Definition
Wharton's Jelly is the gelatinous connective tissue that surrounds the blood vessels of the umbilical cord and serves as a rich source of mesenchymal stem cells (MSCs) and other bioactive components; products derived from Wharton's Jelly are regulated by the FDA as human cells, tissues, and cellular and tissue-based products (HCT/Ps) under 21 CFR Part 1271.
Comprehensive Definition
Wharton's Jelly is the mucoid connective tissue that fills the umbilical cord, surrounding and protecting the umbilical arteries and vein. It is composed primarily of a proteoglycan-rich extracellular matrix containing hyaluronic acid, chondroitin sulfate, and other glycosaminoglycans, along with a population of mesenchymal stem cells (MSCs), fibroblasts, and other stromal cells. The tissue was first described by the English physician Thomas Wharton in 1656, who noted its gelatinous consistency.
Wharton's Jelly-derived MSCs (WJ-MSCs) have attracted significant scientific interest because of their relative abundance compared to MSCs from other sources (such as bone marrow or adipose tissue), their immunomodulatory properties, and their ability to differentiate into multiple cell lineages including osteoblasts, chondrocytes, and adipocytes under appropriate conditions. WJ-MSCs also express lower levels of major histocompatibility complex (MHC) class II antigens than adult MSCs, which may reduce the risk of immune rejection in allogeneic applications.
Commercially available Wharton's Jelly products are derived from donated umbilical cords collected at the time of birth, typically from elective cesarean sections. The cords are processed to isolate the Wharton's Jelly tissue or the cells derived from it, and the resulting products are cryopreserved for distribution. These products are marketed under various names and are used in a wide range of clinical applications, including orthopedic conditions, wound care, and aesthetic procedures.
From a regulatory standpoint, Wharton's Jelly products are classified as human cells, tissues, and cellular and tissue-based products (HCT/Ps) under 21 CFR Part 1271. To qualify for the Section 361 exemption from FDA drug approval requirements, an HCT/P must meet four criteria: it must be minimally manipulated, it must be intended for homologous use, the manufacturing process must not involve the combination of the cells or tissues with a drug or device (with limited exceptions), and the product must not have a systemic effect and must not be dependent on the metabolic activity of living cells for its primary function (or must be for autologous use, allogeneic use in a first- or second-degree relative, or reproductive use). Products that do not meet all four criteria are regulated as drugs, biologics, or devices and require FDA approval before marketing.
The regulatory status of specific Wharton's Jelly products depends on how they are processed and how they are intended to be used. Products that are minimally manipulated and used for homologous purposes may qualify for the Section 361 exemption. However, many commercially marketed Wharton's Jelly products make claims that go beyond homologous use or involve processing that may constitute more than minimal manipulation, potentially subjecting them to FDA drug approval requirements.
Why It Matters
Wharton's Jelly products have become widely marketed in the regenerative medicine space, and many healthcare operators offer them as part of their clinical services. Understanding the FDA regulatory framework for these products is essential for operators who want to use them compliantly and avoid the significant regulatory and legal risks associated with non-compliant use.
The FDA has taken an increasingly active enforcement posture toward regenerative medicine products, including Wharton's Jelly products, that are marketed with claims that go beyond the Section 361 exemption. The agency has issued warning letters to companies that market Wharton's Jelly products as treatments for specific diseases or conditions without FDA approval, and has taken enforcement action against practitioners who administer unapproved biological products. Operators who administer Wharton's Jelly products must understand the regulatory status of the specific products they use and ensure that their clinical practices and marketing claims are consistent with that status.
The scientific evidence base for Wharton's Jelly products in clinical applications is still developing. While there is promising preclinical and early clinical data for some applications, the evidence for many of the conditions for which these products are marketed is limited. Operators should be cautious about making clinical claims that are not supported by the available evidence and should ensure that their informed consent processes accurately represent the current state of the evidence.
Historical Background
The scientific study of Wharton's Jelly as a source of stem cells began in earnest in the early 2000s, when researchers demonstrated that the tissue contained a population of MSCs with properties similar to bone marrow-derived MSCs. The relative ease of obtaining umbilical cord tissue compared to bone marrow, combined with the immunological properties of WJ-MSCs, generated significant interest in their potential clinical applications.
The commercialization of Wharton's Jelly products accelerated in the 2010s, driven by growing interest in regenerative medicine and the development of processing and cryopreservation technologies that enabled the distribution of these products to healthcare providers. By the mid-2010s, dozens of companies were marketing Wharton's Jelly products for a wide range of clinical applications.
The FDA's regulatory framework for HCT/Ps, established under 21 CFR Part 1271, was developed in the late 1990s and early 2000s to address the growing use of human cells and tissues in clinical practice. The framework has been the subject of ongoing regulatory development as the FDA has worked to apply it to increasingly complex regenerative medicine products, including Wharton's Jelly products.
Federal Regulations
Wharton's Jelly products are regulated as HCT/Ps under 21 CFR Part 1271, which implements Section 361 of the Public Health Service Act (42 U.S.C. § 264). To qualify for the Section 361 exemption from FDA drug approval requirements, an HCT/P must meet the criteria set forth in 21 CFR § 1271.10(a): minimal manipulation, homologous use, no combination with a drug or device (with limited exceptions), and no systemic effect or dependence on metabolic activity of living cells (with exceptions for autologous, first- or second-degree relative, and reproductive use).
Products that do not meet all Section 361 criteria are regulated as drugs under Section 351 of the Public Health Service Act (42 U.S.C. § 262) and require FDA approval (a Biologics License Application, or BLA) before marketing. The FDA has issued guidance on the minimal manipulation and homologous use criteria that is essential reading for operators who use Wharton's Jelly products.
The FDA's November 2017 guidance documents on HCT/Ps, including the guidance on minimal manipulation and homologous use, provide the current regulatory framework for evaluating the status of specific Wharton's Jelly products. The FDA also issued a statement in 2019 clarifying its enforcement priorities for HCT/Ps, including a commitment to take action against products that pose significant safety risks or that are marketed with unsubstantiated claims.
State Considerations
State medical boards regulate the clinical practice of physicians and other licensed practitioners who administer Wharton's Jelly products. Practitioners who administer unapproved biological products may be subject to disciplinary action by their state medical board, in addition to FDA enforcement action.
Some states have enacted specific regulations or issued guidance on the use of regenerative medicine products, including Wharton's Jelly products. Operators should be aware of any state-specific requirements in the states where they practice.
The marketing of Wharton's Jelly products is also subject to state consumer protection laws and FTC regulations governing advertising claims. Operators who make unsubstantiated clinical claims in their marketing materials may be subject to enforcement action by state attorneys general or the FTC, in addition to FDA enforcement.
Common Mistakes
- Administering Wharton's Jelly products that do not qualify for the Section 361 HCT/P exemption without understanding that they require FDA approval as biologics.
- Making marketing claims about Wharton's Jelly products that go beyond homologous use or that attribute specific therapeutic effects to the products without FDA approval.
- Not verifying that the Wharton's Jelly product supplier is registered with the FDA as an HCT/P establishment and complies with 21 CFR Part 1271 donor eligibility, processing, and labeling requirements.
- Failing to obtain appropriate informed consent from patients that accurately describes the regulatory status of the product and the current state of the clinical evidence.
- Confusing Wharton's Jelly products with FDA-approved drugs or biologics — no Wharton's Jelly product currently has FDA approval as a drug or biologic for any clinical indication.
- Not staying current on FDA enforcement actions and guidance in the regenerative medicine space, which is evolving rapidly.
Operator Insight
Wharton's Jelly products are among the most heavily marketed regenerative medicine products in the current healthcare landscape, and the regulatory situation is genuinely complex. I work with operators who want to offer these products, and my first question is always: what specific product are you using, who is the supplier, and what is the regulatory basis for using it? The key regulatory question is whether the specific product qualifies for the Section 361 HCT/P exemption. This requires a careful analysis of whether the product is minimally manipulated and whether the intended use is homologous. Many commercially marketed Wharton's Jelly products make claims that go beyond homologous use — for example, claiming that the product treats osteoarthritis or promotes wound healing — which may take the product outside the Section 361 exemption and into the territory of an unapproved biologic. My advice to operators is to work only with suppliers who can provide clear documentation of the regulatory basis for their products, who are registered with the FDA as HCT/P establishments, and who have not been the subject of FDA warning letters or enforcement actions. I also strongly recommend that operators have their informed consent documents reviewed by a healthcare attorney who understands the HCT/P regulatory framework before they begin offering these products.
— AJ Pakpour, Healthcare Practice Startup & Strategy Expert
In Practice
An orthopedic practice wants to offer Wharton's Jelly injections for patients with knee osteoarthritis. Before implementing the service, the practice's compliance consultant reviews the regulatory status of the specific product under consideration, confirms that the supplier is FDA-registered and compliant with 21 CFR Part 1271, and advises the practice on the marketing claims that are consistent with the product's regulatory status. The practice implements an informed consent process that accurately describes the product's regulatory status and the current state of the clinical evidence, and trains its clinical staff on the applicable regulatory requirements. A regenerative medicine clinic receives an FDA warning letter after marketing Wharton's Jelly products with claims that they treat specific diseases and conditions. The clinic's attorney advises that the marketing claims go beyond homologous use and that the products may be subject to FDA drug approval requirements. The clinic removes the non-compliant marketing materials, revises its informed consent documents, and implements a compliance program to ensure that future marketing and clinical practices are consistent with the applicable regulatory framework.
Frequently Asked Questions
References
- 1.FDA: Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products
- 2.21 CFR Part 1271 — Human Cells, Tissues, and Cellular and Tissue-Based Products
- 3.FDA: Guidance on Minimal Manipulation and Homologous Use (2017)
- 4.FDA: Statement on Regenerative Medicine Products (2019)
Further Reading
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