Introduction

The International Federation of Adipose Therapeutics and Sciences (IFATS) appreciates this opportunity to submit the following comments to supplement its earlier written comments and recent testimony at the September 12-13, 2016 Public Hearing on the 2014-2015 Draft HCT/P Guidances concerning: a) Minimal Manipulation; b) Same Surgical Procedure; c) Adipose Tissue; and d) Homologous Use.

IFATS Overview

International Federation of Adipose Therapeutics and Sciences (IFATS)
45 Lyme Road – Suite 304
Hanover, NH 03755 USA
Tel: 1-603-643-2325, Fax: 1-603-643-1444

Date: September 26, 2016

Addressed to:
Division of Dockets Management (HFA–305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

Re: FDA-2014-D-1856 – Comments to 2014-2015 Draft Guidance regarding:

• Docket FDA-2014-D-1584: “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Draft Guidance for Industry”
• Docket FDA-2014-D-1696: “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and Food and Drug Administration Staff”
• Docket FDA-2014-D-1856: “Human Cells, Tissues, and Cellular and Tissue-Based Products from Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry”
• Docket FDA-2015-D-3581: “Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and FDA Staff”

Commitment to Advancing Adipose-Based Therapies

IFATS is committed to the responsible advancement of the science and translation of new adipose therapies, ensuring patient safety. Founded in 2003 by pioneering adipose stem cell biologists and clinician–scientists, IFATS aims to advance the science of adipose tissue biology and its clinical translation to therapeutic applications.

IFATS’s Global Influence and Expertise

Membership now spans 40 countries across North America, Europe, Africa, the Middle East, Asia, Australia, and Central and South America. It includes basic scientists, translational researchers, clinicians, and regulatory and biotech representatives. IFATS is aligned with prestigious journals, Stem Cells and Stem Cells Translational Medicine, and has contributed to defining adipose-derived cells in the publication Cytotherapy.

Review of FDA Draft Guidances

Drawing on this expertise, IFATS has reviewed the 4 draft guidances with great care. It respectfully requests the FDA to reconsider and modify the 4 draft HCT/P guidances as follows:

Recommendations

Recommendation #1: Cell-Based Risks

Interpret and evaluate an HCT/P’s homologous use and minimal manipulation based on its manufacturer’s intended use in the patient.

Recommendation #2: Provider-Based Risks

Reduce provider-created risks by targeting provider behavior.

Recommendation #3: Recognize Structural and Nonstructural Functions

Recognize that adipose HCT/Ps have both structural and nonstructural functions, and regulate based on its manufacturer’s intended use in the patient.

Recommendation #4: Revise Evaluation of Minimal Manipulation and Homologous Use

Revise the evaluation of minimal manipulation and homologous use as they pertain to particular applications of adipose tissue.

Conclusion

IFATS is committed to collaborating with the FDA to meet the challenges of regulating HCT/P therapies. We respectfully request a meeting with FDA representatives to discuss these issues and others related to the advancement and regulation of adipose-based therapies.

Respectfully submitted on behalf of IFATS,

Adam J. Katz, MD, FACS
Chair, IFATS Regulatory Affairs Committee & IFATS Co-Founder
University of Florida College of Medicine
Professor
Director of Plastic Surgery Research, Laboratory of BioInnovation and Translational Therapeutics
Division of Plastic Surgery, Department of Surgery

IFATS Board of Directors

• Bruce Bunnell, PhD – Tulane University / United States
• Louis Casteilla, PhD – University of Toulouse / France
• Sydney Coleman, MD – New York & Pittsburgh Universities / United States
• Julie Fradette, PhD – Lavalle University / Canada
• William Futrell, MD – Founders’ Board, University of Pittsburgh / United States
• Marco Helder, PhD – VU University Medical Center Amsterdam / The Netherlands
• Adam J. Katz, MD, FACS – Founders’ Board, University of Florida / United States
• Ramon Llull, MD, PhD – Founders’ Board, University of Barcelona / Spain
• Kacey Marra, PhD – University of Pittsburgh / United States
• Ricardo Rodriguez, MD – President (2016), Private Practice / Johns Hopkins / United States
• Peter Rubin, MD, FACS – Chair, Founders’ Board, Chairman of the Board, University of Pittsburgh / United States
• Stuart K. Williams, PhD – University of Louisville / United States

Members-at-Large

• Jeff Gimble, MD, PhD – Pennington Biomedical / United States
• Keith March, MD, PhD – Indiana University / United States

IFATS Recommendations for FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products

Introduction

IFATS recognizes the FDA’s challenge in developing regulations that fulfill the agency’s dual and interrelated responsibilities of protecting patients while promoting innovation. Although these are complementary rather than competing objectives, they are often difficult to pursue simultaneously. The FDA’s 3-tiered, risk-based §§ 361 – 351 framework balances these concerns by making the degree of regulatory oversight proportionate to the degree of an HCT/P therapy’s risk.

Key Regulatory Concepts

The concepts of homologous use and minimal manipulation are key determinants of whether an HCT/P will be classified as a § 361 product (which does not need premarket approval) or a § 351 drug, device, and/or biological product (which requires formal premarket approval). The applicability of § 351’s “same surgical procedure” exception also turns on homologous use and minimal manipulation.

Challenges for Manufacturer-Clinicians

For most manufacturer-clinicians, § 351 categorization raises insurmountable obstacles due to the time and expense of obtaining premarket approval. In such cases, § 351 classification effectively prohibits access to safe and effective HCT/P therapies, even when those therapies involve a patient’s own cells and/or can deliver superior results with reduced risks. At the same time, § 351 oversight is essential for therapies that pose greater risks due to the HCT/P’s characteristics, mechanism(s) of action, and circumstances of use.

Addressing Provider Misconduct

A second type of risk involves rogue clinicians offering false promises in the form of unproven therapies performed with few safeguards and less training. Provider misconduct is not unique to HCT/P therapies; it pervades all areas of medical practice. Nevertheless, IFATS shares the FDA’s alarm over such practices in the context of HCT/Ps and is equally determined to curtail them. Effective regulation of HCT/P-related risks must recognize and respond to their multivariate causes. Put simply:

• Sections 351 and 361 appropriately attempt to regulate HCT/P therapies proportionate to the risks of unpredictable and/or unsafe cell behavior.
• However, the risks of untrained providers misusing HCT/P therapies are caused by providers misbehaving, not cells misbehaving.

Comprehensive Risk Management Strategy

Interpretive guidance that restricts the definition and application of HCT/P terminology can only go so far in restricting provider-based risks. Additionally, restrictive, inaccurate, or imprecise definitions and interpretations carry their own risks of restricting access to therapies and a patient’s right to evaluate risk through the process of informed consent. Therefore, IFATS recommends that the FDA adopt an overall two-part strategy that focuses on both categories of HCT/P risks: those relating to cell behavior and those that pertain to provider behavior.

Recommendations

Recommendation #1 – Cell-Based Risks

Interpret and evaluate an HCT/P’s homologous use and minimal manipulation based on its manufacturer’s intended use in the patient. Interpretive guidance should predicate each definition on the functions and/or characteristics of the specific composition (i.e., cell type(s) and/or matrix or other component(s)) that are involved in, and/or relevant to, the manufacturer-clinician’s intended use in the patient.

Recommendation #2 – Provider-Based Risks

To reduce provider-created risks, the FDA should target provider behavior by collaborating with IFATS and comparable organizations to draw on and supplement existing federal and state methods of certification, registration, and similar measures.

Detailed Explanation of Recommendations

Recommendation #1 – Cell-Based Risks

The four draft guidances on homologous use, minimal manipulation, same surgical procedure, and adipose tissue individually and collectively intend to “improve stakeholders’ understanding” of 21 CFR 1271 by clarifying the FDA’s interpretation of homologous use and minimal manipulation. As demonstrated by the initial round of public comments and the ensuing public hearing on September 12 and 13, 2016, the draft guidance documents have not clarified applicable regulations. They have instead compounded the difficulty of understanding and complying with them. The drafts’ introduction of new definitional inaccuracies has also amplified rather than reduced patient risk.

IFATS respectfully requests the agency to clarify the definitions and application of homologous use and minimal manipulation by interpreting each as referring to the characteristics of the specific cell type(s) and/or the matrix or other component(s) that are involved in, and/or relevant to, the manufacturer’s intended use in the patient.

Homologous Use Definition:

21 CFR 1271.3(c): Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.

Recommended Guidance:

As used in this section, “performs the same basic function or functions in the recipient as in the donor” shall be interpreted as referring to one or more of the functions of the specific composition of the therapeutic/product, reflecting the specific cell type(s) and/or the specific matrix or other component(s) in the donor tissue that are involved in, and/or relevant to, the manufacturer’s intended use in the patient.

Minimal Manipulation Definition:

21 CFR 1271.3(f) Minimal manipulation means:

• For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement;
• For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells.

Recommended Guidance:

As used in this section, “relevant” characteristics shall be interpreted to mean the characteristics of the specific cell type(s) and/or the specific matrix or other component(s) in the donor tissue that are involved in, and/or relevant to, the manufacturer’s intended use in the patient.

Rationale:

Incorporating and relying on the manufacturer’s intended use harmonizes the interpretation and definition of homologous use and minimal manipulation with statutory directives to predicate the regulation of drugs, devices, and biologics on the manufacturer’s intended use. Defining relevant characteristics in terms of “the characteristics of specific cell type(s) and/or the matrix or other component(s) in the donor tissue that are involved in, and/or relevant to the manufacturer’s intended use in the patient” promotes patient safety by insisting on a reasonable and scientifically supportable rationale for using an HCT/P for a particular mechanism of action. This clarification balances the FDA’s dual responsibilities of protecting patients from undue safety risks while promoting the ongoing availability and continued development of HCT/P therapies.

Example of Non-Homologous Use:

Decellularized adipose matrix used to accomplish the manufacturer’s intended use of a particular metabolic or systemic effect in the patient (e.g., reducing insulin levels in a diabetic patient) is non-homologous because decellularized matrix is not relevant to metabolic or systemic activity.

Conclusion

Adopting this two-part strategy can control risk more comprehensively—and therefore more effectively—in furtherance of the FDA’s dual and interrelated obligations of protecting patients and promoting the availability of HCT/P therapies.

Introduction to FDA Regulations and IFATS Recognition

IFATS acknowledges the FDA’s dual role in patient protection and innovation promotion within the HCT/P sector. Balancing these objectives is crucial yet challenging.

Understanding the FDA’s Risk-Based Framework

The FDA’s § 361 – § 351 framework categorizes HCT/P therapies based on risk levels, influenced by concepts like homologous use and minimal manipulation.

Impact of Regulatory Classification on Access to HCT/P Therapies

Homologous use and minimal manipulation determine whether an HCT/P falls under § 361 (no premarket approval needed) or § 351 (requires premarket approval), affecting accessibility and innovation.

Provider Misconduct Risks in HCT/P Therapies

Rogue clinicians offering unproven therapies pose significant risks. Addressing provider behavior is essential for patient safety and regulatory efficacy.

IFATS Recommendations for Risk Mitigation

Recommendation #1 – Cell-Based Risks: Interpreting Homologous Use and Minimal Manipulation

IFATS proposes clarifying homologous use and minimal manipulation definitions based on manufacturer-intended use, enhancing regulatory clarity and patient safety.

Recommendation #2 – Provider-Based Risks: Targeting Provider Behavior

Collaboration with IFATS and other bodies to enhance certification and monitoring mechanisms can mitigate risks associated with provider misconduct effectively.

Recommendation #3 – Regulatory Scope for Adipose HCT/Ps

Expanding the definition of adipose tissue to include both structural and nonstructural functions aligns with biological accuracy and regulatory intent.

Conclusion: Enhancing Patient Safety and Access to HCT/P Therapies

IFATS urges the FDA to adopt a comprehensive strategy that addresses both cell-based and provider-based risks to uphold patient safety and foster innovation in HCT/P therapies.

Regulating an HCT/P’s Risks Based on Manufacturer’s Intended Use

Regulating the risks of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) is crucially tied to their intended use and mechanisms of action in patients. This ensures effective regulatory oversight and evaluation.

Regulatory Framework: §§ 351-361

The regulatory oversight of HCT/Ps under §§ 351-361 hinges on assessing the product’s risk level. Central to this determination are the criteria of homologous use and minimal manipulation.

Homologous Use Defined (21 CFR 1271.3(c))

Homologous use is defined as the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function as in the donor.

Minimal Manipulation Criteria (21 CFR 1271.3(f))

Minimal manipulation of structural tissue involves processing that preserves the tissue’s original characteristics essential for its utility in repair, reconstruction, or replacement. For nonstructural tissues, it preserves relevant biological characteristics.

Impact on Adipose Tissue

The classification of adipose tissue as exclusively structural neglects its nonstructural functions, limiting evaluation under § 361 criteria and obstructing risk assessment.

Same Surgical Procedure Exception

The § 351 “same surgical procedure” exception applies only to HCT/Ps meeting homologous use and minimal manipulation criteria, impacting nonstructural adipose applications.

Recommendation #4: Revising Evaluation Criteria

IFATS urges the FDA to reconsider specific adipose tissue applications concerning homologous use and minimal manipulation criteria.

Example A: Decellularizing Adipose Tissue

Decellularization of adipose tissue for structural use should be recognized as minimal manipulation under §§ 351 and 361 guidelines.

Example B: Structural Use of Fat in Breast Surgery

Applying adipose tissue for breast augmentation should be considered homologous use due to its structural function in restoring form and shape.

Example C: Stromal Vascular Fraction (SVF) for Nonstructural Use

SVF extraction from adipose tissue retains nonstructural components crucial for nonstructural applications, meeting minimal manipulation and homologous use criteria.

Conclusion and Call to Action

IFATS requests the FDA to amend draft guidance on HCT/Ps to align with scientific understanding and clinical practices of adipose tissue applications.

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66. Cuomo R, Zerini I, Botteri G, Barberi L, Nisi G, D’ANIELLO Postsurgical pain related to breast implant: Reduction with lipofilling procedure. In Vivo. 2014;28:993-996
67. Maione L,  Vinci  V,  Caviggioli  F,  Klinger  F,  Banzatti  B,  Catania  B,  Lisa  A,  Klinger   Autologous fat graft in postmastectomy pain syndrome following breast conservative surgery and radiotherapy. Aesthetic plastic surgery. 2014;38:528-532
68. Caviggioli F,  Maione  L,  Forcellini D,  Klinger  F,  Klinger    Autologous  fat   graft   in postmastectomy pain syndrome. Plastic and reconstructive surgery. 2011;128:349-352
69. Caviggioli F, Vinci V, Codolini Autologous fat grafting: An innovative solution for the treatment of post-mastectomy pain syndrome. Breast Cancer. 2013;20:281-282
70. Salgarello M, Visconti The role of sacrolumbar fat grafting in the treatment of spinal fusion instrumentation-related chronic  low  back  pain:  A  preliminary  report.  Spine. 2014;39:E360-E362
71. Faroni A, Terenghi G, Reid Adipose-derived stem cells and nerve regeneration: Promises and pitfalls. Int Rev Neurobiol. 2013;108:121-136
72. Vaienti L, Gazzola R, Villani F, Parodi Perineural fat grafting in the treatment of painful neuromas. Techniques in hand & upper extremity surgery. 2012;16:52-55
73. Marangi GF, Pallara T, Cagli B, Schena E, Giurazza F, Faiella E, Zobel BB, Persichetti Treatment of  early-stage  pressure  ulcers  by  using  autologous  adipose  tissue  grafts. Plastic Surgery International. 2014;2014
74. Lolli P, Malleo G, Rigotti Treatment of chronic anal fissures and associated stenosis by autologous adipose tissue transplant: A pilot study. Diseases of the Colon & Rectum. 2010;53:460-466
75. Cantarella G,  Baracca  G,  Forti  S,  Gaffuri  M,  Mazzola    Outcomes  of  structural  fat grafting for paralytic and non-paralytic dysphonia. Acta Otorhinolaryngologica Italica. 2011;31:154
76. DeFatta  RA,   DeFatta  RJ,   Sataloff      Laryngeal   lipotransfer:   Review   of   a   14-year experience. Journal of Voice. 2013;27:512-515
77. Sataloff    Autologous  fat   implantation  for  vocal  fold   scar.   Current  opinion  in otolaryngology & head and neck surgery. 2010;18:503-506

78. Cantarella G, Mazzola RF, Mantovani M, Baracca G, Pignataro Treatment of velopharyngeal insufficiency by pharyngeal and velar fat injections. Otolaryngology– Head and Neck Surgery. 2011;145:401-403
79. Papa N, Luca G, Sambataro D, Zaccara E, Maglione W, Gabrielli A, Fraticelli P, Moroncini G, Beretta L, Santaniello A. Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis. Cell transplantation. 2014

80. Hovius SE, Kan HJ, Smit X, Selles RW, Cardoso E,  Khouri    Extensive  percutaneous aponeurotomy and lipografting: A new treatment for dupuytren disease. Plastic and reconstructive surgery. 2011;128:221-228
81. Verhoekx JS, Mudera V, Walbeehm ET, Hovius Adipose-derived stem cells inhibit the contractile myofibroblast in  dupuytren’s  disease.  Plastic  and  reconstructive  surgery. 2013;132:1139-1148

82. Bank J, Fuller SM, Henry GI, Zachary Fat grafting to the hand in patients with raynaud phenomenon: A  novel   therapeutic   modality.   Plastic   and   reconstructive   surgery. 2014;133:1109-1118
83. Damgaard OE, Siemssen Lipografted tenolysis. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2010;63:e637-e638
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86. Mojallal A,   Lequeux  C,  Shipkov  C,  Breton  P,  Foyatier  J-L,  Braye  F,  Damour   Improvement  of skin quality after  fat  grafting: Clinical observation and  an  animal  study. Plastic and reconstructive surgery. 2009;124:765-774
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88. Song AY, Askari M, Azemi E, Alber S, Hurwitz DJ, Marra KG, Shestak KC, Debski R, Rubin Biomechanical properties of the superficial fascial system. Aesthetic Surgery Journal. 2006;26:395-403
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94. Healy C, Allen Sr The evolution of perforator flap breast reconstruction: Twenty years after the first diep flap. Journal of reconstructive microsurgery. 2014;30:121-125
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SATURDAY, 01 OCTOBER 2016 / PUBLISHED IN BLOG

Researchers from the Medical University of South Carolina (MUSC) and the University of Pennsylvania have discovered a new methodology for purifying liver cells generated from induced pluripotent stem cells (iPSCs) that could facilitate progress toward an important clinical goal: treating patients with disease-causing liver mutations by transplanting unmutated liver cells derived from their own stem cells.

Background on Liver Cell Generation from iPSCs

Previous attempts to generate liver-like cells from stem cells have yielded heterogeneous cell populations with little similarity to diseased livers in patients.

The Role of the Next Generation Genetic Association Studies Program

The National Heart, Lung, and Blood Institute (NHLBI)’s Next Generation Genetic Association Studies Program (Next Gen) was created to bank stem cell lines sourced from patients in genome-wide association studies (GWAS). The goal of the Next Gen Lipid Conditions sub-section, a collaborative effort between Stephen A. Duncan, Ph.D., chair of regenerative medicine at MUSC, and Daniel J. Rader, M.D., and Edward E. Morrisey, Ph.D., both at the University of Pennsylvania, is to help determine the genetic sources of heart, lung, or blood conditions that also include the liver.

Genome-Wide Association Studies (GWAS)

GWAS studies map the genomes in hundreds of people to look for genetic mutation patterns that differ from the genomes of healthy individuals. As GWAS studies map more genomes, they become more likely to find the correct genetic mutations that cause a disease. Once a panel of suspected mutations is built, stem cells from these individuals can be manipulated in culture dishes to differentiate into any of the body’s cells. The cells can be screened to learn more about the mutations and to test panels of drugs that might ultimately help treat patients harboring a disease.

Challenges in Cell Manipulation Process

Problems arise during the cell manipulation process. For example, iPSCs persistently refuse to mature uniformly into liver-like cells when fed growth factors. Traditionally, antibodies have been used to recognize features of maturity on the surfaces of cells and purify cells that are similar, an approach that has been crucial to stem cell research. But available antibodies that recognize mature liver cells are scanty and tend to recognize many different kinds of cells. The many types of cells in mixed populations have diverse characteristics that can obscure underlying disease-causing genetic variations, which tend to be subtle.

Introduction of Chemo Proteomic Cell Surface Capture (CSC) Technology

Instead of relying on antibodies, Duncan and his team embraced a new technology called chemo proteomic cell surface capture (CSC) technology. CSC technology allowed the researchers to map the most highly produced proteins on the surface of liver cells during the final stages of differentiation of stem cells into liver cells. The most abundant protein was targeted with an antibody labeled with a fluorescent marker and used to sort the mature liver cells from the rest.

Successful Generation of Pure Liver-like Cells

The procedure was highly successful: The team had a population of highly pure, homogeneous, and mature liver-like cells. Labeled cells had far more similar traits of mature hepatocytes than unlabeled cells. Pluripotent stem cells that had not differentiated were excluded from the group of labeled cells.

“That’s important,” says Duncan. “If you’re wanting to transplant cells into somebody that has liver disease, you really don’t want to be transplanting pluripotent cells because pluripotent cells form tumors called teratocarcinomas.”

Future Implications

Duncan cautioned that transplantation of iPSC-derived liver cells is not yet ready for translation to the clinic, but the technology for sorting homogeneous liver cells can be used now to successfully and accurately model and study disease in the cell culture dish.

“We think that the ability to generate pure populations will get rid of the variability, and therefore really help us combine with GWAS studies to identify allelic variations that are causative of a disease, at least in the liver,” he says.

Contributions to the Study

Researchers at the University of Minnesota (Minneapolis) and the Medical College of Wisconsin (Milwaukee) contributed to the study, published August 25, in Stem Cell Reports.

SATURDAY, 01 OCTOBER 2016 / PUBLISHED IN BLOG

Scientists from the U.K. and Sweden have achieved a significant breakthrough in creating human stem cells that addresses the challenge of large-scale production, unlocking the full potential of stem cells for disease understanding and treatment.

Understanding Human Pluripotent Stem Cells

Human pluripotent stem cells, capable of developing into any type of cell in the body, hold immense promise in disease modeling, drug screening, regenerative medicine, and tissue engineering. The demand for these cells is rapidly increasing in clinical and pharmaceutical settings.

Challenges in Stem Cell Production

Despite their potential, producing stem cells at the necessary scale for research and healthcare applications has been challenging due to expensive culture methods or unsafe substances unsuitable for clinical use.

Breakthrough Methodology

Published in Nature Communications in July, researchers from The University of Nottingham’s Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, Uppsala University, and GE Healthcare in Sweden have developed and enhanced human stem cell culture techniques. They have identified a method using Inter-alpha inhibitor, a protein derived from human blood, to grow human pluripotent stem cells in a minimal medium without costly biological substrates.

Advantages of Inter-alpha Inhibitor

Inter-alpha inhibitor, abundant in human blood and a by-product of drug purification, promotes stem cell attachment to unmodified tissue culture plastic. This innovation eliminates the need for coating in defined human pluripotent stem cell culture and enhances cell survival in challenging conditions.

Cost and Efficiency Benefits

This breakthrough method is the first to eliminate the requirement for pre-treated biological substrates, making it more cost-effective and efficient for large-scale production. It holds promise for accelerating high-throughput cultures essential for both basic research and commercial applications.

Future Directions

Future research aims to integrate Inter-alpha inhibitor with advanced hydrogel technologies to further refine cell differentiation control and disease modeling capabilities. The focus includes rare conditions such as Multiple Osteochondroma, aiming to replicate cellular environments accurately for disease modeling.

Research Impact and Recognition

Dr. Sara Pijuan-Galitó, the study’s lead author and a Swedish Research Council Research Fellow at Nottingham, continues to advance this work under the Sir Henry Wellcome Postdoctoral Fellowship. Collaborating with Professor Morgan Alexander and Professor Chris Denning, pioneers in regenerative medicine, the team seeks to develop an economical and safe method for large-scale human stem cell culture.

The study titled “Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture” was published in Nature Communications in July 2016.

MONDAY, 19 SEPTEMBER 2016 / PUBLISHED IN BLOG

Russian researchers have concluded that reprogramming does not create differences between reprogrammed and embryonic stem cells.

Understanding Stem Cells and Reprogramming

Stem cells are specialized, undifferentiated cells with the potential to develop into various cell types in the body. Pluripotent stem cells, capable of generating any cell type, are naturally found in early embryos. They are crucial for internal repair and growth during early life.

Reprogramming Techniques and Their Importance

Reprogramming adult cells involves activating genes typically active in stem cells and deactivating those responsible for cell specialization. This pioneering work by Shinya Yamanaka, Nobel laureate, demonstrated that specific proteins could convert adult cells into pluripotent stem cells, known as induced pluripotent stem cells (iPSCs). This breakthrough avoids ethical concerns associated with using embryonic stem cells.

Potential Applications in Medicine

Stem cells hold promise for treating various diseases. Examples include transplanting retinal pigment epithelium and spinal cells, as well as regenerating teeth in mice. Reprogrammed iPSCs offer a revolutionary approach by allowing personalized treatment using a patient’s own cells.

Scientific Comparison: iPSCs vs. Embryonic Stem Cells

Recent studies have highlighted similarities and differences between iPSCs and embryonic stem cells. Researchers compared isogenic iPSC lines reprogrammed from different adult cell types previously derived from embryonic stem cells. Analysis of transcriptomes and methylated DNA areas showed comparable gene activity regulation mechanisms.

Research Findings and Implications

The study, published in the journal Cell Cycle, concluded that reprogramming adult cells into iPSCs does not leave distinguishing marks compared to embryonic stem cells. Differences observed were attributed to random factors rather than the reprogramming process itself.

“We defined the best induced pluripotent stem cell line concept,” says Dmitry Ischenko, Ph.D., researcher at the Moscow Institute of Physics and Technology.

Future Directions in Stem Cell Research

While this research doesn’t propose organ growth in vitro, it represents a crucial step toward understanding how specialized cells develop from pluripotent cells. Both iPSCs and embryonic stem cells offer potential for generating replacement cells and tissues to treat currently untreatable diseases.

Conclusion

The study, titled “An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion,” involved researchers from the Vavilov Institute of General Genetics, Research Institute of Physical Chemical Medicine, and the Moscow Institute of Physics and Technology (MIPT).

MONDAY, 29 AUGUST 2016 / PUBLISHED IN BLOG

Adult stem cells are gaining significant attention in the scientific community due to their ability to self-renew and generate various types of cells and tissues. Unlike embryonic stem cells, which can differentiate into multiple cell types, adult stem cells primarily produce the specific tissue from which they originate. This focus on adult stem cells has intensified amidst ethical concerns surrounding the use of embryonic stem cells.

Diversity of Adult Stem Cell Sources

Research has identified several adult tissues that harbor stem cells, offering promising avenues for treating degenerative conditions such as osteoarthritis, muscular dystrophy, and Alzheimer’s disease. The expanding list of these tissues includes:

• Bone Marrow: Known for hematopoietic stem cells (HSCs) that can differentiate into blood cells and skeletal stem cells (STCs) contributing to bone and cartilage.
• Brain Tissue: Neural stem cells (NSCs) capable of generating various types of neurons, under study for conditions like multiple sclerosis and Parkinson’s disease.
• Peripheral Blood and Blood Vessel Tissue: Contains hematopoietic stem cells critical for immune function and blood clotting.
• Skeletal Muscle Tissue: Houses muscle stem cells important for muscle repair and regeneration.
• Liver and Pancreas Tissue: Liver’s hepatocytes possess regenerative capabilities, while pancreatic precursor cells from the biliary tree show promise in diabetes research.

Applications in Regenerative Medicine

Adult stem cells offer practical advantages over embryonic stem cells, including lower rejection rates (often sourced from the patient) and higher differentiation potential. This makes them valuable for developing therapies to treat currently incurable diseases in humans.

Future Directions in Stem Cell Research

Scientific advancements continue to uncover new insights into adult stem cells, their capabilities, and potential applications in regenerative medicine. Ongoing research aims to harness these cells’ regenerative properties more effectively, paving the way for novel treatments and therapeutic strategies.

References

For further details, refer to the original research articles and sources:

• MacKlis et al., Nature 2000
• Biliary Tree Stem Cells, Diabetes Research Institute

MONDAY, 29 AUGUST 2016 / PUBLISHED IN BLOG

Recent studies from the Weizmann Institute of Science suggest promising applications of stem cells in repairing damaged lung tissue. This breakthrough offers hope for treating prevalent conditions such as bronchitis, asthma, cystic fibrosis, and emphysema, which collectively affect millions globally and rank among the leading causes of death.

Bone Marrow Stem Cells: Potential for Lung Tissue Regeneration

Researchers at the Weizmann Institute have explored the similarities between lung and bone marrow stem cells. They found that bone marrow stem cells, when transplanted into patients, can migrate through the bloodstream to damaged lung areas and differentiate into lung tissue.

Acknowledging these similarities, Professor Yair Reisner from the Immunology Department conducted experiments where lung stem cell compartments were cleared in mice models before introducing bone marrow stem cells. This approach allowed transplanted stem cells to populate the lungs, differentiate into functional lung tissue, and significantly improve respiratory function over time.

The Weizmann team aims to expand this research to establish a bank of lung-specific stem cells for potential future transplantation in patients with severe respiratory diseases.

Lung-Specific Induced Pluripotent Stem Cells (iPSCs): A Promising Alternative

In parallel research, scientists at the Boston University Medical Center have generated lung-disease-specific induced pluripotent stem cells (iPSCs) from patients with conditions like emphysema and cystic fibrosis. These iPSCs offer advantages over bone marrow stem cells, including easier cultivation and reduced risk of rejection due to genetic similarity to the patient’s own cells.

By manipulating skin stem cells into iPSCs capable of differentiating into lung tissue, researchers have demonstrated their potential in laboratory settings. This approach could circumvent several challenges associated with other stem cell therapies, making it a viable option for future clinical applications.

References

For further reading and detailed studies:

• Chava Rosen et al., Nature Medicine 2015
• Aba Somers et al., Stem Cells 2010

SUNDAY, 28 AUGUST 2016 / PUBLISHED IN BLO

Stem cell medicine leverages the body’s innate ability to heal itself, offering alternatives to conventional drugs and invasive surgeries. Stem cell therapies involve engineering human stem cells to repair or restore damaged organs and tissues, aiming to reinstate normal function.

Types of Stem Cell Therapies

Stem cell therapies encompass a range of approaches, including progenitor cells like those used in bone marrow transplants and cellular products such as platelet-rich plasma (PRP). While PRP and progenitor cells have been extensively used in clinical settings, stem cell therapies are rapidly advancing to address various medical conditions.

Autologous vs. Allogeneic Stem Cells

Stem cell treatments typically fall into two categories:

Autologous Stem Cells

Derived from the patient’s own body, autologous stem cells are used exclusively for the patient’s benefit. This approach minimizes the risk of rejection and allows for immediate treatment without the need for donor matching. Common sources include bone marrow and adipose tissue, facilitating therapies ranging from orthopedic conditions to wound healing.

Allogeneic Stem Cells

Harvested from donors, allogeneic stem cells undergo rigorous testing for diseases and are often cultured to increase cell counts. These stem cells, regulated under strict FDA guidelines, hold potential for large-scale production and widespread therapeutic applications across diverse patient populations.

Understanding Stem Cell Types

Adult Stem Cells (ASCs)

Found in various tissues, adult stem cells replenish dying cells and regenerate tissues like bone, cartilage, and adipose tissue. Over 2,000 clinical trials worldwide have explored their therapeutic potential, primarily from bone marrow and adipose tissue sources.

Induced Pluripotent Stem Cells (iPSCs)

Derived from adult cells, iPSCs are genetically reprogrammed to exhibit pluripotency, meaning they can differentiate into any cell type. Despite their versatility, iPSCs carry higher risk profiles compared to adult and embryonic stem cells.

Embryonic Stem Cells (ESCs)

Derived from human embryos, embryonic stem cells are a subject of ethical debate but remain vital for understanding regenerative processes and advancing medical research.

Types of Adult Stem Cells

Bone Marrow Stem Cells

First identified in bone marrow, these stem cells play crucial roles in healing bones and replacing blood cell types. FDA-approved under specific conditions, their use requires meticulous lab cultivation and regulatory oversight.

Adipose-Derived Stem Cells

Discovered in fat tissues, adipose-derived stem cells (ADSCs) can differentiate into diverse cell types, revolutionizing fields from plastic surgery to regenerative medicine.

THURSDAY, 25 AUGUST 2016 / PUBLISHED IN BLOG

Adipose stem cells (pictured) harvested from body fat. (Photo: Genetic Engineering & Biotechnology News).

Introduction to Adipose Stem Cells

The discovery of abundant stem cell populations in body fat tissue changed everything the medical community thought it knew about stem cells overnight. Now, adipose stem cell therapies are driving the plastic and cosmetic surgery industries, and demand among patients keeps rising.

Discovery of Adipose Stem Cells

In 2001, researchers and plastic surgeons from the University of Pittsburgh discovered that human fat tissue is a very rich source of mesenchymal stem cells (MSCs), multipotent stromal cells that can differentiate into a variety of cell types. When their findings were published in the Tissue Engineering Journal, the discovery stirred quite an epiphany in the medical and scientific community—until then, adult MSCs were predominantly believed to be strictly a bone marrow product. Little did those researchers realize at the time that their discovery would revolutionize cosmetic surgery in less than a decade.

Advantages of Adipose Tissue Over Bone Marrow

Adipose tissue offers distinct advantages over bone marrow tissue. Adipose fat is easier to extract than bone marrow, and the stem cell population contained in fat tissue is far more abundant than in bone marrow. One ounce of fat contains 300-500 times as many mesenchymal stem cells as an ounce of bone marrow. And unlike bone marrow, because of autologous adipose tissue’s copious stem cell count, most procedures using them do not require cells to be expanded in a lab, which means that most adipose stem cell therapies can be performed in the same operative procedure. Because bone marrow typically needs to be culture expanded for days in a lab before they can be re-injected back into a patient and adipose cells do not, there are plenty of advantages to adipose stem cell therapies.

Adipose Stem Cell Therapy Procedures

Over the past 10 years, plastic surgeons have established safe and convenient ways to remove fat and isolate the stem cells for use in cosmetic procedures. And since adipose stem cells are extracted and reintroduced to the patient’s own body, the risk of rejection that goes with donor stem cells is eliminated. Scores of ongoing clinical trials using adipose stem cells have already proven their safety and efficacy in a variety of applications. Anti-aging therapies using adipose stem cells, for instance, have grown exponentially in popularity.

Anti-Aging Benefits of Adipose Stem Cells

As we age, cells become progressively damaged over time from sun, toxins in the environment, and the natural loss of moisture that keeps youthful skin full and wrinkle-free. Adipose stem cells work to regenerate and repair that damaged tissue, and adjunctive treatments can potentially slow down or reverse the aging process. Those cells possess a unique anti-aging effect by means of regenerating and repairing organs—including skin—damaged by environmental elements we are exposed to in our daily life, and by improving immune functions.

International Demand for Stem Cell Anti-Aging Therapies

This discovery has created an international demand for stem cell anti-aging therapies, which since these procedures are non-invasive (no surgery involved), make for a faster recovery and significantly less downtime for patients. Many patients and physicians feel that adipose stem cells also create a more natural appearance for recipients than traditional cosmetic surgery procedures. Some cosmetic stem cell physicians have taken it up a notch with cell-assisted fat transfer, in which autologous adipose-derived (stromal) stem cells are used in combination with lipoinjection for even softer, more natural results.

Procedure of Cell-Assisted Fat Transfer

Here’s how it works: a stromal vascular fraction (SVF) containing ASCs is freshly isolated from half of the aspirated fat and recombined with the other half. This process converts relatively ASC-poor aspirated fat to ASC-rich fat, reducing the potential for postoperative atrophy of injected fat to a minimal level, which clinical trials have found does not change substantially after two months.

Adipose Tissue as a Regenerative Therapy

While adipose tissue is a definitive source of stem cells, what if you don’t need to isolate or separate the stem cells to benefit from their regenerative powers?

Radiation to treat a tumor severely affected this boy’s facial growth and development, caused significant facial asymmetry and left a large cosmetic defect on the side of his head. Fat grafting surgery restored his appearance to that of any healthy, happy, 14-year-old.

Regenerative Properties of Fat Grafting

Plastic surgeons have known for years that fat grafting itself, without extracting the stem cells, has regenerative properties. Cosmetic surgeons have developed safe and predictable techniques for fat grafting and have documented the regenerative effects of fat grafting in different tissues, for a variety of conditions and diseases. Adipose stem cell-rich fat grafting has been documented to reverse radiation tissue damage, something that was considered irreversible until recently. Current clinical studies are documenting the regenerative effects of fat grafting in areas no one suspected, such as autoimmune diseases and degenerative joint disease. Unlike bone marrow tissue, adipose tissue is easy to extract, it’s abundant, and it’s effective in ways researchers have only begun to discover. Cell-assisted fat grafting serves a valuable role in helping people with disfiguring injuries and birth defects.

Advancements in Adipose Tissue Applications

Plastic surgeons have acquired decades of experience in harvesting and refining adipose tissue for treating patients. Thanks to the remarkable level of expertise they have developed with adipose tissue, experts now play a leading role in developing its evolving regenerative applications. Regenerative medicine is changing the landscape of cosmetic and reconstructive surgery, and aesthetic medicine—and it keeps getting better!