Executive Summary

Cartilage grafts are not governed by a single regulatory pathway. An autogenous graft uses the patient's own tissue, an allogeneic graft uses tissue recovered from another human donor, and manufactured autologous cellular products begin with the patient's cells but undergo additional ex vivo processing before implantation.

These distinctions lead to different regulatory routes. Autogenous tissue transferred within the same patient during the same surgical procedure can fall within the same surgical procedure exception. Qualifying donor cartilage can be regulated as a human cell, tissue, or cellular or tissue-based product under Section 361 and 21 CFR Part 1271. More extensively manufactured cartilage products can instead enter a drug, biologic, device, or combination-product development pathway.

The cartilage landscape illustrates all of these approaches. Commercial allogeneic grafts include juvenile articular cartilage, viable osteochondral constructs, and costal cartilage used in reconstructive procedures. By comparison, CBER's licensed cartilage cellular precedent includes MACI and the historical Carticel, both based on autologous cultured chondrocytes.

Autogenous and Allogeneic Cartilage Start From Different Sources

Autogenous, or autologous, cartilage originates from the same individual who ultimately receives it. In a conventional surgical autograft, cartilage can be harvested from one anatomical location and transferred to another location in the same patient. Allogeneic cartilage, or an allograft, is recovered from a different human donor and subsequently implanted into a recipient. FDA defines autologous use as implantation, transplantation, infusion, or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered. 1

The source distinction has practical consequences beyond terminology. Allogeneic tissue introduces donor eligibility, recovery, processing, storage, distribution, and communicable-disease controls that do not arise in the same manner when tissue is removed from and implanted back into the same patient during one surgical procedure. 12

Cartilage Product Design and Regulatory Pathway

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Source alone, however, does not determine the entire pathway. FDA's human cell and tissue framework also considers the degree of processing, the intended function of the tissue after implantation, whether the product is combined with other articles, and whether its primary function depends on the metabolic activity of living cells. 13

The Allogeneic Cartilage Graft Landscape

Allogeneic cartilage products encompass several distinct tissue forms. Zimmer Biomet describes DeNovo NT as a particulated juvenile cartilage implant for articular cartilage repair. Arthrex describes Cartiform as a cryopreserved viable osteochondral allograft containing viable chondrocytes, extracellular matrix proteins, and chondrogenic growth factors. ProChondrix CR is described as a cryopreserved osteochondral allograft containing living cells and other biological components for cartilage repair. 456

A separate allogeneic cartilage segment serves plastic and reconstructive surgery. MTF Biologics markets Profile costal cartilage allografts for applications that include rhinoplasty and Extearna costal cartilage allograft for ear reconstruction. AlloSource similarly supplies costal cartilage allografts derived from donor rib cartilage. These products illustrate how the same tissue type can be supplied in different configurations for orthopedic and craniofacial reconstruction. 789

Fresh, frozen, cryopreserved, particulated, osteochondral, and costal cartilage preparations can differ substantially in processing and biological composition. Those distinctions matter to regulatory analysis because FDA's HCT/P framework evaluates the characteristics retained after processing and the function the tissue is intended to perform in the recipient. 3

The Section 361 HCT/P Pathway

FDA uses a tiered, risk-based framework for human cells, tissues, and cellular and tissue-based products. Under 21 CFR 1271.10, an HCT/P can be regulated solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271 when all applicable criteria are met. Those criteria address minimal manipulation, homologous use, combination with other articles, and systemic effect or dependence on living-cell metabolic activity. 110

For qualifying allogeneic cartilage grafts, the resulting regulatory framework centers on tissue establishment registration and listing, donor eligibility, processing controls, current good tissue practice, labeling, adverse-reaction reporting, inspection, and enforcement. 1112

Cartilage is addressed in FDA's minimal manipulation guidance as structural tissue, making preservation of its relevant physical characteristics an important part of the regulatory analysis. 3

Minimal Manipulation Is a Cartilage-Specific Regulatory Question

For structural tissue, FDA defines minimal manipulation by asking whether processing alters the original relevant characteristics of the tissue relating to its utility for reconstruction, repair, or replacement. FDA's guidance identifies relevant cartilage characteristics that include firmness, smoothness, flexibility, and resistance to deformation. 13

Processing can preserve some cartilage characteristics while altering others, which makes manufacturing design central to regulatory strategy. FDA gives homogenization of cartilage allograft into a slurry as an example in which processing alters the tissue's original relevant characteristics and is therefore generally more than minimal manipulation. 3

The regulatory assessment therefore depends on the specific manufacturing process and its effect on the characteristics necessary for the tissue's intended reconstructive, repair, or replacement function. 3

Homologous Use Connects the Graft to Its Intended Function

Homologous use is evaluated separately from minimal manipulation. Under Part 1271, 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. The manufacturer's labeling, advertising, and other expressions of objective intent are relevant to that assessment. 13

For cartilage, this makes the claimed function important. A graft positioned as structural cartilage for reconstruction, repair, or replacement presents a different regulatory analysis from a product whose proposed function depends on biological activity beyond the basic function attributed to the donor tissue. 310

The distinction becomes particularly important for viable allogeneic cartilage products because the Section 361 criteria separately address HCT/Ps that have a systemic effect or depend on the metabolic activity of living cells for their primary function. The presence of viable chondrocytes must therefore be considered together with the product's primary function. 110

Autogenous Cartilage and the Same Surgical Procedure Pathway

Autogenous cartilage begins from a different regulatory position because the donor and recipient are the same person. Under 21 CFR 1271.15(b), an establishment is excepted from the requirements of Part 1271 when it removes HCT/Ps from an individual and implants those HCT/Ps into the same individual during the same surgical procedure, provided the circumstances remain within the scope of the exception. 1213

FDA's guidance emphasizes that application of the exception depends in part on the processing performed between removal and implantation. The same surgical procedure framework is therefore distinct from autologous cellular manufacturing in which tissue is collected, cells are isolated or expanded, and a manufactured product is administered at a later time. 13

Cultured Chondrocytes Illustrate the Section 351 Pathway

CBER's cartilage cellular therapy precedent illustrates how the pathway changes when manufacturing extends beyond transfer of structural tissue. MACI consists of autologous cultured chondrocytes on a porcine collagen membrane and is indicated for repair of symptomatic, single or multiple full-thickness cartilage defects of the knee with or without bone involvement in adults. FDA identifies MACI under BLA 125603, and the Purple Book records its original approval date as December 13, 2016. 1415

Carticel provides an earlier precedent. The Purple Book identifies Carticel as autologous cultured chondrocytes under BLA 103661, with an original approval date of August 22, 1997. The product is listed with discontinued marketing status. 16

These products demonstrate that autologous source does not itself imply a surgical graft pathway. Once cells are recovered and manufactured ex vivo as a therapeutic product, the regulatory analysis can shift to the biological product framework. FDA's cartilage development guidance addresses investigational products intended to repair or replace knee cartilage and discusses Investigational New Drug applications for cellular therapy products and Investigational Device Exemptions for device products. 17

When Cartilage Development Moves Toward Premarket Review

FDA's guidance for products intended to repair or replace knee cartilage recognizes that cartilage products can fall within biologic, device, or combination-product jurisdictions. Products regulated solely as HCT/Ps under Section 361 are outside the scope of that development guidance, while cellular therapy products regulated as biological products can proceed through an Investigational New Drug application and subsequent marketing application. 17

For CBER-regulated biological products, an Investigational New Drug application supports clinical investigation, while a Biologics License Application (BLA) is the formal marketing application used to request permission to introduce a biological product into interstate commerce. FDA describes the BLA framework as encompassing manufacturing information, nonclinical information, clinical data, and labeling. 18

For cartilage developers, manufacturing decisions can therefore influence regulatory classification as well as production strategy. Expansion of donor chondrocytes, substantial alteration of cartilage structure, incorporation of additional components, or intended functions that extend beyond those performed by the donor tissue can alter the applicable regulatory analysis and development requirements. 31710

Regulatory Pathways at a Glance

The cartilage landscape is best understood as a continuum in which tissue source establishes the starting point and manufacturing determines much of what follows. A conventional autogenous graft can remain closely tied to the surgical procedure, an allogeneic structural graft can enter the Part 1271 tissue framework, and cultured or extensively engineered products can move into premarket development pathways. 12117

Conclusion

Cartilage graft regulation reflects a broader principle in CBER's oversight of human tissue: biological origin alone does not determine the pathway. Autogenous, allogeneic, and cultured cellular products may all contain human cartilage or chondrocytes, yet their regulatory treatment diverges according to how the tissue is obtained, processed, characterized, and intended to function.

For allogeneic cartilage, the Section 361 HCT/P framework provides an established route for qualifying human tissue products, accompanied by donor eligibility and tissue-specific manufacturing controls. Autogenous cartilage can occupy the same surgical procedure framework when its conditions are satisfied, while cultured or more extensively manufactured products can require an IND and subsequent premarket application. For developers, the pivotal regulatory questions therefore arise early, at the intersection of product design, manufacturing, tissue function, and intended clinical use.