Lessons from Translation in Biomaterials Design
J. Elisseeff, PhD Morton Goldberg Professor and Director of the Translational Tissue Engineering Center, Department of Biomedical Engineering and Wilmer Eye Institute, Johns Hopkins University
AABB 2018 Boston Elsie Russell's Prometheus
The beautiful fables of the Greeks, being proper creations of the imagination and not of the fancy, are universal verities. What a range of meanings and what perpetual pertinence has the story of Prometheus!-- Ralph Waldo Emerson, "Essays"
Lessons from translation
Hillel et al., Science Translational Medicine, 2011 Kythera Biopharma Pilot clinical testing: pre-abdominoplasty
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Hillel et al., Science Translational Medicine, 2011 What are important cells in the biomaterials response? Location, location, location…....
CD4+ T Cells Implant
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Beachley, Wolf, Sadtler et al., Nature Methods, 2015 Can we learn more about the impact of the local environment?
Beachley, Wolf, Sadtler et al., Nature Methods, 2015 Structure and Composition of ECM array Lung ECM: ECM-Associated: Collagens ECM Glycoproteins 10,000 Adipose Proteoglycans ECM Regulators Bladder ECM-affiliated Proteins Secreted Factors Bone 1,000 Adipose Bladder Bone Brain Kidney Brain Cartilage 100 Cardiac Kidney 10 Liver Cartilage Cardiac Spleen Liver Sm. Intestine PSMs Normalized Lung 1 SI ECM ECM-Associated Non-ECM Spleen
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Particles Hydrogels
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Synthetic Natural
Sadtler et al., Science, 2016 Innate and Adaptive Immune System are Intimately Linked
Innate Immunity Adaptive Immunity Fast, less specific Infected Slower, very specific Tumorcell MaterialsTrauma Antigen Presenting Cell (APC) Dendritic Cell NK Cell Macrophage
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Jonathan Powell Th2 T cells are Critical in Shaping the Regenerative Microenvironment
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• Macrophages
• Dendritic cells
• T cells Acellular Adipose Tissue (AAT)
• An Off-the-shelf alternative to fat grafting
• Cadaveric adipose tissue • Lipid/Cell remnants removed • GMP injectable format Phase I Clinical Trial Design
Sample Study Title Population Size Design End Points Follow-up
Men & Pilot Clinical IMPLANT EXCISION women, Testing of a Novel 2 x 1 mL (Panniculectomy, 1 – 12 aged 18-50 Treatment Soft Tissue subcutaneous abdominoplasty) weeks years, Group (n=8) Reconstruction injections post- healthy, with Solution per subject 1 – 18 weeks excision no tissue post-injection defects.
PRIMARY OUTCOMES: - Safety Implant - Patient/physician satisfaction - Histocompatibility
EXPLORATORY OUTCOMES: - Cell migration - Immune modulation - Gene expression
Confidential 32 Cell Migration into ECM in people Vascularization and Adipose Stem Cells
Nuclei Endothelial cells Adipose / perivascular stem cells
DAPI CD31 CD34
H H H
I I I
18 weeks post-injection Vascularization and Adipose Stem Cells
DAPI CD31 CD34 Role of immune cells in ECM materials and tissue repair (in people)
DAPI CD4 CD8
DAPI CD4 CD8 Tissue/ECM materials are biologically active!! • Intracellular proteins are there • The immune response is local and systemic • Local cellular activity stimulated • Complex processing and biology • Therapeutic potential will expand when understanding and leveraging the biology Acknowledgements
Kaitlyn Sadtler Ken Estrellas Brian Allen Matthew Wolf, PhD Vince Beachley, PhD Xiaokun Wang, PhD Sven Sommerfeld, PhD Ani Singh Joel Bader Eyegenix Powell Lab: Chirag Patel Drew Pardoll, MD PhD DoD Pardoll Lab: Franck Housseau, PhD Bloomberg~Kimmel Hongni Fan Institute for Cancer SKCCC FACS Core: Immunotherapy Ada Tam
SKCCC Biostatistics: Hao Wang, PhD Brandon Luber www.hopkinsmedicine.org Exploring the underlying science behind the function, interactions and design of biomaterials
International Associate Editors: - Jianjun Cheng (University of Illinois at Urbana Champaign, USA) - Matthias Lutolf (École Polytechnique Fédérale de Lausanne, Switzerland) - Shyni Varghese (University of California, San Diego, USA) - Jun Wang (South China University of Technology, China) led by Editor-in-Chief Jennifer Elisseeff (Johns Hopkins University, USA)
- Indexed in MEDLINE
- Fastest publication in the field
- Estimated 2016 impact factor: 4.2 (based on Web of Science data) @BioMaterSci www.rsc.org/BiomaterialsScience Making a connection: systems analysis Macrophages
M1: flat, round pancake M2: elongated
Leavy, Macrophages: The Shape of Things to Come, Nat Rev Imm., 2013 EPFL, Swartz OVERVIEW OF AFIRM GENITOURINARY/LOWER ABDOMEN RECONSTRUCTION (GU) PROGRAM
John D Jackson, PhD Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine AFIRM II
• Five program areas – Extremity Regeneration Program • Dr. Kenton Gregory and Dr. Robert Goldberg – Craniomaxillofacial Program • Dr. Antonios Mikos and Dr. Mark Wong – Skin Regeneration program • Dr. Geoffrey Gurtner and Dr. Richard Clark – Composite Tissue Allotransplantation and Immunomodulation Program • Dr. Maria Siemionow and Dr. Andrew Lee – Genitourinary Program • Dr. Tom Lue and Dr. John Jackson • 60 individual projects • 30 Research Centers • Administered out of Wake Forest Institute for Regenerative Medicine
2 GU Focus Area Military Relevance
• Pelvic and urogenital injury accounts for the majority (86%) of the urologic injuries that occurred during recent US armed conflicts. • Most of the injuries are extensive and cause major damage to the tissues and organs in the pelvis often resulting in dysfunction of the entire anal and urogenital system. • It is likely that in spite of improved protective gear, the incidence of injuries to the pelvis, its organs, anal canal and external genitalia due to fragmentation devices such as improvised explosive devices (IEDs) will increase • Recent statistics indicate that the number of soldiers with genital injuries in Afghanistan increased nearly 12 fold from 2009 to 2011 • Since 2005, more than 1,500 military personnel have sustained significant genital wounds.
3 Philosophy of GU Focus Area
• The overall philosophy of the Genitourinary/Lower Abdomen Reconstruction (GU) Focus Area is to repair battlefield injuries through the use of regenerative medicine and tissue engineering technologies utilizing basic and translational sciences
• Nine individual projects make up the GU focus area with investigators from four different institutions
• Many of the projects combine both basic scientists and clinicians that involve translational studies that contain clinical trials or will lead to clinical trial.
4 Study Areas
• One study addresses bladder reconstruction – GU-01: Engineered bladder tissue for soldiers with battlefield injury • One study addresses urethral repair – GU-02: Urethral tissue repair due to battlefield injury • Two studies address penile repair and erectile dysfunction – GU-03: Engineered penile tissue for the repair of battlefield urologic injuries – GU-05: Restoration of penile tissue function using stem cells • One study addresses testicular repair – GU-04: Engineered testicular tissue organoids for young solders with injury to the testes • One study addresses large volume muscle loss in the pelvic floor – GU-06: Engineering of innervated volumetric skeletal muscle tissue for accelerated restoration of pelvic floor muscle function • Three studies address repair of the anal sphincter – GU-07: Implantation of bioengineered innervated terminal gut as a replacement therapy for injured anus – GU-08: Engineering scaffold and cell therapy for treatment of fecal incontinence due to defects in the anal sphincter – GU-09: Medically engineered functional anal sphincters using composite tissue engineering and novel electrode (ME-FASTE)
5 Urological Project: GU-02
Urethral Tissue Repair Due to Battlefield Injury
Project Leader: James J. Yoo, M.D., Ph.D. Wake Forest Institute for Regenerative Medicine
6 7 Urological Project Clinical Need • Urethral injury due to complex pelvic trauma often results in scarring and stricture formation • Long urethral defects requiring tubularized tissue grafts have a high proportion of failures (sometimes over 50%) • Often, the urethra is reconstructed with non- urethral tissue substitutes • However, the use of these substitutes often leads to complications, such as infection, urolithiasis, fistulae and strictures Urological Project
To provide injured soldiers with autologous engineered urethral tissues to restore a functional urethra
To develop a strategy for repairing damaged urethral tissues due to penetrating and blunt injuries
To conduct a pilot clinical trial to determine the safety and feasibility of using autologous cells for urethral tissue reconstruction
8 Engineered Urethras: Clinical Study
Pre-Op 12 Months Recent • 5 Pediatric Patients
• Traumatic Urethral Strictures Uroflowmetry
• Up to 72 months of Follow up
Raya-Rivera A et.al. Lancet. 2011 Approach
• Adult autologous urethral tissues will be engineered using urologic cells combined with tubularized urethral scaffolds
• Develop standard operating procedures (SOPs) for the urethral tissue system, and perform toxicology studies
• Validate the SOPs for manufacturing engineered urethral tissue before advancing to a pilot clinical trial
10 Urological Project: GU-02
11 Manufacturing of Urethral Construct
12 Urological Project: GU-02
Manufacturing and QC Testing
• Performing Biocompatibility Testing • Once completed, will begin
enrolling patients 13 Corpora Project: GU-03
Engineered Penile Tissue for the Repair of Battlefield Urologic Injuries
Project Leader: John D. Jackson, Ph.D. Wake Forest Institute for Regenerative Medicine
14 Corpora Engineering Project
• Due to increased use of improvised explosives and dismounted patrols, soldiers are experiencing increased wounds to external genitalia • Various penile reconstructive procedures, such as penile prostheses and autograft implantation have been attempted • While cosmetic appearance may be improved, restoration of spontaneous and natural erectile function is usually not achieved due to the lack of the corpora cavernosa, which are responsible for erectile function • Tissue engineering-based therapy may offer treatment to restore normal anatomical tissue configuration and erectile function
15 Definitive Rabbit Study Design
After a pre-IND meeting with the FDA, a definitive rabbit study was designed to provide safety data for the IND submission
Group Treatment # of Sacrifice Time Points animals
3 mo 6 mo 9 mo
1 Corporal tissue biopsy only 18 6 6 6
2 Corporal tissue removed with acellular corporal matrix implant 18 6 6 6
3 Corporal tissue removed with engineered corporal tissue implant 18 6 6 6
4 Normal control animals 18 6 6 6
16 Decellularization Procedure for Rabbit Scaffold Preparation
. Tissue specimens were obtained from donor rabbits. . Tissues were treated with deionized-water at 4°C for 1 day followed by treatment with 1% triton-X100 and 0.1% ammonium hydroxide at 4°C for 7 days. . After washing, the tissues were treated with 0.0025% Dnase (in 10mM MgCl2 solution) at 37°C for 1 day.
17 Characterization of Autologous Rabbit Corporal Cells
Brightfield image of rabbit corporal smooth muscle cells
Staining with alpha Smooth Muscle Actin
Brightfield image of rabbit corporal endothelial cells
Staining with VCAM-1
18 Seeding of Rabbit Penile Scaffold
• 1st day – Smooth Muscle Cells - 60,000,000 cells/mL • 2nd day – Endothelial Cells - 3,000,000 cells/mL • 3rd day – Smooth Muscle Cells - 120,000,000 cells/mL • Culture Period: 10 days
19 Characterization of Rabbit Seeded Scaffold
Smooth muscle actin (green) and CD31 (red) staining of Engineered Penile Tissue Construct
Scanning Electron Microscopy of Native Penile Tissue and Engineered Penile Tissue Construct (Seeded) as compared to Decellularized Penile scaffold (Unseeded) Arrows indicate cellular material in the seeded construct. 20 Trimming of Rabbit Seeded Penile Scaffold
21 Implantation of Rabbit Engineered Construct
Corporal Tissue Tunica Construct
Skin closed over construct
22 Intracorporal Pressure Measurement
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23 Process Development for Human Construct
EC Media
Characterization of Cells Biopsy Corporal Minced tissue Biopsy SMC Media
Digestion
Seeding EC and SMC onto Decel Scaffold
Decel Solution and Nuclease Treatment Bioreactor Donor tissue Decellularized scaffold Dynamic Culture of Seeded Scaffold Characterization of Characterization of Seeded Acellular Scaffold Scaffold
24 Cell Yield Human Corporal Tissue Biopsy
Average yield per gm tissue biopsy 3.00 3.00 SMCs/gm ECs/gm SMCs/gm ECs/gm 2.50 2.50 1.81 millions SMC/ gm 0.47 millions EC/ gm 2.00 2.00
1.50 1.50
1.00 1.00
0.50 0.50
Passage 1 Yield of Cell (in millions) (in Cell of Yield 1 Passage Mean Mean Passage Cell of Yield 1 millions) (in 0.00 0.00 HUM001 (38) HUM002 (42) HUM003 (49) HUM004 (70) HUM006 (66) Sample ID (Donor Age)
25 Endothelial and Smooth Muscle Cells
(A) Brightfield image of smooth muscle cells exhibiting spindle-shaped morphology; (B) and (C) showing positive staining with smooth muscle marker alpha smooth muscle actin
(A) Brightfield image of endothelial cells exhibiting cobblestone morphology; (B) and (C) showing positive staining with endothelial marker von Willebrand Factor (vWF) 26 Decellularization of Human Donor Penile Tissue
Decellularization Procedure
Treatments Days
Washing - dWater 1 Decellularization - 2% Triton X-100; 2% Ammonium Hydroxide 10 Washing- dWater 5 Nuclease Treatment 2 Washing – dWater 1 Washing – dWater 5 Washing – PBS 1 Freeze 1 Sterilize 1
18x 100x 200x 27 Recellularization of Human Penile Scaffold
Injection of Cells
28 Cell Distribution in Seeded Human Scaffolds
H&E and DAPI staining of Engineered Penile Tissue Construct indicate presence of cells.
Smooth muscle actin (green) as smooth muscle marker and CD31 (red) as endothelial marker were used for staining the engineered penile tissue construct as well as native tissue.
29 Glucose/Latate Assay Human Cells
During construct maturation, glucose content decreased while lactate concentration increased in seeded construct implying that cells were metabolically active during manufacturing of final engineered penile tissue.
30 Mechanical Testing of Seeded Human Scaffold
No significant change in the tensile strength was observed upon decellularization as well as in final construct, both had tensile strength equal to native tissue. 31 Summary
• Data analysis of rabbit definitive study showed that implantation of a seeded penile scaffold restored erectile function when compared to the non-seeded scaffold.
• Successful in obtaining FDA, IRB and HRPO approval for phase 1 safety clinical trial.
• Patient recruitment and enrollment of patients in the Phase I clinical trial will begin soon.
32 Anal Sphincter Repair Project: GU-07
Implantation of Bioengineered Innervated Terminal Gut as a Replacement Therapy for Injured Anus
Khalil N. Bitar, PhD, AGAF Wake Forest Institute for Regenerative Medicine
33 Fecal Incontinence – Unmet Need
• Solders injured by IED in the wars in Iraq and Afghanistan
• 2-17 % of the general population, increasing to 30% in older (65+) individuals.
• Many of the surgical procedures involve the repair or replacement of a part of the anus or external sphincter.
• Implantable devices: have not shown success, and have a high rate of infection. Product Concept
1. Gut biopsy
2. Expansion of smooth muscle cells (A) and enteric neuronal progenitor cells (B) in tissue culture
3. Bioengineered three-dimensional Model: Rodents, intrinsically innervated Sphincters for rabbits, humans implantation
5.Implantation of BioSphincterTM
4. Physiological testing & quality control of bioengineered sphincters Anorectal Manometry: Comparison pre/post sphincterectomy Manometry post-sphincterectomy
Decreased resting pressure post-sphincterectomy BioSphincter
• Bioengineered Physiologically Functional Intrinsically Innervated Neuromuscular Constructs
• Novel bioengineered intrinsically innervated sphincters (BioSphincters) mimic native digestive tract architecture and function
• Constructed with autologous neuronal progenitor cells and smooth muscle cells BioSphincter Anorectal Manometry: BioSphincterRestores Function Manometry post-implantation
Resting pressure restored Conclusion
This regenerative medicine approach to treat passive fecal incontinence using BioSphincters is promising for translation into clinical practice. Potential Impact
• The research projects comprising the genitourinary focus area cover the majority of tissues and structures in the pelvic region • It is reasonable that combinations of these treatments will be needed to address the injuries sustained by wounded solders • The regenerative medicine approach used by these research teams for addressing catastrophic loss of tissue and function will have a significant impact on moving the fields of tissue engineering and cell therapies forward • It is expected that some or all these projects will generate new technologies that have the potential for translation and commercialization • Not only will the results from the studies contribute to the treatment of wounded worriers but will have a much wider contribution to the health and well-being of the civilian population that suffer from debilitating genitourinary dysfunction due to injuries and disease
43 Acknowledgements
This work was supported by the Army, Navy, NIH, Air Force, VA and Health Affairs to support the AFIRM II effort, under Award No. W81XWH-13-2- 0052. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. 44 Regenerative Medicine Therapies for the Clinic (AABB/TERMIS-AM Joint Session)
10/14/2018 Faculty Disclosures
The following faculty have no relevant financial relationships to disclose: – James Yoo MD, PhD – Jennifer Elisseeff PhD – John Jackson – Julie Allickson PhD
www.aabb.org 2 Learning Objectives
• Discuss basic principles of cell-based therapies • Recognize the regulatory processes and requirements for manufacturing tissue engineered products • Discuss ongoing/planned applications of regenerative medicine therapy
www.aabb.org 3 AABB/TERMIS-Americas Joint Session: Regenerative Medicine Therapies in the Clinic Institute for Regenerative Medicine Academic Model: Clinical Translation for Regenerative Medicine
Julie G. Allickson, PhD, Director, Regenerative Medicine Clinical Center, Wake Forest Institute for Regenerative Medicine Our Mission: Improve patients’ lives through regenerative medicine.
Our Vision: Leading a global transformation from treatments to cures.
Core Values: Innovation / Teamwork / Integrity
Wake Forest Institute for Regenerative Medicine Platforms in Regenerative Medicine
WFIRM Translational Regenerative Medicine Platforms
Cell Therapy Small Molecules
Tissue Engineering Biomaterials Devices Drugs, metabolites Auto cells and -ROCK inhibitor Y- MCBs 27632 -Muscle progenitor -Placental Cells -Testicular Tissue Natural or Synthetic -Urethra Polymers -Bladder Procure, isolate, -Collagen -Corpora expand, deliver, test -Hyaluronic acid -Vagina -Bioprinter -PGA -Muscle -Bioreactor -PLGA -Anal Sphincter -PCL -Decellularized Tissue Matrices
Wake Forest Institute for Regenerative Medicine How do we transfer these Technologies to Clinical Trials at Institute for Regenerative Medicine WFIRM • For organs, tissues and cell therapies
4 Organized for Innovation and Translation
Multi-Disciplinary and Cross-Functional Core Programs
Pharmacology
Translational and FDA Approved Pre-Clinical Commercialization GMP Manufacturing Services Wake Forest Institute for Regenerative Medicine Regenerative Medicine Clinical Center
Wake Forest Institute for Regenerative Medicine
Regenerative Medicine Clinical Center Pre-Clinical IND Enabling Process & Studies Product Regulatory Development Affairs Translational Team Quality Manufacturing Assurance
Quality Control/Testing Clinical Translation Goal
• Start with the end in mind- the final product • Move preclinical manufactured product and ROA to human clinical trials. • Preclinical product > Process/Product Development > GMP/GTP-compliant Manufacturing. • Communication is Key- team meetings • Process/Product Development • Quality Control Testing • Quality Assurance • Manufacturing • Project Management • Develop Regulatory Submissions: PPIND, PIND, or IND (for Phase I / II clinical trials)
Wake Forest Institute for Regenerative Medicine Regenerative Medicine Clinical Center (RMCC) Roadmap in Translation
Preclinical Clinical Trials Clinical Trials Post R&D IND BLA Studies Pre-Pre-IND Pre-IND PHI/II PHIII Marketing
-Coordinate FDA -GLP Training -Liaison for IND documentation -PH III generally will -Guidance with PPIND meeting -critical step monitored by FDA -lead draft briefing and questions occur in industry after marketing the product preclinical studies document for FDA -lead IND -test article production document for FDA -assay development
-Coordinate FDA -Finalizes the manufacturing process We may be able to assist with PIND meeting according to GMP/GTP - -lead draft briefing -preforms the manufacturing qualification the BLA if we are involved in PH III document for FDA -manufactures the product according to GMP and GTP-compliance RMCC includes: 1. Preclinical Project Management (GLP-Definitive Studies) 2. Process & Product Development ( test article production and scalable human product) 3. Project Management ( Process Product Development to clinical trials) 4. GMP/GTP-compliant Manufacturing (Biologic, Drug, Device or Combination Product) 5. Quality Control (in-process and lot release testing) 6. Quality Assurance 7. Regulatory Assistance Wake Forest Institute for Regenerative Medicine From Discovery to Clinical Translation
POST PRE- FDA MARKET SCIENTIFIC DISCOVERY CLINICAL TRIALS CLINICAL REVIEW STUDY-
PHASE IV
IND, IDE IND,
NDA, BLA NDA, SUBMITTED
( PMA,510k) SUBMITTED PMA,510k)
1-2 3-7 Yr .5 -2 Yr 1-2 Yr 2-3.5 Yr 2.5-4 Yr Years 1. Biopsy of leg muscle 2. Expand in tissue culture 3. Inject in damaged sphincter region
Wake Forest Institute for Regenerative Medicine Autologous MPC Therapy for Urinary Incontinence – Study Design
Purpose • To evaluate the safety of muscle progenitor cells (MPCs) for the treatment of urinary incontinence due to incompetent outlet (bladder neck/urethra). Study Design • The proposed study is a prospective, open-label, uncontrolled, Phase 1 study. Specific Aims • Aim 1: To demonstrate safety of muscle cell harvesting, expansion, and implantation for urinary incontinence. • Aim 2: To determine whether the injection of muscle cells improves continence at 6 and 12 months post-injection.
Wake Forest Institute for Regenerative Medicine Isolation of amniotic stem cell lines with potential for therapy. De Coppi P, Bartsch G Jr, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A. Nature Biotechnology. 2007 Jan;25(1):100-6.
Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome. Moschidou D, Corcelli M, Hau KL, Ekwalla VJ, Behmoaras JV, De Coppi P, David AL, Bou-Gharios G, Cook HT, Pusey CD, Fisk NM, Guillot PV. Stem Cells Dev. 2016 Mar 1;25(5):395-404.
Cell therapy for kidney injury: different options and mechanisms--mesenchymal and amniotic fluid stem cells. Morigi M, De Coppi P. Nephron Exp Nephrol. 2014;126(2):59. doi: 10.1159/000360667. Review.
Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Zani A, Cananzi M, Fascetti-Leon F, Lauriti G, Smith VV, Bollini S, Ghionzoli M, D'Arrigo A, Pozzobon M, Piccoli M, Hicks A, Wells J, Siow B, Sebire NJ, Bishop C, Leon A, Atala A, Lythgoe MF, Pierro A, Eaton S, De Coppi P. Gut. 2014 Feb;63(2):300-9.
Potential of human fetal chorionic stem cells for the treatment of osteogenesis imperfecta. Jones GN, Moschidou D, Abdulrazzak H, Kalirai BS, Vanleene M, Osatis S, Shefelbine SJ, Horwood NJ, Marenzana M, De Coppi P, Bassett JH, Williams GR, Fisk NM, Guillot PV. Stem Cells Dev. 2014 Feb 1;23(3):262-76.
Human amniotic fluid stem cells protect rat lungs exposed to moderate hyperoxia. Grisafi D, Pozzobon M, Dedja A, Vanzo V, Tomanin R, Porzionato A, Macchi V, Salmaso R, Scarpa M, Cozzi E, Fassina A, Navaglia F, Maran C, Onisto M, Caenazzo L, De Coppi P, De Caro R, Chiandetti L, Zaramella P. Pediatr Pulmonol. 2013 Nov;48(11):1070-80.
Isolation of amniotic stem cell lines with potential for therapy. De Coppi P, Bartsch G Jr, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A. Nat Biotechnol. 2007 Jan;25(1):100-6.
Wake Forest Institute for Regenerative Medicine Placental Procurement for Cell and Tissue Banking
Wake Forest Institute for Regenerative Medicine Master Cell Bank Derived from Fetal Placenta Tissue (currently in research studies)
Wake Forest Institute for Regenerative Medicine Clinical Translation of Tissue Engineering
Wake Forest Institute for Regenerative Medicine
Manufacturing of a Tissue Engineered Organ Wake Forest Institute for Regenerative Medicine Reconstruction of Penile Organ
References:
Yoo JJ, Park HJ, Lee I, Atala A. Autologous engineered cartilage rods for penile reconstruction. J Urol. 1999 Sep;162(3 Pt 2):1119-21.
Yoo JJ, Park HJ, Atala A. Tissue-engineering applications for phallic reconstruction. World J Urol. 2000 Feb;18(1):62-6.
Kwon TG, Yoo JJ, Atala A. Autologous penile corpora cavernosa replacement using tissue engineering techniques. J Urol. 2002 Oct;168(4 Pt 2):1754-8.
Kim BS, Yoo JJ, Atala A. Engineering of human cartilage rods: potential application for penile prostheses. J Urol. 2002 Oct;168(4 Pt 2):1794-7.
Eberli D, Susaeta R, Yoo JJ, Atala A. A method to improve cellular content for corporal tissue engineering. Tissue Eng Part A. 2008 Oct;14(10):1581-9. doi: 10.1089/tea.2007.0249.
Chen KL, Eberli D, Yoo JJ, Atala A. Bioengineered corporal tissue for structural and functional restoration of the penis. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3346-50.
Patel MN, Atala A. Tissue engineering of the penis. ScientificWorldJournal. 2011;11:2567-78.
Wake Forest Institute for Regenerative Medicine Non-Clinical Studies Tissue Engineered Corpora
Wake Forest Institute for Regenerative Medicine Human Engineered Penile Construct
Wake Forest Institute for Regenerative Medicine Training to Implement Early Phase Clinical Trial
Wake Forest Institute for Regenerative Medicine Challenges in Clinical Manufacturing
• Tissue/Cell Quality • Scale up, Scale out • Standardization, Characterization, Qualification (Biocompatibility) • Supply chain, logistics • In-process/ lot release testing • Automation • Cryopreservation Benefits of Early Academic Translation
• Innovation with a multidisciplinary team of faculty • Maintaining the technology within one facility from preclinical to product manufacturing can save time. • Preclinical development performed by the Principal Investigator and the team can save on financial considerations. Regulatory Tools to Accelerate Clinical Translation
• FDA Guidance Document's • Pathways to Facilitate Translation to the Clinic Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products
Recommendations for General Preclinical and Investigational Cell Therapy Program Design.
• Animal Species Selection • Selection of Animal Models of Disease/Injury • Proof-of-Concept (POC) Studies • Toxicology/Tumorgenicity/Biodistribution Studies • Product Delivery Considerations • Post Administration Survival/Engraftment • Good Laboratory Practice (GLP) • The Principles of Reduction, Refinement, and Replacement of Animal Use • Product Development for Later-Phase Clinical Trials • Preclinical Study Reports • Communication with OCTGT Pharmacology/Toxicology Staff
Wake Forest Institute for Regenerative Medicine FDA Cellular & Gene Therapy Guidance
•Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Draft Guidance for Industry, July 2018
•Long Term Follow-up After Administration of Human Gene Therapy Products; Draft Guidance for Industry, July 2018
•Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Draft Guidance for Industry, July 2018
•Human Gene Therapy for Hemophilia; Draft Guidance for Industry, July 2018
•Human Gene Therapy for Rare Diseases; Draft Guidance for Industry, July 2018
•Human Gene Therapy for Retinal Disorders; Draft Guidance for Industry, July 2018
•Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration Staff, December 2017
•Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry, November 2017
•Evaluation of Devices Used with Regenerative Medicine Advanced Therapies; Draft Guidance for Industry, November 2017
•Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Draft Guidance for Industry, November 2017
•Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR Part 1271; Guidance for Industry, September 2017
•Recommendations for Microbial Vectors Used for Gene Therapy; Guidance for Industry, September 2016
Wake Forest Institute for Regenerative Medicine Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Flowchart to illustrate how to apply the criteria in 21 CFR 1271.15(b) and 1271.10(a)in21CFRPart1271.
Wake Forest Institute for Regenerative Medicine FDA Pathways to Facilitate Clinical Translation
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
A Priority Review designation means FDA’s goal is to take action on an application within 6 months.
Wake Forest Institute for Regenerative Medicine Regenerative Medicine Advanced Therapy (RMAT) Designation
An investigational drug is eligible for RMAT designation if:
• It meets the definition of regenerative medicine therapy
• It is intended to treat, modify, reverse, or cure a serious condition
• Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition.
Regenerative medicine therapies, which are defined in section 506(g)(8) of the FD&C Act, as including: cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act (PHS Act) (42 U.S.C. 264) and Title 21 of the Code of Federal Regulations Part 1271 (21 CFR Part 1271).
Wake Forest Institute for Regenerative Medicine FDA Approved Cell and Gene Therapy Products
•ALLOCORD (HPC Cord Blood) SSM Cardinal Glennon Children's Medical Center
•LAVIV (Azficel-T) Fibrocell Technologies
•MACI (Autologous Cultured Chondrocytes on a Porcine Collagen Membrane) Vericel Corp.
•CLEVECORD (HPC Cord Blood) Cleveland Cord Blood Center
•GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen) Organogenesis Inc
•HEMACORD (HPC, cord blood) New York Blood Center
•Ducord, HPC Cord Blood Duke University School of Medicine
•HPC, Cord Blood Clinimmune Labs, University of Colorado Cord Blood Bank
•HPC, Cord Blood - MD Anderson Cord Blood Bank MD Anderson Cord Blood Bank
•HPC, Cord Blood - LifeSouth LifeSouth Community Blood Centers, Inc.
•HPC, Cord Blood - Bloodworks Bloodworks
•IMLYGIC (talimogene laherparepvec) BioVex, Inc., a subsidiary of Amgen Inc.
•KYMRIAH (tisagenlecleucel) Novartis Pharmaceuticals Corporation
•LUXTURNA Spark Therapeutics, Inc
•PROVENGE (sipuleucel-T) Dendreon Corp.
•YESCARTA (axicabtagene ciloleucel) Kite Pharma, Inc
Wake Forest Institute for Regenerative Medicine Wake Forest Institute for Regenerative Medicine Wake Forest Institute for Regenerative Medicine In Summary……
• Clinical Translation Begins with the End in Mind • Important to Educate the Regulatory Authorities- YOU ARE THE EXPERT • Multidisciplinary Teams Required to Move Regenerative Medicine Technology to the Patient
Wake Forest Institute for Regenerative Medicine Some of the work in this presentation was made possible, in part, by grants from the following institutions:
NIH, NASA, Department of Defense, The Crown Foundation, Christopher Mosely Foundation, Errett Fisher Foundation, The State of North Carolina, The Rosenfeld Fund, The Chapman Foundation, The Egan Foundation, The JBJ Foundation, NC Biotech, Sens Foundation, Rena Shulsky David Foundation, Circle of Service Foundation, American Lung Association, Cystic Fibrosis Wake Forest Institute for Regenerative Medicine
• WFIRM: >350 Members: (Dr. Anthony Atala-Director) • Working on over 35 different tissues and organs
Wake Forest Institute for Regenerative Medicine Thank You
Julie G. Allickson, PhD Wake Forest Institute for Regenerative Medicine [email protected] www.wakehealth.edu/wfirm wfirmnews wfirmnews
Wake Forest Baptist Medical Center