IFATS Recommendations for FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products
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
September 26, 2016
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Re: FDA-2014-D-1856 – Comments to 2014-2015 Draft Guidance regarding: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“Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Draft Guidance for Industry”;
- Docket FDA-2014-D-1696: “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and Food and Drug Administration Staff”;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“Human Cells, Tissues, and Cellular and Tissue-Based Products from Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry”;
- Docket FDA-2015-D-3581: “Homologous Use of Human Cells, Tissues, and Cellular and Tissue- Based Products; Draft Guidance for Industry and FDA Staff.”
Dear Sirs and Madams:
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 is committed to the responsible advance of the science and translation of new adipose therapies, and it is determined to ensure patient safety. It was founded in 2003 by pioneering adipose stem cell biologists and clinician–scientists with the goal of advancing the science of adipose tissue biology and its clinical translation to therapeutic applications. Since that time, IFATS has remained at the forefront of regenerative medical applications involving adipose tissue and cells. Membership now spans 40 countries in North America, Europe, Africa, the Middle East, Asia, Australia, and Central and South America, and includes basic scientists, translational researchers, clinicians, and regulatory and biotech representatives. IFATS is formally aligned with, and its members serve on the editorial boards of the prestigious journals, Stem Cells and Stem Cells Translational Medicine. With the International Society for Cellular Therapy (ISCT), IFATS has provided the scientific community with a detailed description and definition of adipose derived cells (both stromal vascular fraction, or SVF, and adipose-derived stromal/stem cells, or ASCs) in the formal publication entitled Cytotherapy. Thus, IFATS possesses the necessary expertise to assist regulatory agencies in understanding adipose tissue, and regulating the safety and efficacy of adipose-related products and therapies.
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:
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 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 the evaluation of minimal manipulation and homologous use as they pertain to particular applications of adipose tissue.
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IFATS recognizes the FDA’s challenge in developing regulations that fulfill the agency’s dual and interrelated responsibilities of protecting patients while promoting innovation. IFATS further recognizes that 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.
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. 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 the HCT/P’s characteristics, mechanism(s) of action and circumstances of use.
A second type of risk involves rogue clinicians offering false promise 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. Because a solution cannot solve a problem without identifying and attacking its root cause, 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.
Consequently, interpretive guidance that restricts the definition and application of HCT/P terminology can only go so far in restricting provider-based risks. In addition, restrictive, inaccurate or imprecise definitions and interpretations carry their own risks of restricting access to therapies and restricting 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, i.e., those relating to cell behavior and those that pertain to provider behavior.
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 to 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.
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. IFATS explains each recommendation as follows:
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.
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 reduce 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. Thus, the definition of homologous use with interpretive guidance would read as follows:
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 function(s) 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.
Similarly, the definition of minimal manipulation with interpretive guidance would read as follows:
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 or
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.
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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.
For a risk-reduction strategy to succeed, it must target the root cause of the risk. Revising, retracting or replacing interpretations of regulatory terminology can target the risks of cells behaving in an unsafe ways, but can do little to prevent providers from behaving in unsafe ways. Because the risks of irresponsible providers offering unsafe treatments are not exclusive to HCT/P therapies, many federal and state mechanisms already exist for identifying, disciplining and prohibiting clinics and clinicians from endangering patients.
IFATS shares the FDA’s concern about provider-related risks in the HCT/P sector and shares its determination to end or minimize these risks. IFATS respectfully requests the FDA to collaborate with it and comparable organizations to identify and draw on existing federal and state methods for curtailing provider misconduct, and developing additional protections in the form of provider certification, registration, monitoring and similar measures. At present, the §§ 351-361 regulatory framework does not – and cannot – adequately respond to this form of risk. Collaboration among stakeholders and coordination with existing means of provider oversight offers the most effective and efficient strategy for protecting patients from provider-created risk.
Therefore, IFATS respectfully requests the FDA to meet with IFATS, the American Association of Blood Banks and other accreditation bodies for the purpose of working together to identify provider-focused safety objectives and measures that can be translated into formal accreditation requirements and interpretive guidance.
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Recommendation #3: Recognize that adipose HCT/Ps have both structural and nonstructural functions, and regulate based on its manufacturer’s intended use in the patient.
IFATS requests the FDA to expand its definition of adipose tissue from exclusively structural in function to include both structural and/or nonstructural functions, depending on the manufacturer’s intended use in the patient. This modification is critically necessary in order to:
- Reconcile the interpretive guidance on the definition and regulation of adipose with applicable statutory and regulatory requirements;
- Reflect and ensure biological accuracy; and most importantly,
- Regulate an HCT/P’s risks based on the manufacturer’s intended use and mechanisms of action in the patient.
a. Recognizing adipose tissue’s structural and/or nonstructural functions is required by applicable statutory and regulatory requirements.
Adipose HCT/Ps must be defined as having structural and/or nonstructural functions to align the draft guidance with statutory and regulatory recognition that cells and tissues may have more than one function. According to 42 USC § 321(g)(1), “[t]he term ‘drug’ means … (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). (emphasis added). Statutory directives to focus on intended use pervade FDA regulation, including the regulation of drugs, biologics, devices, cosmetics, pesticides and more. Applicable statutes and regulations explicitly and implicitly recognize that the human body is complex, and its tissues and cells are often versatile and multi-functional. For example, 21 CFR 1271.3(c)’s definition of homologous use correctly recognizes that an HCT/P may have more than one “basic function.” It never says or even suggests that an HCT/P can only have one function, or that the regulator has sole authority to define that function and thereby dictate a manufacturer’s intended use. And yet the draft guidances do just that by insisting that adipose HCT/Ps are solely structural.
To align interpretive guidance with the regulations and statutory provisions being interpreted, IFATS respectfully requests the FDA to avoid pre-determining specific functions and uses for specific HCT/Ps. Instead, it should base regulations and guidance on the HCT/P’s function(s) and characteristic(s) that are relevant to its intended use by the manufacturer.
b. Recognizing adipose tissue’s structural and/or nonstructural functions is necessary to correct factual inaccuracy.
Regulation 21 CFR 1271.10(a)(4) categorizes an HCT/P as “either” structural or nonstructural, depending on its function. A structural HCT/P “does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function.” A nonstructural HCT/P “has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function.”
The draft adipose guidance expressly acknowledges that adipose tissue contains adipocytes, preadipocytes, fibroblasts, vascular endothelial cells, a variety of immune cells, and also stores energy in the form of lipids. Citing only Junqueira ’s Basic Histology: Text & Atlas , the draft guidance classifies adipose as a connective and therefore structural tissue. This result is internally inconsistent and factually inaccurate – and the FDA’s sole cited authority explains why.
Junqueira classifies connective tissue as: 1) connective tissue proper; 2) embryonic connective tissues; and 3) specialized connective tissues. The latter category defines specialized connective based on their principal specialized functions. Blood, reticular connective tissue, adipose tissue, bone and cartilage all qualify as specialized connective tissues with specialized, nonstructural functions. Junqueira ’s examples include the following:
- Blood is a specialized connective tissue; its principal function of transport is nonstructural.
- Reticular connective tissues include the liver, pancreas, bone marrow and lymph They are nonstructural tissues because their principal functions are metabolic, including endocrine.
- According to Junqueira – the FDA’s sole cited authority – adipose tissue is nonstructural specialized connective tissue; its primary function is metabolic with co-existing structural
Junqueira ’s categorization of adipose as primarily nonstructural reflects longstanding scientific consensus. In1893, Gustav Neuber described his use of fat grafting in the orbital region to heal the adherent scarring which was the sequela of osteomyelitis. As a result of its nonstructural healing functions, the fat graft transformed facial scarring to more normal appearing skin and subcutaneous tissues.  In 1912, Holländer described the successful use of fat injections to prevent the recurrence of scarring following breast surgery.  In 1926, Charles Conrad Miller developed a new system for injecting fat grafts, and described 36 cases of correcting cicatricial contraction on the face and neck, and reported “excellent results” for another 2 cases after using fat grafts to treat “very persistent parotid fistulas…which defied all other methods of treatment.”  These and similarly favorable outcomes resulted from fat’s transformational nonstructural repair of the tissues into which it was placed. 
The understanding of the diverse roles of adipose tissue has steadily expanded , due in large part to the discovery of the first widely accepted adipokine, leptin, in the mid-1990’s.  Adipose tissue secretes proteins with systemic actions on hematopoietic, reproductive, metabolic, and other cells and tissues demonstrates unequivocally that adipose meets the definition of a true “endocrine” organ.[11,12] A Google scholar search of all available online medical and research databases for “the primary function of Adipose Tissue” returns 538,000 journal articles. Although the search did not designate a specific function, the search results referred to adipose tissue almost exclusively as a nonstructural metabolic and endocrine organ with secretory properties. A search for an exact match of the phrase “primary function of adipose tissue” yielded the following: “It was long believed the primary function of adipose tissue was energy storage; in fact, stromal adipose is a complicated endocrine organ.” However, even energy storage is nonstructural.
The FDA’s draft guidance on minimal manipulation defines nonstructural tissues as “serv[ing] predominantly metabolic or other biochemical roles in the body such as hematopoietic, immune, and endocrine functions.” To illustrate, the draft guidance offers “cord blood, lymph nodes, pancreatic tissue” as examples of nonstructural tissue. These tissues are indeed nonstructural – but they are also specialized connective tissue, as explained in Junqueira. In addition adipose has “hematopoietic, immune, and endocrine functions,” as explained below. As demonstrated by Junqueira, adipose HCT/Ps clearly do more than “reconstruction, repair, or replacement that relate to its utility to cushion and support the other tissues in the subcutaneous layer (subcutaneum) and skin.” And the FDA’s own nonstructural examples prove that classifying connective tissue, including adipose tissue as solely structural is factually inaccurate and logically flawed.
Thus, IFATS strongly recommends that the draft guidances be revised to define and categorize adipose tissue has both structural and nonstructural functions.
In support, IFATS offers the following examples of adipose’s nonstructural, and combined nonstructural and structural functions.
Nonstructural Functions of Adipose HCT/Ps:
- Nonstructural Endocrine Functions – It is well recognized that adipose is an endocrine organ which, like other endocrine organs, performs a variety of nonstructural Adipose tissue secretes proteins with nonstructural, systemic actions on hematopoietic, reproductive, metabolic, and other cells and tissues. [11, 12]
- Glucose and lipid metabolism control via adipokine secretion 
- Reproductive and endocrine control via adipokine secretion [14-16]
- Immunomodulatory and immunosuppressive systemic control via cytokine and protein factor secretion [17-22]
2. Nonstructural Paracrine Functions
- Angiogenic control via vasculogenic cytokine secretion [22-26]
- Hematopoietic control via cytokine secretion, both locally and systemically 
- Neurogenesis via secretion of cytokine factors [28-34]
3. Nonstructural Hematopietic Potential of adipose stem cells in adipose deposits
- Reservoir for hematopoietic and lymphoid progenitor cells similar to bone marrow [18, 35, 36]
- Thermogenesis (brown and beige fat)[37-41]
- Energy reservoir (white adipose depots) [42,43]
4. Nonstructural Promotion of Lactation
- Fat serves as an energy reservoir and nutrient supply for breast epithelial cells.
- As pregnancy progresses, the breast epithelium proliferates in a branching manner to occupy the majority of the adjacent adipose tissue and
- At parturition, the epithelial cells draw on the lipid reserves of adipocytes within immediate proximity and secrete these nutrients into the milk available to the newborn infant during
- As long as the mother continues to breast feed the infant, the epithelial cells remain viable and
- If suckling is discontinued for periods of 24 to 48 hours, the epithelial cells undergo rapid apoptosis, leaving pre-adipocytes and adipocytes as the predominant cell within the breast
- While the presence and organization of epithelial cells within the breast tissue provide it with a unique architecture, the mammary adipocytes themselves show remarkable similarity to adipocytes from elsewhere in the Thus, the mammary fat pad displays homology to other adipose tissue depots.
5. Nonstructural Regenerative Functions
- Local and circulating multipotent progenitor cells can repair and regenerate damaged tissues such as repairing irradiated skin, alleviating fibrotic changes, improving mobility and vitality, and repairing structures such as hair follicles and [45-47]. Specific examples include:
- Modulation of scarring
- Treatingold burn scars [55-57]
- Release of adherent scarring/fasciotomies 
- Modulation of scarring in primary cleft lip repair 
- Multipotent progenitor cells may be recruited for repair and regeneration of ischemic damage induced by acute myocardial infarction. 
- Adipose mesenchymal stem cells as progenitor cells in a perivascular position contribute to vascular network formation and vascular structures.[49-52] As such, the adipose mesenchymal stem cells are located in a position and serve a role shared by mesenchymal stem cells located in nearly all body tissues . Adipose MSCs located in a range of tissues can enhance vascularity and perfusion, and thus provide cells that are precisely homologous to those already present in the
- Adipose mesenchymal stem cells induce a monocyte/macrophage phenotype switch from M1 to M2 macrophages, contributing to improved infarct healing post-acute myocardial 
6. Nonstructural Functions in Bone Marrow – Bone marrow and blood products are exempt from regulation under § 351 and 361. For over 40 years, it has been clearly established that adipose is present in bone marrow where it serves a wide variety of nonstructural functions. The following physiologic processes have nothing to do with providing cushioning and support and therefore are not properly categorized as a structural use or function of adipose cells. 
- Pre-adipocytes as mesenchymal cells in bone marrow: Bone marrow contains a spectrum of mesenchymal cells, including pre-adipocytes that can perform the nonstructural function of differentiating into adipocytes, osteoblasts and chondrocytes depending on the organism’s current needs.
- Pre-adipocytes and adipocytes regulate lympho-hematopoiesis and enable the bone marrow microenvironment to regulate proliferation within blood cell lineages to favor erythropoiesis rather than Adipocytes also contain nonstructural metabolic precursors and energy for the purpose of lympho-hematopoiesis. This is a nonstructural function.
- Adipocytes are essential for synthesizing plasma membranes during blood cell development because they contain cholesterol esters, triglycerides and lipoproteins.
- Bone marrow and extramedullary adipocytes are critical for homeostatic control of temperature in the bone marrow microenvironment and throughout the body, and thus contribute to the overall energy metabolism of the organism.
- Bone marrow adipose tissue is an essential endocrine organ. Bone marrow adipose tissue (MAT) increases during caloric restriction (CR), is responsible for increased adipokine secretion, and alters skeletal muscle adaptation to These and other observations identify MAT as an endocrine organ.
BOTH Nonstructural and Structural Functions: In the following examples, adipose’s structural and nonstructural functions combine for the patient’s benefit:
- Reversal of damage caused by therapeutic radiation [60-63]
- Structural (filling tissue defect) uses, and
- Nonstructural tissue repair and regenerative uses 
- Treatingacute thermal injury [64-65]
- Treating Pain Mitigating implant breast pain 
- Improving post-mastectomy pain [67-68]
- Improving lower back pain 
- Nerveor neuroma repair [71-72]
- Healing ulcers
- Treatingpressure sores 
- Treating chronic non-healing anal fissures and associated stenosis 
- Treating vocal fold paralysis [75-77]
- Treating velopharyngeal insufficiency 
- Treating scleroderma and systemic sclerosis 
- TreatingDupuytren’s disease of the hand [80, 81]
- Treating Raynaud’s phenomenon – After fat grafting, there is improved symptomatology with evidence suggestive of measurably increased perfusion 
- Improving tendon repair
- Adipose tissue assists in tenolysis for foot and hand tendon 
- Treating adherent tendons and joints in burn patients with fat graft 
- Preventing osseous reunion of skull defects 
- Improvingthe quality of skin 
c. Regulating an HCT/P’s risks based on the manufacturer’s intended use and mechanisms of action in the patient ensures meaningful evaluation and effective regulation of risk.
The §§ 351-361 framework conditions the degree of regulatory oversight on the degree of an HCT/P’s risk. The homologous use and minimal manipulation criteria are central to determining whether an HCT/P will be classified as a § 361 or § 351 product, and if the latter, whether § 351’s “same surgical procedure” exception will apply. In turn, the existence of homologous use and minimal manipulation depend on the HCT/P’s structural or nonstructural function. More specifically:
21 CFR 1271.3(c) defines homologous use as “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.”
21 CFR 1271.3(f) evaluates minimal manipulation of structural tissue in terms of processing that does not alter “the original relevant characteristics of the tissue relating to” the tissue’s utility for reconstruction, repair, or replacement. For nonstructural tissues, it evaluates “the relevant biological characteristics of cells or tissues.”
Insisting that adipose be evaluated as exclusively structural precludes any evaluation of its nonstructural functions despite their presence and importance in the donor and intended use and therapeutic benefits for the recipient. Failing § 361’s homologous use and minimal manipulation criteria are virtually guaranteed. This effectively prohibits any nonstructural use, and precludes any meaningful evaluation of their risks.
As a result, it effectively prohibits patient access to safe nonstructural applications of adipose tissue and thereby undermines the FDA’s obligations to protect patients and promote innovation.
The “ same surgical procedure” exception to § 351 also becomes completely unavailable for nonstructural use of adipose because it similarly requires homologous use and minimal manipulation.
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Recommendation #4: Revise the evaluation of minimal manipulation and homologous use as they pertain to particular applications of adipose tissue, (as detailed below).
IFATS respectfully requests the FDA to reconsider three particular applications of adipose tissue with regard to homologous use and minimal manipulation, each of which is required for § 361 classification as well as § 351’s “same surgical procedure” exception. In specific, IFATS requests the FDA to change its prior examples of the absence of homologous use and/or minimal manipulation to recognize the following:
- Decellularizing adipose tissue for structural use is minimal manipulation.
- Structural use of fat in the breast constitutes homologous
- Stromal vascular fractionation (SVF) of adipose to obtain nonstructural adipose components for use as a nonstructural tissue constitutes minimal
Each is explained in order
a. Decellularizing adipose tissue for structural use is minimal manipulation.
The draft guidance currently states that decellularizing structural adipose tissue constitutes more than minimal manipulation because the process alters the tissue’s ability to perform structural functions. This is incorrect. Adipose tissue’s structural functions are performed by a dense and interconnected skeleton of reticular fiber and dense connective tissue. Its biomechanical properties include tensile strength and elasticity, both of which are central to the structural functions of padding and cushioning.
Nonstructural components such as adipocytes, pre-adipocytes, lipids, etc. do not contribute to adipose’s structural characteristics or functions. It is well recognized that decellularization leaves adipose’s structural components fully intact. It does not alter, disturb or weaken the remaining reticular fiber and dense connective tissue skeleton, or compromise its ability to perform structural functions. Multiple reports have demonstrated that decellularized adipose tissue retains structural properties and can be injected to impart padding and cushioning of soft tissues. [89-93] The FDA already classifies decellularized dermis as minimally manipulated, thereby acknowledging that the process of decellularization does not alter structural characteristics or functions of the remaining structural matrix. Removing cells from dermis and removing cells from adipose employ comparable methods to achieve comparable results. Decellularizing adipose for structural use, like decellularizing dermis for structural use, does not alter structural characteristics.
For these reasons, IFATS respectfully requests the FDA to revise the draft guidance to recognize that decellularized adipose is minimally manipulated as required by § 361 and § 351’s “same surgical procedure exception.”
b. Structural use of fat in the breast constitutes homologous use.
Example B-3 of the draft adipose guidance states that application of adipose-based HCT/Ps to the breast is nonhomologous use because “[t]he basic function of breast tissue is to produce milk (lactation) after childbirth. Because this is not a basic function of adipose tissue, using HCT/Ps from adipose tissues for breast augmentation would generally be considered a non-homologous use.” This logic is flawed and must be corrected because it mischaracterizes the function of the breast, and mischaracterizes the function of adipose in breast surgery.
- For the purpose of determining homologous use, the basic function of the breast is a secondary sex organ. In terms of shape, form and appearance, the breast is vital to a woman’s bodily integrity and body image, psychological sense of self, and overall physical and emotional health and well-being.
- Lactation is not the sole or even primary function of the breast.
- Most women never lactate, but their breasts do function as secondary sex organs throughout their adolescence and
- When lactation does occur, it is episodic, time-limited, and accounts for a very small fraction of a woman’s lifespan.
- Even when healthy, post-menopausal women cannot Restoring lactation is thus completely irrelevant to restoring breast function.
- All men have breasts, thousands develop breast cancer each year, and many will need reconstructive surgery — even though men do not lactate.
- Federal law recognizes and protects the breast’s importance as a secondary organ.
- The Women’s Health and Cancer Rights Act, 29 USC 1185b(a), requires group health insurers to cover “all stages” of breast reconstruction following mastectomy or irradiation, including bilateral correction of asymmetrical appearance where one breast is otherwise unaffected.
- Restoring lactation is not a goal or even a remote concern of this In fact, lactation is never mentioned in the statute’s text, legislative history or associated regulations.
- The function of adipose tissue in breast surgery is structural and therefore
- Mastectomy removes more than the ability to lactate. It removes size, shape and form by removing the breast mound, which is predominantly adipose. Consequently, applying adipose tissue for the structural purpose of restoring form and shape is homologous use.
- By classifying adipose based tissues as non-homologous when applied to the breast, an entire class of Centers for Medicare & Medicaid Services (CMS) approved breast reconstruction procedures would be at risk for not complying with the same surgical procedure For example:
- Autologous free tissue flap transfer (“free flap” breast reconstruction) is performed by transferring complex musculocutaneous flaps containing adipose One of the most common methods of reconstruction, it qualifies as an HCT/P because it completely removes fat-containing tissue flaps from the body before implanting. [94-96] Fat grafting for breast reconstruction is another common clinical practice.
- According to the draft adipose guidance, these and other methods of breast reconstruction could no longer be used without formal premarket approval because they do not restore lactation and are therefore non-homologous. Focusing solely on restoration of lactation ignores the fact that the breast is largely composed of fat tissue and its size, shape and form can be reconstructed with fat
- This and other methods of breast reconstruction will no longer be available for clinical use under 361 or § 351’s same surgical procedure exception because they will not restore lactation.
- Removing these and other reconstructive methods from clinical application has nothing to do with risk. It is instead a perverse outcome of insisting that breast reconstruction be evaluated for its ability to restore the breast’s minor and episodic function of lactation despite fat’s ability to restore the breast’s size, shape and function as a secondary sex organ.
For these reasons, IFATS respectfully requests the FDA to revise the draft HCT/P guidance documents to recognize that as applied to the breast, adipose tissue is homologous use because it performs the structural functions of restoring, repairing or reforming size, form and shape.
c. When intended for a nonstructural use in the patient, stromal vascular fractio n (SVF)cells should be evaluated as nonstructural when determining minimal manipulated and homologous use.
The FDA’s draft adipose guidance expressly acknowledges that adipose tissue contains a variety of nonstructural components, including adipocytes, preadipocytes, fibroblasts, vascular endothelial cells, a variety of immune cells, and also stores energy in the form of lipids. These are nonstructural because the cells perform the same regenerative functions in vivo as they do in vitro and animal models. [97- 98] Nonstructural adipose HCT/Ps are readily available in the stromal vascular fraction (SVF). Stromal vascular fractionation of lipoaspirate (typically obtained through liposuction) can remove fat’s structural components, making nonstructural SVF cells available for nonstructural use in a patient. Just as removing nonstructural cells through decellularization does not alter the relevant structural characteristics or structural function of the remaining structural matrix, removing structural components does not alter the relevant nonstructural characteristics or nonstructural function of the remaining nonstructural SVF components.
This is minimal manipulation under 21 CFR 1271.3(f)(2) because extracting nonstructural cells or tissues from lipoaspirate “does not alter the relevant biological characteristics of cells or tissues.”
Also, this is homologous use under 21 CFR 1271.3(c) because it uses lipoaspirate’s nonstructural HCT/Ps for “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.”
Examples: Nonstructural adipose tissue for homologous use, with minimal and more than minimal manipulation à Reversal of radiation damage as intended nonstructural use
Homologous use with no manipulation: Using liposuction aspirate to perform fat grafting/adipose tissue therapy for the intended use or of reversing radiation damage in the breast – a nonstructural function – is homologous use. The structural side-effect of increasing volume may be a collateral benefit, but the intended use is still nonstructural tissue repair.
- Use is homologous because the HCT/P performs that same basic nonstructural function in both donor and
Homologous use with minimal manipulation: Using liposuction aspirate is indicated for the nonstructural function of reversing radiation damage in the neck without the volume gain of a fat graft. Separating nonstructural from structural components obtains nonstructural SVF cells for nonstructural use in the patient.
- Use is homologous because it is performing the intended nonstructural function of reversing radiation
- Manipulation is minimal because processing does not alter relevant nonstructural biological characteristics.
Homologous use with more than minimal manipulation: Using liposuction aspirate is indicated for the nonstructural function of reversing radiation damage in the intestines by catheter injection of nonstructural SVF. However, an adequate dose is difficult to obtain because the patient is cachectic (low body fat caused by caloric depletion from radiation enteritis). Culture expansion is considered as a means of increasing dose.
- Use is again homologous because SVF cells would perform the intended nonstructural function of reversing radiation
- Manipulation is more than minimal because culture expansion of cells to yield a therapeutic dose alters relevant biological characteristic. SVF cells in their natural state do not engage in linear growth to create a homogeneous monoculture. Even tumors do not produce homogeneous monocultures.
Examples: SVF for nonhomologous use >>>Bone (re)generation
SVF cells do not normally form bone in their native location. Delivering SVF cells to bone for the intended structural function of directly (re)generating new bone (via action of “stem cells”) might be considered. Processing might involve combining SVF cells with one or more additives (such as ex vivo culture media additives) for the intended structural function of (re)generating NEW bone (such as additives added to our culture medias ex vivo). For this scenario:
- Use is nonhomologous because the basic function in donor and patient will differ if nonstructural SVF cells are combined with one or more additives (such as ex vivo culture media additives) for the intended structural function of (re)generating NEW bone (such as additives added to our culture medias ex vivo).
- Manipulation is more than minimal because processing would alter the nonstructural SVF’s original relevant characteristics.
◊ ◊ ◊ ◊ ◊ ◊ ◊
The members of IFATS are grateful for the FDA’s willingness to re-open and extend the period for public comments and allow additional time for the September 2016 public hearing on the 2014-2015 draft HCT/P draft guidances. As a multidisciplinary scientific society composed of adipose stem cell biologists and clinician–scientists, IFATS would greatly appreciate the opportunity to work with the FDA in meeting the challenges of regulating HCT/P therapies. We respectfully request that representatives of the FDA, including the Director of CBER, meet with members of IFATS to discuss the issues addressed herein as well as others that pertain 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
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
Jeff Gimble, MD, PhD
Pennington Biomedical / United States
Keith March, MD, PhD
Indiana University / United States
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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.
This new technique follows previous attempts to generate liver-like cells from stem cells, which have yielded heterogeneous cell populations with little similarity to diseased livers in patients.
The GWAS studies map the genomes in hundreds of people as a way to look for genetic mutation patterns that differ from the genomes of healthy individuals. As GWAS study 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.
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.
“Without having a pure population of liver cells, it was incredibly difficult to pick up these relatively subtle differences caused by the mutations, but these differences are important in the life of an individual,” Duncan says.
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.
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.”
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.
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.
Scientists from the U.K. and Sweden have discovered a new method of creating human stem cells that could solve the problem of meeting large-scale production needs, allowing researchers to fully realize the potential of stem cells for understanding and treating disease.
Human pluripotent stem cells are undifferentiated cells that have the unique potential to develop into all the different types of
cells in the body. With applications in disease modeling, drug screening, regenerative medicine and tissue engineering, there is already an enormous demand for these cells, and that demand will continue grow as their use in clinical settings and the pharmaceutical industry increases.
The research results, published in Nature Communications in July, describe how the scientific team from The University of Nottingham’s Wolfson Centre for Stem Cells, Tissue Engineering and Modelling at Uppsala University in Sweden and GE Healthcare also in Sweden have identified and improved human stem cell culture methods that could lead to quicker and cheaper large scale industrial production of human pluripotent stem cells.
By using a protein derived from human blood called Inter-alpha inhibitor, the team has grown human pluripotent stem cells in a minimal medium without the need for costly and time-consuming biological substrates. Inter-alpha inhibitor is found in human blood at high concentrations, and is currently a by-product of standard drug purification schemes.
The human serum-derived protein can make stem cells attach to unmodified tissue culture plastic, eliminating the need for coating in defined human pluripotent stem cell culture, and improving survival capabilities of the stem cells in harsh conditions.
It is the first stem cell culture method that does not require a pre-treated biological substrate for attachment, and therefore, is more cost and time efficient, paving the way for easier and cheaper large-scale production.
Existing methods are time consuming and make developing human stem cell cultures prohibitively costly. This new method has the potential to save time and money in large-scale and high-throughput cultures, and be highly valuable for both basic research and commercial applications.
The work began at Uppsala University, and the study’s first author, Sara Pijuan-Galitó PhD., is continuing her work as a Swedish Research Council Research Fellow at Nottingham.
Researchers now intend to combine Inter-alpha inhibitor protein with an innovative hydrogel technology to improve on current methods for controlling cell differentiation, and also apply it to disease modelling. The discovery, according to the findings, will help facilitate research into many diseases although their focus is currently on understanding rare conditions like Multiple Osteochondroma) at the cellular level. The aim is to replicate the 3 dimensional environment that cells experience within the body so that lab-bench biology is more accurate in modelling diseases.
Pijuan-Galitó has been awarded the Sir Henry Wellcome Postdoctoral Fellowship at Nottingham University for her work on the research, which will enable her to combine Inter-alpha inhibitor with improved synthetic polymers in collaboration with fellow regenerative medicine pioneers Professor Morgan Alexander and Professor Chris Denning. The team plans to further improve on current human stem cell culture by designing an economical and safe method that can be easily translated to large-scale production and can deliver billions of stem cells necessary move cellular therapeutics forward in patient settings.
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.
The term muscular dystrophy (MD) refers to a group of disorders in which a genetic abnormality causes muscles responsible for controlling movement to become weak, and muscle mass to be lost. These inherited disorders usually affect voluntary (skeletal) muscles, although weakness can also extend to the muscles that control respiration and swallowing.
Given that the genetic mutations triggering MD interfere with the normal production of certain critical proteins, the body is not able to reverse muscle weakening or loss of mass, so even when the disease progresses slowly, it eventually affects one’s ability to walk in a more or less conducive manner.
Who is affected by muscular dystrophy?
In most cases MD appears in infancy, but it’s not uncommon for symptoms to start manifesting in teens or adults.
There are different kinds of muscular dystrophy, the most common and severe form being Duchenne muscular dystrophy (DMD) Caused by a genetic flaw or defect, Duchenne MD is more common in males than females [1} and affects about 1 in every 3,500 boys worldwide.
The onset of Duchenne muscular dystrophy occurs between the ages of 2 and 6, and evolves slowly. Muscles becoming weaker year after year, and the spine and limbs becoming progressively deformed. In most cases, children affected by this form of the disease become wheelchair dependent by the age of 12.
People suffering from Duchenne MD often die in their 20s, and those who survive usually experience some degree of cognitive impairment. The shortening of tendons and muscles limits the mobility of sufferers even more, and breathing and heart problems can occur.
Treatments for Duchenne muscular dystrophyThere is currently no known cure for DMD, but there are treatments that help to reduce some of the symptoms and strengthen the patient’s muscles to some degree.
Physiotherapy is commonly used for slowing down the loss of muscle mass and for maintaining flexibility or reducing muscle stiffness. Steroids are also used to slow down muscle wasting, but the severe side effects of steroids often cause more harm than good, such as bone weakening or cardiovascular problems.
In a healthy organism, damaged muscles repair themselves thanks to a series of cells that include muscle stem cells, called satellite cells. In Duchene muscular dystrophy, the muscles lack dystrophin, the protein needed for maintaining the integrity of muscle fibers. Without this protein, the burden placed on the body’s naturally occurring muscle stem cells is too intense, rendering the cells unable to repair damaged muscle tissue or to generate new muscle mass to replace wasted mass .
For this reason, scar tissue and fat cells take the place of damaged muscle tissue, contributing to muscle weakening and, over time, cause muscles to lose their functional ability. Would it be possible for the damaged muscle fibers to regain their regenerative ability with help from transplanted stem cells?
Research suggests stem cells could be a potential solution for muscle wastingDifferent strategies involving stem cells for muscular dystrophy may be on the horizon, research suggests. Scientists have been using stem cells isolated from muscle tissue, bone marrow and blood vessels in lab animals to regenerate muscle fibers that are deficient in dystrophin and results are encouraging.
In 2006, researchers managed to restore mobility in two afflicted dogs using stem cells isolated from muscle blood vessels , and in 2007 scientists managed to treat Duchenne MD in research mice using a combination of genetic correction and stem cells . The latter study showed that it is possible to correct the genetic error in the cells that no longer produce dystrophin protein, and inject corrected cells stimulating the regeneration of muscles.
Researchers at the Harvard Stem Cell Institute obtained similar results, demonstrating that transplanted muscle stem cells can improve function in mice with MD, while replenishing the stem cell population in muscle fibers .
Although it’s still too early to say whether stem cells can cure DMD in humans, it’s clear that there are some promising stem-cell-based approaches for Duchenne MD. One solution is to replace the defective stem cells with healthy stem cells, as these may be able to generate working muscle fibers to replace damaged muscle fibers .
A second solution would be to reduce the inflammation that speeds up the loss and weakening of muscles using certain types of stem cells . Combined treatments, such as mixing stem cell therapies with gene therapies are also being tested and may prove successful in the near future.
Photo: iPS cells feature – reprogrammed stem cells: Credit: Moscow Institute of Physics and Technology
Russian researchers have concluded that reprogramming does not create differences between reprogrammed and embryonic stem cells.
Stem cells are specialized, undifferentiated cells that can divide and have the remarkable potential to develop into many different cell types in the body during early life and growth. They serve as a sort of internal repair system in many tissues, dividing essentially without limit to replenish other cells. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another more specialized cell type, such as a muscle cell, a red blood cell, or a brain cell. Scientists
distinguish several types of stem cells—pluripotent stem cells can potentially produce any cell in the body. No pluripotent stem cells exist in an adult body, rather they are found naturally in
There are two ways to harvest pluripotent stem cells. The first is to extract them from the excess embryos produced during invitro fertilization procedures, although this practice is still ethically and technically controversial because it does destroy an embryo that could have been implanted. For this reason, researchers came up with the second way to get pluripotent stem cells— reprogramming adult cells.
Reprogramming, the process of “turning on” genes that are active in a stem cell and “turning off” genes that are responsible for cell specialization was pioneered by Shinya Yamanaka, who showed that the introduction of four specific proteins essential during early embryonic development could be used to convert adult cells into pluripotent cells. Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon for the discovery that mature stem cells can be reprogrammed to become pluripotent.
However, the extent of the similarity between induced pluripotent stem cells and human embryonic stem cells remains unclear. Recent studies highlighted significant differences between these two types of stem cells, although only a limited number of cell lines of different origins were analyzed.
Researchers compared induced pluripotent stem cell (iPSC) lines reprogrammed from adult cell types that were previously differentiated from embryonic stem cells. All these cells were isogenic, meaning they all had the same gene set.
Scientists analyzed the transcriptome – the set of all products encoded, synthesized and used in a cell. Moreover, they elicited methylated DNA areas, because methylation plays a critical role in cell specialization. Comprehensive studies of changes in the gene activity regulation mechanism showed similarities between reprogrammed and embryonic stem cells. In addition, researchers produced a list of the activity of 275 key genes that can present reprogramming results.
Researchers studied three types of adult cells – fibroblasts, retinal pigment epithelium and neural cells, all of which consist of the same gene set; but a chemical modification (e.g. methylation) combined with other changes determines which part of DNA will be used for product synthesis.
Scientists concluded that the type of adult cells that were reprogrammed and the process of reprogramming did not leave any marks. Differences between cells that did occur were thought to be the result of random factors.
“We defined the best induced pluripotent stem cells line concept,” says Dmitry Ischenko, MIPT Ph.D. and Institute of Physical Chemical Medicine researcher.
The minimum number of iPSC clones that would be enough for at least one to be similar to embryonic pluripotent cells with 95 percent confidence is five.”
Clearly, no one is going to convert embryonic stem cells into neurons and reprogram them into induced stem cells. Such a process would be too time-consuming and expensive. This experiment simulated the reprogramming of a patient’s adult cells into induced pluripotent stem cells for further medical use, and even though the reprogramming paper, published in the journal Cell Cycle, does not currently propose a method of organ growth in vitro, it is an important step in the right direction. Both induced pluripotent cells and embryonic stem cells can help researchers understand how specialized cells develop from pluripotent cells. In the future, they may also provide an unlimited supply of replacement cells and tissues that can benefit many patients with diseases that are currently untreatable.
The study, titled, “An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion,” concluded that reprogramming does not create differences between reprogrammed and embryonic stem cells, involved researchers from the Vavilov Institute of General Genetics, Research Institute of Physical Chemical Medicine, and the Moscow Institute of Physics and Technology (MIPT).
Stem Cell Research Goes Crimson: International Leader in Stem Cell Research Named New Dean of Harvard Medical School
George Q. Daley, MD, PhD, Harvard Medical School’s newly appointed dean, led dozens of international colleagues in developing ethical guidelines for stem cell research. On March 9, 2009, President Barack H. Obama issued Executive Order 13505: Removing Barriers to Responsible Scientific Research involving Human Stem Cells, stating that the Secretary of Health and Human Services, through the Director of the National Institute of Health (NIH), may support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell (hESC) research, to the extent permitted by law. Internal NIH policies and procedures, consistent with Executive Order 13505 and these Guidelines, govern the conduct of intramural NIH stem cell research.
A prominent stem cell researcher has been named the new dean of Harvard Medical School, the university announced August 9th
George Q. Daley, MD, PhD, who led dozens of international colleagues to unite around ethical guidelines for stem cell research, is taking on a new challenge—unifying the powerful hospitals that train Harvard’s medical students.
Daley will assume the position effective Jan. 1, 2017, succeeding Jeffrey Flier, MD, who stepped down July 31st. Barbara McNeil, MD, the founding head of the Department of Health Care Policy at Harvard Medical School, is filling the position in the interim.
The internationally recognized leader in stem cell science and cancer biology and a longtime member of the Harvard Medical School (HMS) faculty whose work includes the fields of basic science and clinical medicine, Daley was the driving force behind creating international guidelines around first, human embryonic stem cell research, and then the clinical application of stem cells, according to Nancy Witty, CEO of the International Society for Stem Cell Research (ISSCR).
Daley, who cofounded the organization, counseled two dozen scientists through the sensitive ethical discussions involved in establishing stem cell research guidelines, utilized additional input from 60 groups around the world to construct the guidelines which were first published by the National Institute of Health in 2009.
“That’s a very difficult task,” Witty said. “It takes a tremendous amount of diplomacy.”
Daley is working to adapt insights in stem cell research to improved therapies for genetic and malignant diseases. Important research contributions from his laboratory at Harvard-affiliated Boston Children’s Hospital include the development of customized stem cells to treat genetic immune deficiency in a mouse model (in collaboration with Rudolf Jaenisch, a Professor of Biology at MIT); the differentiation of germ cells from embryonic stem cells (cited as a “Top Ten Breakthrough” by Science magazine in 2003), and the generation of disease-specific pluripotent stem cells by direct reprogramming of human fibroblasts (cited in the “Breakthrough of the Year” issue of Science magazine in 2008).
As a graduate student working with Nobel laureate Dr. David Baltimore, Daley demonstrated that the BCR/ABL oncogene induces chronic myeloid leukemia (CML) in a mouse model, which validated BCR/ABL as a target for drug blockade and encouraged the development of imatinib (GleevecTM; Novartis), a revolutionary magic-bullet chemotherapy that induces remissions in virtually every CML patient. Dr. Daley’s recent studies have clarified mechanisms of Gleevec resistance and informed novel combination chemotherapeutic regimens.
Daley has spent his entire career in Cambridge and Boston, earning a medical degree from Harvard and a PhD in biology from MIT. As Dean of Harvard Med School, Daley’s achievements in stem cell research is expected to shine a distinguished light on the stem cell industry.
Although the position of dean of Harvard Med may be one of the most prominent roles in medicine, the position is not as powerful it might seem: Harvard Med does not directly oversee any hospitals. Instead it relies on 15 affiliated hospitals and clinical sites, which have historically operated as separate, competitive bailiwicks, to train its students and postdoctoral fellows, and support its researchers. Only 151 of the nearly 12,000 people who call themselves Harvard Medical faculty actually work directly for Harvard in its 10 basic science departments.
Daley sees his new position as a congregator who “builds bridges among the institutions” —heavyweight research institutions such as Brigham and Women’s, Massachusetts General, and Boston Children’s hospitals. Persuasiveness, rather than power, is all that Daley says is needed to achieve an alliance.
Daley’s predecessor, Flier, says he spent a full 30 percent to 40 percent of his time as dean trying to build relationships with and coordinate Harvard’s affiliated hospitals and clinics, a challenge Daley says he’s up to. He has a head start in building those relationships through the many positions he has held around Boston’s biomedical community, including chief resident at Mass. General
“My vision is one of increasing connectivity across the community,” Daley says.
Currently a professor of biological chemistry and molecular pharmacology at Harvard Medical School and director of the stem cell transplantation program at Boston Children’s and Dana-Farber Cancer Institute, Daley sees areas of common interest, such as immuno-oncology, which harnesses the body’s own immune system against cancer cells, where the hospitals can work more closely together.
Described by colleagues as a natural leader, Daley recently led an effort to coordinate big-name scientists across several institutions on a collaborative grant to compare two types of stem cells—just one example of how he earned a reputation; he knows how to get different groups talking together in a constructive way.
He also says he wants Harvard Medical’s faculty, students, and staff to reflect the global community the school intends to serve, and that he promotes diversity in hiring for his 30-person lab.
Daley has a keen interest in sickle-cell anemia, which affects people of African descent, including African Americans, and he believes the federal government should invest in a moonshot effort to cure the disease.
Daley plans to continue teaching molecular medicine at Harvard Med after assuming his position as dean. He also plans to spend one day per week in his lab researching blood stem cells.
“It’s important for a dean to remain relevant by continuing to publish papers,” Daley says. “Plus, I just love science.”
Among his priorities is raising money. Despite its worldwide reputation, and its relative influence when it comes to landing federal grants, Harvard Med has seen annual deficits of between $31 million and $45 million for three consecutive years. Suggestions are being made for Harvard to rename its medical school in return for a billion-dollar donation. Daley only says that the idea would be worth considering down the road.
With opportunities for federal grants in decline, Daley says he sees an opportunity to bring in money from corporate partnerships.
For the stem cell research and medical community, Daley’s appointment as dean of Harvard Med is a fitting step toward validating regenerative medicine’s place as an authoritative leader in the future of medicine—one that’s been a long time coming.
Learn more about Dr. Daley here.
Where do adult stem cells come from?
Adult stem cells receive much interest in the scientific community thanks to their ability to self-renew and generate numerous types of cells and tissues. There are two categories of stem cells: embryonic and adult.
Unlike embryonic stem cells, which have the ability to differentiate into more than one cell type, most adult stem cells are capable of forming only the types of tissue from which they originated. However, due to the controversy surrounding embryonic stem cell use, more and more researchers have turned their attention to the study of adult stem cells.
As a result, we now know of several adult tissues that serve as sources for stem cells. This is great news for people who suffer from degenerative conditions like osteoarthritis, muscular dystrophy and even Alzheimer’s disease.
The list of adult tissues known to contain stem cells keeps growing, and it includes bone marrow, brain tissue, peripheral blood and blood vessel tissue, skeletal muscle tissue, and liver and pancreas tissue.
Adult stem cells can be obtained from multiple tissues
Neural brain cells (NSCs) are multipotent cells that generate the central nervous system. They undergo asymmetric cell division, resulting in one non-specialized (blank) cell and one specialized cell. Japanese researchers have been able to use NSCs to replace dying neurons in lab mice . Currently there are numerous ongoing investigations into the response of NSCs in multiple sclerosis (MS) and Parkinson’s disease patients. The results may have future applications in the treatment of additional neurological conditions.
Hematopoietic stem cells (HSCs) are stem cells harvested from blood or bone marrow. They can differentiate into variety of specialized cells, such as white blood cells, which fight infection, and red blood cells, which carry hydrogen and platelets, and are responsible for blood clotting.
The downside of HSC stem cells is that their ratio in bone marrow is very low—1 in every 10,000-15,000 cells, which slows down the harvesting process considerably. Bone marrow also hosts skeletal stem cells (STCs), which give rise to osteoblasts (bone cells), cartilage and hematopoietic stroma.
An interesting niche of stem cells is found in the surface lining of the small and large intestines (ISCs). These stem cells divide continuously throughout life and are believed to be the source of most forms of cancer of the small intestine and colon. The longevity and renewal rates of ISCs becomes problematic in colorectal cancer, because they promote regeneration of the tumor after therapy.
In healthy adults, the liver is responsible for maintaining the balance between cell gain and cell loss. The liver’s impressive regenerative functions are attributed to hepatocytes, which are believed to be the adult stem cells of the liver. When the liver tears apart from virus infections, inflammation or is sectioned through hepatectomy, hepatocytes activate a stem cell-like behavior, giving rise to new tissue, replacing the lost liver cells.
Another important discovery has been made by Dr. Lola Reid of the University of North Carolina, an accredited expert in the research of liver development . As it turns out, the biliary tree, a network of vessels that connect the liver and pancreas to the intestine, generates a special type of adult stem cells, their major characteristic being pancreatic precursor cells, meaning they are destined to differentiate as pancreatic cells.
In a series of lab tests, these biliary cells have been manipulated to become islets, structures responsible for the production of insulin and c-peptide, a key component in the natural production of insulin. As a result, the blood sugar control in has been found to increased dramatically in lab mice. Dr. Reid hopes that her team’s efforts will speed up the process of finding a cure for diabetes.
Over the past few decades, scientific research has provided us with great insight on adult stem cells and their applications in regenerative medicine.
Unlike embryonic stem cells, adult stem cells can be isolated from a variety of adult tissue, including the brain, bone marrow, peripheral blood and even tumor-derived tissue cells, allowing scientists to avoid the ethical dilemma of using embryonic stem cells entirely. The risk of rejection with adult stem cells is considerably lower (the donor is usually the patient himself), and the differentiation rates are higher, providing much hope for future research to find cures for degenerative conditions in humans.
REFERENCES: MacKlis, Jeffrey D.; Magavi, Sanjay S.; Leavitt, Blair R. (2000). “Induction of neurogenesis in the neocortex of adult mice”. Nature 405 (6789): 951–5
 Biliary Tree Stem Cells, Precursors to Pancreatic Committed Progenitors: Evidence for Possible Life-long Pancreatic Organogenesis – http://www.diabetesresearch.org/file/research-publications/2013-Stem-Cells_Biliary-Tree-Stem-Cells-to-Islets.pdf
Healing damaged lungs with stem cells.
A New study published by scientists from the Weizmann Institute of Science suggests that stem cells may be used for repairing damaged lung tissue. This discovery gives new hope for treating conditions like bronchitis, asthma, cystic fibrosis or emphysema, which affect more than 35 million Americans and are the second leading cause of death worldwide.
[su_spacer] Bone Marrow stem cells able to generate new lung tissue
The treatment method proposed by scientists at the Weizmann Institute is based on the similarities between stem cells that reside in the lungs and those in bone marrow. Bone marrow stem cells, when transplanted to a patient, manage to find their way through the blood and to navigate to the designated area where they differentiate.
Acknowledging the similarities between lung and bone marrow stem cells, Professor Yair Reisner of the Immunology Department of the Weizmann Institute tested the ability of lung stem cells to travel to a specific region after transplantation in mice . Before introducing the bone marrow stem cells into mouse models with lung damage, the group of scientists cleared the lungs’ stem cell compartments to clear a path for the transplanted cells.
The injected stem cells managed to reach the empty lung compartments and settle in the lungs, where they differentiated into normal lung tissue,six weeks after transplantation. Results showed that new lung cells continued to be created from the transplanted stem cells 16 weeks after the implantation, ultimately healing the damaged lungs and improving their breathing ability.
The Weizman scientists intend to continue their research by exploring this option further, and possibly create a bank of lung stem cells that can provide cells ready to be transplanted to patients with severe respiratory diseases.
Lung-specific induced pluripotent stem cells (iPSCs)— potential alternative to bone marrow stem cells
Darrell Kotton, the study’s lead author, highlighted the fact that iPSCs are easier to cultivate in lab conditions than bone marrow stem cells, and are genetically identical to the patient’s cells, so the risk of rejection in such transplants is eliminated. The lung-specific iPSCs obtained by manipulating adult stem cells into a primitive stem cell state could solve some of the hurdles impacting other kinds of stem cell research.
In this study, scientists used skin stem cells manipulated into primitive pluripotent stem cells, with results showing that the iPSCs have the ability to multiply and differentiate into endoderm tissue–the natural precursor of lung cells .
- Chava Rosen, Elias Shezen, Anna Aronovich, Yael Zlotnikov Klionsky et al. – Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice, Nature Medicine, 2015, http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3889.html
- Aba Somers, Jyh-Chang Jean, Cesar A. Sommer, Amel Omari et al. – Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette, Stem Cells, 2010, 28 (10):1728, http://onlinelibrary.wiley.com/doi/10.1002/stem.495/full
The Language of Stem Cell Medicine: What are They? What Makes Them so Special? And What do all Those Acronyms Mean?
Stem cell medicine is based on the concept that physicians can harness the body’s own reserves to heal itself, rather than relying exclusively on drugs or invasive surgical procedures. Stem cell medicine works by deals engineering human stem cells to replace or restore damaged or diseased organs or tissue, or establish normal function in them. While regenerative medicine primarily includes therapies a that utilize stem cells, the term is also used to describe therapies that use progenitor cells, used for many decades in the form of bone marrow transplants, as well as other cellular products such as platelet-rich plasma (PRP).
While both PRP and progenitor cells are widely used in clinical settings, stem cell therapies are still playing catch-up. PRP is used to treat orthopedic injuries and degenerative joint disease.
However, stem cells are in high demand worldwide. The burgeoning field of stem cell medicine is widely understood in a vague sort of way, but few people are aware that there are different kinds of stem cells. They can be derived from different tissue sources, harvested from the patient’s own body or donated. To help establish a better understanding of the stem cell landscape, we’ll start with some basic concepts.
Autologous vs. Allogenic Stem Cells
Stem cell treatments are generally divided into two classes:
- Autologous stem cells – collected from your own body, exclusively for your own use
- allogeneic stem cells, harvested from another person (donor)
Current clinical trials involving both autologous and allogeneic therapies are taking place all over the world. These trials target a wide range of diseases and conditions, from heart disease to orthopedic conditions, to wound healing.
Autologous treatments using your own stem cells can be performed in the same operative session, which eliminates concerns over your body rejecting donor cells. Your stem cells are extracted from your tissue, and reinjected back into your body targeting the area or organ that needs mending. This is a one-to-one therapy.
Allogeneic therapies use stem cells donated from another person. Before these cells can be put into a different human body than the one they came from, they must undergo extensive testing for diseases, and the cells are usually culture expanded in laboratories to achieve higher cell counts. Allogeneic therapies are performed under strict FDA guidelines, as these stem cells can eventually scale up in mass production, be stored and potentially distributed to millions of patients.
Stem Cell Types
Adult stem cells (non-embryonic) are undifferentiated cells found throughout the body that multiply by cell division to replenish dying cells and regenerate damaged tissues.
Stem cells are acquired from various tissue sources, and each tissue source has different potentials for the cells to differentiate. The following information explains these tissue sources and corresponding type of stem cells:
Adult Stem Cells (ASC’s)
In recent decades researchers discovered that stem cells can be found in all adult tissues. These are called adult stem cells, and although they cannot differentiate into every type of cell like embryonic stem cells, they can differentiate into bone, cartilage and adipose (fat) tissue readily. The two most familiar sources of adult stem cells are bone marrow and adipose tissue. More than 2,000 clinical trials have been conducted worldwide using the various tissue sources of adult stem cells.
IPS Cells (induced pluripotent cells)
IPS cells come from adult cells. Their genetic code is biologically manipulated to become pluripotent, which means they can differentiate, or become any other type of cell. Because the genetic code of IPS cells has been altered, they carry a higher risk profile than both adult stem cells and embryonic stem cells.
Embryonic Stem Cells (ES)
Embryonic stem cells, first isolated in mouse embryos in 1981, are derived from the embryo of a human fetus. Controversy has pursued embryonic stem cell research since its inception, over of ethical and religious perceptions. Embryonic stem cells are currently used mainly for research and understanding how regenerative cells work.
Types of Adult Stem Cells
Adult stem cells can be isolated from bone marrow, adipose tissue, umbilical cord blood, peripheral blood, dental pump, and other sources. Most recently, a large number of clinical trials are focusing on stem cells derived from bone marrow and adipose tissue.
Bone Marrow Stem Cells
Bone marrow stem cells were the first recognized form of adult stem cells in the body. Researchers found they could be used to help heal bone and to replace different cell types in the blood. They could also be used in cancer patients whose bone marrow was destroyed by radiation therapy or chemotherapy. Use of bone marrow stem cells is FDA approved under certain conditions.
The drawback with bone marrow stem cells is that they are difficult to extract and not abundant. In order to be used as a treatment, bone marrow stem cells must be expanded in culture in a lab. The FDA places this therapy in the category of a drug, and requires rigorous oversight and testing.
Adipose Derived 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, and the findings were published in Tissue Engineering Journal. Upon publication, this 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.
Adipose stem cells (pictured) harvested from body fat. (Photo: Genetic Engineering & Biotechnology News).
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.
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 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.
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.
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.
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.
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?
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!