Resource CenterCenter for Mass Spectrometry and ProteomicsFlow Cytometry CoreGenomics CenterMolecular Cellular Therapeutics (MCT; see inset for more information)Masonic Cancer CenterSchulze Diabetes InstituteOffice for Technology Commercialization (OTC)

SUPPORT & SERVICES: ACADEMIC & INSTITUTIONAL RESOURCES

University of Minnesota

The University of Minnesota offers many additional resources and facilities, and is part of the greater consortium of the 62 Clinical and Translational Science Award (CTSA) institutions. CTSA institutions are committed to the improvement of “human health by streamlining science, transforming training environments and improving the conduct, quality and dissemination of clinical and translational research.” Listed below are the several existing research and service facilities for biotechnology and life sciences at the University of Minnesota.

+ Mayo Clinic Ventures is helping to bridge science technologies with the market-place. Mayo Clinic currently has over 2,000 technologies available for licensing. They have been involved in the creation of 65 startup companies and over 2,600 licensing deals since inception.


Molecular and Cellular Therapeutics (MCT) is a 36,000 square foot Good Manufacturing Practices (GMP) facility on the University of Minnesota, Twin Cities campus. The focus of MCT is on translational development and clinical production of biologics for human use by facilitating the scale-up of products that have gone through the proof of concept stage for Phase I and II clinical trials. It is one of the few stand-alone GMP manufacturing facilities in the nation and one of five sites in the US that was awarded with a Production Assistance for Cellular Therapeutics (PACT) grant from the National Heart, Blood and Lung Institute. The purpose of the PACT grant is to assist the translational research of cellular therapeutics and support the manufacture of novel cellular therapeutic products.

MCT has a strategic development process for bio-therapeutics, which consists of a five phase Product Development Process, an independent cGMP / cGTP Quality Assurance Program, and routine Risk Management Analysis Unit. Currently MCT has dedicated spaces for six programs: Cancer Center Translational Laboratory, UMMC Cell Therapy Laboratory, Schulze Diabetes Institute, Fecal Microbiota Transplant, Targeted Toxins, and Institute for Therapeutics Discovery & Development. In addition to this space, MCT also has clean room production suites available for short-term or temporary programs.

MOLECULAR & CELLULAR THERAPEUTICS


As exhibited by the wide variety of companies that provide services from idea development to early stage manufacturing to regulatory testing to funding sources, private Minnesota companies are able to provide many services that complement those offered by research institutions. Several companies in the service sector are profiled below:

SUPPORT & SERVICES: PRIVATE SECTOR SERVICE PROVIDERS

NACS began as a production development company in 1991, and has since transitioned into contract manufacturing and development for the life sciences. With approximately 180 projects per year, their FDA-certified facility with clean rooms is geared to assist companies from idea to global launch and everything in between. In particular, they have expertise in GMPs for North America, Europe and Asia. They also specialize in helping companies find innovative funding sources for new products in their pipeline.

NAMSA began in 1967 as a company focused on safety testing and microbiology services. Ten years later, they helped the FDA set up testing guidelines for medical devices, and have continued to be an expert in worldwide regulatory and quality assurance standards. Today, NAMSA not only sells sterility products, but also acts as a service organization to other companies, assisting them with research and development of products through post-market support, with expertise in all disciplines. Particularly, the recent acquisitions of the Integra Group and Alquest have added a deep level of expertise in the preclinical and clinical trial stages of product development. NAMSA has the capability to help companies at any stage of the pipeline, from biocompatibility testing to early feasibility studies to GLP studies to post market clinical trials, and also plays matchmaker between companies and potential funding sources.

StemoniX produces robust heart and brain cell populations using a proprietary process of stem cell differentiation. Their process uses a suite of techniques to produce standard size microtiter plates for preclinical in vitro testing and diagnostics. While these are primarily for drug screening purposes, there is potential for many downstream applications. Despite incorporation in April of 2014, StemoniX has already progressed beyond seed stage funding to collaborations with two pharmaceutical companies. While their R&D facilities are based out of a Johnson & Johnson incubator in San Diego, manufacturing operations will begin soon in Minnesota.


TissX, founded here in Minnesota in 2013, not only produces their own tissue-based devices, but also assists other companies in the complicated road from product development to utilization in the clinic. Their facility is FDA-compliant, and they are experienced in leveraging their robust infrastructure to assist companies from initial pre-clinical tests through production, packaging, sterilization, sales and distribution. They have experience and connections within foreign medical device markets, with knowledge of both import and export requirements for a number of countries. They have a pragmatic approach to product development, knowing that all companies have different goals and requirements for their individual products.

SUPPORT & SERVICES: PRIVATE SECTOR SERVICE PROVIDERS

The Seed Partners is a newly opened biosciences incubator, accelerator and investor in the North Loop. Their 27,000 square foot space includes a 5,000 square foot wet lab facility, including fume hoods, cell culture space, and other basic & specialized life science equipment. Their Seed R&D company, in addition to providing shared lab and collaborative work spaces, can assist clients from the early stages of an idea to product concept, as well as provide business support, office support and laboratory support services.

Innovative Blood Resources (IBR) is widely known as a provider of human cells and tissues for use in research, manufacturing, product development and design and clinical trials within the life sciences industry. Offering unparalleled consulting expertise, IBR assists companies in navigating the complex world of regulatory and quality control to achieve FDA approval. IBR has widespread experience in maintaining programs requiring human subjects and cGMP compliance, and their FDA-certified facility provides lab space for testing during pre-clinical and clinical trials. Additionally, they have an efficient infrastructure for storing, shipping and handling biologics.

Dohmen Life Science Services provides outsourced insight and infrastructure to entrepreneurs seeking speed, scale and certainty as they bring their biopharma or medical device products to market. Dohmen's industry experts help hundreds of companies preserve capital, mitigate risk and stay focused on the future by supplying exceptional people, processes and tools within the areas of finance, technology, quality, regulatory compliance, supply chain, customer services and patient support.

25Sector Landscapes: Tissue & Biologics | Conclusion

The Tissue & Biologics sector in Minnesota is a rapidly growing field with a repertoire of a few established key players and an extensive array of small companies working on new emerging technologies. First, the University of Minnesota and the Mayo Clinic not only provide a highly educated workforce, but also world class research facilities and resources. Second, Minnesota has a substantial presence of key opinion and thought leaders in core capabilities such as cardiovascular disease, tissue and organ transplantation and biomaterial technologies. Finally, the diverse private companies that are able to assist in technology development from idea to post-market support lower the cost of operations and expansion, especially when compared to other cities in the nation.

Overall, Minnesota continues to foster an environment that allows for businesses to advance the rapidly changing field of regenerative medicine.

IN CONCLUSION


TISSUE & BIOLOGICS RESOURCE DIRECTORY

4.

27Sector Landscapes: Tissue & Biologics | Tissue & Biologics Resource Directory

Company City, State Founded Summary

Baxter International, Inc.Synovis SurgicalInnovations

St. Paul, MN 1985 ACTIFUSE bone grafts, soft tissue repair, microsurgery products.

Conventus Orthopedics Maple Grove, MN 2008 Fixation of distal radius fractures using nitinol mesh system.

Liventa Bioscience Woodbury, MN 2006 Placenta-derived graft for wound care and amnionic fluid for orthopedic applications.

Lifecore Biomedical LLC(part of Landec) Chaska, MN 1986

Manufactures Hyaluronan and other biomaterials for various medical applications.

Medtronic, Spine &Biologics Business Minneapolis, MN 1949 Infuse bone graft for spinal, maxilofacial, and

tibial bone growth.

Nordson Micromedics St. Paul, MN 1982 Bone graft, fibrin gel injection delivery systems. CDO capabilities.

Rotation Medical Plymouth, MN 2009Bioinductive implant (collagen) for formation of new tendonous tissue for rotator cuff tears.

Signus Medical LLC Chanhassen, MN 2001Bone conductive matrix for spine made from HA/TCP (hydroxyapatite/tricalcium phosphate).

Smith & Nephew Bloomington, MN 1856 Various orthopedic products.

SOTA Inc. Eden Prairie, MN 1990 Distributor of bone graft products.

Stellen Medical St. Paul, MN - Manufacturer of porcine xenografts

Tornier Biologics(Wright Medical merger) Bloomington, MN 1930

Many osteoconductive matrices in biologics division; develops synthetic, resorbable scaffolds.

Zyga Technology, Inc. Minnetonka, MN 2008 Sacroiliac spine fusion system, delivers bone grafts.

THERAPEUTICS: ORTHOPEDICS



Admedus Minneapolis, MN 2013 Decellularized bovine pericardium using ADAPT technology.

Baxter International, Inc.Synovis Surgical Innovations

St. Paul, MN 1985 ACTIFUSE bone grafts, soft tissue repair, mi-crosurgery products.

Gel-Del Technologies -VasoLogix / Cosmeta Corp. St. Paul, MN 2000 Blood vessel grafts made from biomaterials,

HyA injections.


Mont-Saint-Guibert, Belgium 2007 Guided cardiopoiesis using hematopoietic

stem cells.

Heart Leaflet Technologies(Bracco Group) Maple Grove, MN 2002 Transcatheter delivery of porcine valve with

wire mesh support system.

Kips Bay Medical Minneapolis, MN 2007 Mesh support for saphenous vein grafts. Im-proves vessel wall support.

St. Jude Medical St. Paul, MN 1976 Heart tissue valves made from porcine leaflets.

Tendyne Holdings, Inc. Roseville, MN 2010 Mitral valve replacement using transcatheter approach without cardio bypass.

TissX Maple Grove, MN -Creator of cardiovascular and orthopedic tissue-based devices; contract manufacturer and product developer.

THERAPEUTICS: CARDIOVASCULAR



3M Critical & Chronic Care St. Paul, MN 1902 Various wound healing products and medical adhesives.

Admedus Minneapolis, MN 2013 Decellularized bovine pericardium using ADAPT technology.

Baxter International, Inc.Synovis Surgical Innovations

St. Paul, MN 1985 ACTIFUSE bone grafts, soft tissue repair, microsurgery products.

BRTI Life Sciences Two Harbors, MN 2013 Hyaluronic Acid / Chitosan matrix for cells.

Coloplast Corporation Minneapolis, MN 1957 Bovine pericardium for urological procedures, Alginate and silicone for wound healing.

Endo Pharmaceuticals - American Medical Systems, Inc. (Acquired by Boston Sci)

Minnetonka, MN 1972 Meshes for pelvic health problems - incontinence and prostate.

Gel-Del Technologies - VasoLogix / Cosmeta Corp. St. Paul, MN 2000 Blood vessel grafts made from biomaterials,

HyA injections.

Impres Medical, Inc. Minnetonka, MN 1999 Minimally invasive treatment for abnormal uterine bleeding.

Kips Bay Medical Minneapolis, MN 2007 Mesh support for saphenous vein grafts. Improves vessel wall support.

Liventa Bioscience Woodbury, MN 2006 Placenta-derived graft for wound care and amnionic fluid for orthopedic applications.

Miromatrix Medical, Inc. Eden Prairie, MN 2009 Decellularized tissue / organ technology. First product was biological mesh for hernia repair.

Rotation Medical Plymouth, MN 2009 Bioinductive implant (collagen) for formation of new tendonous tissue for rotator cuff tears.

Signus Medical LLC Chanhassen, MN 2001 Bone conductive matrix for spine made from HA/TCP (hydroxyapatite/tricalcium phosphate).

Tornier Biologics(Wright Medical merger) Bloomington, MN 1930

Many osteoconductive matrices in biologics division; develops synthetic, resorbable scaffolds.

THERAPEUTICS: SCAFFOLD & MATRIX


THERAPEUTICS: EMERGING TECHNOLOGIES


Altravax Fargo, ND 2009Vaccine development platform Immunogen Optimization System (IOS), Molecular Breeding, Parallelavax, and ParaClin systems.

BioE - CytoMedical Design Group (CMDG) St. Paul, MN 1993

Multi-Lineage Progenitor cells derived from umbilical cords; cord blood processing technology.

BioMatRx LLC Edina, MN 2010 Dental pulp stem cells in place of root canals.

Biothera, Inc. Eagan, MN 1997 Cancer therapy.

Biovest International Minneapolis, MN 1983 Vaccine for non-Hodgkin's Lymphoma; process autologous cells.


Mont-Saint-Guibert, Belgium 2007 Guided cardiopoiesis using hematopoietic

stem cells.

Lifecore Biomedical LLC(part of Landec) Chaska, MN 1986 Manufactures Hyaluronan and other

biomaterials for various medical applications.

Liver Cell Therapies Rochestser, MN 2014 Liver bioreactor using pig islets.

Omnis Pharmaceuticals Rochester, MN 2014 Genetically engineered virus targeting cancer cells.

Rebiotix (formerly MikrobEX Inc.) Roseville, MN 2011 Biologic drug made of microbiota to treat

human metabolic disease.

Silk Tears, Inc. (formerly Seryx Biomedical) Maple Grove, MN 2010 Silk fibroin eye drops for ophthalmic therapies.



Allina Health Laboratories Minneapolis, MN 1882 Fertility.

American Donor Services Hastings, MN 2007 Human tissue donation organization.

American National Red Cross (The) St. Paul, MN 1863 Supplies approximately 66% of all donated

blood in US.

Center for ReproductiveMedicine, P.A. Minneapolis, MN 1987 Fertility.

Cryogenic Laboratories, Inc. Roseville, MN 1974 Fertility (sperm bank).

Hennepin CountyMedical Center Minneapolis, MN 1887 Fertility.

International AssistedReproduction Center Maple Grove, MN 1982 Fertility.

LifeSource - Upper MidwestOPO St. Paul, MN 1989 Human tissue donation organization.

LifeStor Cordblood Services Roseville, MN - Umbilical cordblood.

Lions Eye Bank St. Paul, MN 1989 Human tissue donation organization.

Mayo Clinic Biobank Rochester, MN 2009 Collect any tissue specimens from human volunteers and medical history.

Mayo Clinic Bipolar Disorder Biobank Rochester, MN - Large scale bipolar disorder biobank with bio-

logic samples and clinical data.

Mayo Clinic MitochondrialDisease Biobank Rochester, MN 2009 Collect and distribute specimens from human

patients with mitochondrial diseases.

Mayo Clinic Health SystemMankato Mankato, MN - Organ transplantation.

BIOBANKS


BIOBANKS


Mayo Clinic Rochester Rochester, MN - Fertility.

Mayo Clinic RochesterDivision of TransfusionMedicine

Rochester, MN - Progenitor / Bone marrow transplantation.

Muscoloskeletal TransplantFoundation Eagan, MN 2005 Human tissue donation organization.

National Marrow DonorProgram Minneapolis, MN 1986 Largest, most diverse marrow registry. Leader

in bone marrow transplants.

Regions Hospital St. Paul, MN 1872 Tissue transplantation.

Reproductive Medicine &Infertility Associates Woodbury, MN 1998 Fertility.

ReproTech, Ltd. St Paul, MN 1990 Fertility.

The Midwest Center forReproductive Health, P.A. Maple Grove, MN 1991 Fertility.

Tissue Trust Edina, MN - Human tissue.

University of MinnesotaBioNET Tissue Procurement Facility

Minneapolis, MN 1996 Collects and distributes human tissue specimens to scientific investigators.

University of MinnesotaLiver Tissue Cell Distribution System

Minneapolis, MN - Collects and distributes human liver specimens to scientific investigators.

University of MinnesotaMedical Center, FairviewLaboratories

Minneapolis, MN - Progenitor / Bone marrow transplantation.

University of MinnesotaMedical Center, Fairview Cell Therapy

Saint Paul, MN - Progenitor / Bone marrow transplantation.

University of MinnesotaPhysicians Minneapolis, MN - Fertility.



Airmed Biologics, Inc. Stillwater, MN 2011Regenerative medicine company with expertise in human and animal tissue-derived product design / development.

Biomedical Synergies Wayzata, MN 2005 Consulting and software for tissue management.

Biotest Laboratories, Inc.(STERIS Subsidiary) Brooklyn Park, MN 1998 CRO; testing services for pharmaceutical,

medical device, and material suppliers.

SUPPORT & SERVICES


Altravax Fargo, ND 2009Vaccine development platform Immunogen Optimization System (IOS). Molecular Breeding; Parallelavax; and ParaClin systems.

BioE - CytoMedical DesignGroup (CMDG) St. Paul, MN 1993 Cord blood processing technology, lysing red

blood cells, and activating T-cells.

Celcuity LLC Minneapolis, MN 2014 Microarray using patient's cells.

CellPro Labs Golden Valley, MN 2013 Cell lines (both primary and subcultures) fordiagnostics.

Circle Biologics, Inc. Minneapolis, MN 2008 Medical devices for collecting blood and cells.

Imanis Life Sciences Rochester, MN 2012Noninvasive reporter systems with cell lines, lentivectors, oncolytic viruses, and contract imaging services.

Mill Creek Life Sciences LLC Rochester, MN 2010 Human protein based cell culture supplement

derived from human donor platelets.

Nordson Micromedics St. Paul, MN 1982 Bone graft, fibrin gel injection delivery systems. CDO capabilities.

StemoniX Rochester, MN 2014Provider of derived organ cell populations on standard-size microtiter plates for testing and diagnostics.

TOOLS & DIAGNOSTICS


SUPPORT & SERVICES


Biovest International Minneapolis, MN 1983 Vaccine for Follicular Lymphoma. Process autologous cells.

ChRi Laboratories St. Paul, MN 2013CRO; early stage R&D, drug release / stability / degradation studies and regulatory submissions.

Dohmen Life Science Services

Milwaukee, WI 1858

Dohmen Life Science Services provides outsourced insight and infrastructure to entrepreneurs seeking speed, scale and certainty as they bring their biopharma or medical device products to market. Our industry experts help companies within the areas of finance, technology, quality, regulatory compliance, supply chain, customer services and patient support.

Imanis Life Sciences Rochester, MN 2012Noninvasive reporter systems with cell lines, lentivectors, oncolytic viruses and contract imaging services.

Infinity Transplant Services,Inc. Stillwater, MN - Medical transplant consulting firm.

Innovative Blood Resources St. Paul, MN 2012 Clinical research support, testing services, blood and cellular products and consulting.

Innovative Surface Technologies, Inc. (ISurTec) St. Paul, MN 2004

CRO; develops scaffold/matrices, drug deliv-ery, surface coatings, wound dressing; found-ed by co-Founder of Surmodics.

J. K. Medical, Inc.,Consulting Services Roseville, MN 2004

Consulting firm for product development, compliance and regulation, contract manufacturers and pricing strategies

Mayo Clinic ValidationSupport Services Rochester, MN -

Provides high quality, high volume tissue and biospecimen preparation and storage.

MD Biosciences, Inc.(Morwell DiagnosticsSwitzerland)

St. Paul, MN 1999 Preclinical CRO for inflammation, CNS, pain and cardiovascular.

MedTech Solutions North St. Paul, MN - Medical equipment and supplies.

Medtox Laboratories, Inc. St. Paul, MN 2005 Drug testing laboratory and clinical trial management.


Laboratory City, State Contact Summary

Andre Terzic, M.D., Ph.D.Laboratory/ Cardio3Biosciences

Mayo; Rochester, MN

Andre Terzic, M.D., Ph.D.

Guided cardiopoiesis using hematopoietic stem cells.

Chun Wang Laboratory UMN; Minneapolis, MN

Chun Wang, [email protected]

Polymeric biomaterials with drug delivery and creation of stem cell niches.

Michael Yaszemski, M.D.,Ph.D. Laboratory

Mayo; Rochester, MN

Michael Yaszemski, M.D., [email protected]

Bone, cartilage and nerve tissue engineering using novel biomaterials and scaffolds.

RESEARCH LABORATORIES

SUPPORT & SERVICES


Midwest ResearchSwine - Porcine Recovery Gibbon, MN 1986

Provides high quality traceable porcine tissue and other pigs for medical device and research purposes

Molecular and CellularTherapeutics UMN; St. Paul, MN 1992 Provides cGMP / cGTP grade materials and

support. FDA approved for IND.

NACS, Inc. Ham Lake, MN 1991 Specializes in contract manufacturing and process design for life science products.

NAMSA Minneapolis, MN 1967Helps clients develop medical products from concept to market along the entire develop-ment timeline.

SOTA Inc. Eden Prairie, MN 1990 Distributor of bone graft products.

Spring Point Project Minneapolis, MN 2004Provider of Designated Pathogen Free pigs; clinically suitable, viable porcine tissues and cellular products.

TissX Maple Grove, MN 2013 Develops and manufactures tissue patch and valve impants.

US Medical Technologies Lakeville, MN 1974 Medical / dental supplies and equipment.

WuXi AppTec St. Paul, MN 2000 CRO, medical device testing and material characterization facilities.


RESEARCH LABORATORIES

Laboratory City, State Contact Summary

Peter Amadio, M.D.Laboratory

Mayo; Rochester, MN

Peter Amadio, [email protected]

Combined polymeric scaffolds and stem cells for tendon regeneration.

Robert T TranquilloLaboratory

UMN; Minneapolis, MN

Robert Tranquillo, [email protected]

Cardiovascular tissue engineering.

Scott Nyberg, M.D. Ph.D. Mayo; Rochester, MN

Scott Nyberg, M.D., [email protected]

Development of extracoporeal artificial liver support system (HepatAssist)

Research Facilities City, State Contact Summary

BioCoR UMN; Minneapolis, MN

Alison [email protected]

Services, research & educational resources for biopreservation for biobanking and cell therapy.

RESEARCH FACILITIES


RESEARCH FACILITIES

Research Facilities City, State Contact Summary

Biotechnology Resource Center (BRC) UMN; St. Paul, MN Tim Tripp

[email protected]

Fermentation, downstream processing, protein expression and GMP capabilities

Center for Mass Spectrometry & Proteomics


https://cbs.umn.edu/cmsp/about

Provides support, equipment and expertise for analyzing complex protein mixtures.

Excelen Minneapolis, MN [email protected]

Educates and assists orthopedic researchers as they develop and innovative surgical and rehabilitative techniques

Masonic Cancer Center UMN; Minneapolis, MN

http://www.cancer.umn.edu/research/translation-al-cell-therapy/index.htm

Immune monitoring assays & GMP cell processing for clinical trials.

Mayo Validation SupportServices

Mayo; Rochester, MN [email protected]

Preclinical validation, diagnostics and therapeutic discoveries, and biospecimen prep and storage.

Mayo Clinic Ventures Mayo; Rochester, MN

[email protected]

Link between research and innovations with businesses looking to license technology.

Mayo Clinic BusinessAccelerator

Mayo; Rochester, MN [email protected]

Collaborative office space for startups, entrepreneurs, investors and advisors.

Molecular and CellularTherapeutics UMN; St. Paul, MN Diane Kadidlo

[email protected]

Provides cGMP / cGTP grade materials and support. FDA approved for IND.

Office for Technology Commercialization


Jay [email protected]

Facilitates transfer of UMN research to licensees for development of products/services.

The SEED Partners Minneapolis, MN [email protected]

Incubator/accelerator with 27,000 sq. ft. space, includes 5,000 sq. ft. wet lab facility.

Stem Cell Institute UMN; Minneapolis, MN [email protected] iPS facility, confocal microscopy,

and flow cytometry.

University EnterpriseLaboratories LLC St. Paul, MN Greg LaSalle

[email protected] Bioscience incubator space.

University Flow Cytometry Resource


Paul [email protected] Provides flow cytometry support.

University of Minnesota Genomics Center


http://www.health.umn.edu/research/resources-re-searchers/genomics-center

Genomics research & advises clients on appropriate technology.

University of Minnesota Imaging Center

UMN; Minneapolis, MN http://uic.umn.edu/

Provides advanced imaging technologies and methodologies to UMN and external users.


APPENDIX:LISTING OF RECENT ACQUISITIONS

39Sector Landscapes: Tissue & Biologics | Appendix

Company Acquired Amount Year

Wright Medical Tornier Biologics $3.3B 2014

Zimmer Biomet ~$845M 2014

Baxter International Synovis Life $325M 2011

Endo Pharmaceuticals -American Medical Systems, Inc. (Acquired by Boston Sci)

American Medical Systems $2.9B 2011

Heart Leaflet Technologies Bracco Group undisc. 2010

Landec Lifecore Biomedical $40M 2010

Nordson Micromedics undisc. 2010

LIST OF ACQUISITIONS

sector landscapes: tissue & biologics

Documents