Articular cartilage is one of the most “silent” tissues in the body: no blood vessels, no nerves, no lymphatics — once worn away, it almost never regrows, and left untreated, it often progresses all the way to osteoarthritis.

This review, published in 2026 in Materials Today Advances by teams from Jilin University Affiliated Hospitals, systematically maps the latest progress in bio 3D printing + cell-laden bioinks for cartilage defect repair — how to choose among three printing routes, what temperament each of six seed cell types has, and how to bridge the hardest osteochondral interface. This interpretation walks you through the entire technology chain at once.

*All values are measured data from individual studies cited in the review, not conclusions of a single study. See corresponding sections in the text for details.

PART 01 Why Is Articular Cartilage the Body’s Least Self-Healing Site?

Articular cartilage is a highly specialized connective tissue that spends its entire life absorbing impact and distributing loads for the joint. But it is also one of the most “delicate” tissues in the body: no blood vessels, no nerves, no lymphatics, with very low cell metabolic rate — meaning once worn or injured, it almost cannot self-heal, and left untreated it often progresses to osteoarthritis, bringing persistent pain and joint dysfunction. The background cited in the paper: sports injuries, trauma, and aging are all pushing up the incidence of cartilage damage.

Clinically there are currently three old routes: microfracture, autologous chondrocyte implantation (ACI), and allograft cartilage transplantation. The paper reviews each one’s ceiling —

The core dilemma: repair quality, cell source, and donor-site damage are hard to secure all at once.

Bio 3D printing‘s entry point is direct: customize structures from patient CT/MRI images, layer-by-layer deposit “cell-laden ink,” make porosity, pore size, and internal topology fully designable variables, while replicating cartilage’s mechanical microenvironment. But the paper also states clearly: how to choose the ink, how to balance mechanical strength and biocompatibility, and how to guide directional cell differentiation are three unresolved core questions. This review’s job is to lay out the latest answers to these questions.

PART 02 Three Printing Routes: Inkjet, Extrusion, Photocuring Each Handles a Piece

Inkjet

Driven by heat or piezoelectric actuation, precisely jetting picoliter droplets onto a substrate, with resolution 10–100 μm. It only “eats” low-viscosity inks (3–30 mPa·s, optimal 3.5–12), with a cell concentration ceiling of about 10⁶ cells/mL; advantages include high throughput, low cost, and positioning down to single-cell level. The paper is also honest about hidden risks: thermal inkjet can instantaneously reach 300 °C (the ink itself only rises 4–10 °C), and droplet impact and drying both damage cells.

Extrusion

Continuous extrusion via pneumatic, screw, or piston drive, with the widest viscosity range (30 mPa·s to over 6×10⁷ mPa·s), capable of feeding high-density cells (>10⁸ cells/mL), suitable for bulk 3D structures. The cost is that resolution is limited by nozzle diameter, and pressure and shear stress continuously damage cells.

Photocuring

No nozzle, no shear damage, high resolution, capable of complex microstructures, cell viability 85–95%, significantly higher than extrusion’s 40–80%. The weakness is equally clear: to print human-scale constructs, DLP needs to work continuously for 8–16 hours, with edge cell viability losses exceeding 20%.

PART 03 Ink Is Not Glue: The Formulation Is Full of “Signals”

Early studies used low-concentration single/dual polymer systems like GelMA and still achieved 85%–90% cell viability. But the paper points out the trade-off: if crosslinking is too fast, cell density gets pushed below 10⁷ cells/mL; and such inks lack natural bioadhesive sites, while subsequent functionalization risks cell phenotype “drift.”

So formulations began to move toward natural components: methacryloylated cartilage extracellular matrix (cECM-MA) preserves the triple-helical structure of type II collagen; silk fibroin, hyaluronic acid, and decellularized ECM have joined in succession; even a completely crosslinker-free silk fibroin–decellularized ECM ink appeared, avoiding chemical toxicity at the source. Further still, “let the ink speak for itself” — self-healing hydrogels, supramolecular assembly, and ionic gradient systems have appeared in turn. The paper uses a large table to bring nine ink types under the same standard for quantitative comparison; here are a few representative ones:

PART 04 Where Do Seed Cells Come From? Six Sources, Each With Its Own Temperament

Bone marrow mesenchymal stem cells (BMSC)

The most widely used workhorse: strong in both multilineage differentiation and immunomodulation, with early GelMA system viability 85%–90%; switching to GelMA + methacryloylated chitosan (ChiMA) raised viability to 91.1%. One interesting detail: aggregated BMSC clusters initiate chondrogenic differentiation faster than dispersed cells, with initial SOX9 expression 2.8–3.5× higher — but later-stage nutrient diffusion is limited in the core. Co-culturing BMSC with primary chondrocytes captures both proliferation and chondrogenic expression, while reducing the need for biopsy material.

Adipose-derived stem cells (ADSC)

Easy to harvest, low immunogenicity, but inherently prone to “going off script” — spontaneous hypertrophy and osteogenic differentiation. The paper’s solution is bidirectional regulation: about 10% hydroxyapatite by polymer concentration + hypoxic culture, with the hypoxic environment significantly downregulating COL10A1, ALP, and MMP13, suppressing spontaneous calcification; another study applied RNTK nanotube coating to a GelMA–PEGDA three-layer gradient scaffold, increasing ADSC numbers by 34%, with type II collagen, glycosaminoglycan, and total collagen synthesis increasing by 59%, 71%, and 60% respectively, and chondrogenic gene Col2α1 upregulated 79%.

More “off-the-beaten-path players” are also taking the stage: placental stem cells carry immune privilege and synergize with the ionic gradient of Li-Mg-Si bioceramics; tonsil-derived TMSC with G7H5 ink has produced laryngeal cartilage structures (including thyroid and cricoid cartilage), giving discarded tonsil tissue a new use; iPSC-derived SOX9⁺ progenitors loaded into decellularized dentin matrix/ZrO₂ scaffolds recapitulate endochondral ossification; inferior turbinate hTMSC achieves 92–96% viability through photoinitiator-free gentle printing. Even non-stem cells are joining: chondrocytes handle “the professional work,” and macrophages regulate the immune microenvironment (detailed in PART 07).

PART 05 Letting Cells Differentiate on Script: Welding Signals onto the Scaffold

The paper summarizes the common thread of this generation of research as: from passive biochemical induction to active signal regulation. Five representative paths.

First, covalent TGF-β1 immobilization: the growth factor retains 85–92% bioactivity throughout, versus only 40–55% for conventional physical adsorption — the cost is losing dynamic release capability, with risk of late-stage hypertrophy. Second, GDF5: a key cartilage regeneration factor identified through genome-wide association studies, covalently coupled to BMSC scaffolds, achieving long-term cartilage protection in rabbit knee joint models. Third, DNA–silk fibroin hybrid system: covalent immobilization of glucosamine and small molecule agonist TD-198946, programming cells to the ideal cartilage phenotype within 4 weeks, with transcriptome closely resembling healthy cartilage. Fourth, melatonin-loaded small extracellular vesicles (MT-sEV): promotes BMSC chondrogenesis while modulating M2 macrophage polarization, with inflammatory cytokine TNF-α dropping 60–75%. Fifth, Kartogenin activating the Smad1/5/9 pathway: significantly upregulating type II collagen and proteoglycan expression without toxicity.

PART 06 The Hardest Hurdle: The “Transition Zone” Between Cartilage and Bone

The osteochondral interface is not a simple dividing line but a functional gradient zone where composition, mineralization, cell phenotype, and mechanical properties transition continuously. A single-zone scaffold cannot cross the 0.5–17 kPa modulus span, and after repair is prone to delamination and fibrosis. The paper’s combination approach is: microfluidic printhead real-time mixing multiple inks, cartilage zone viability 89–94%; DLP layer-by-layer stacking of type I/II collagen and mineralization ratios, creating a continuous mechanical gradient from hyaline cartilage 1.35 kPa to subchondral bone 17.29 kPa, with rat osteochondral defects nearly fully repaired within 12 weeks.

A representative bilayer scaffold puts “two microenvironments” into a single construct: the upper layer is a hydrogel loaded with TGF-β3 liposomes, and the lower layer is modified with nano-hydroxyapatite — liposome encapsulation efficiency about 80%, 21-day release about 89%, overall compressive modulus 53.13±4.23 kPa, precisely between the cartilage-oriented layer 37.57 and bone-oriented layer 96.61; in 4.5 mm diameter, 3 mm deep rabbit femoral condyle defects, 12-week repair was superior to either single-layer scaffold. Another approach is “divide and conquer”: layered printing of articular cartilage progenitor cells (ACPC) and BMSC into a biphasic living hydrogel, using different paracrine signals from the two cell types to stabilize their respective phenotypes, simultaneously regenerating cartilage and subchondral bone in vivo.

But the paper also sounds the alarm: most constructs still simplify the natural gradient into two or three discrete zones; long-term resistance to joint cyclic loading and whether cell zoning will “cross over” as tissue matures remain unsolved questions.

PART 07 The Overlooked Player: Immune Cells Also Need to Enter the “Ink”

The chronic inflammatory microenvironment common in osteochondral defects — persistently active M1 macrophages — significantly drags down the repair process. The paper cites a representative work: loading the anti-inflammatory plant molecule honokiol into a PEGDA/ECM printed scaffold. In vitro, the drug-loaded scaffold significantly inhibited pro-inflammatory cytokine release from LPS-stimulated macrophages, with TNF-α dropping 65–75% and IL-6 dropping 58–68%; in rabbit knee joint defect models, cartilage coverage reached 78–85% (control 55–68%), with simultaneous regeneration of hyaline cartilage and subchondral bone.

This study also candidly notes unresolved points: the in vivo release kinetics of honokiol and the durability of immunomodulation remain unclear — if the drug is depleted too early, the microenvironment may return to a pro-inflammatory state at weeks 4–6. Bringing immune cells and immune molecules into the variable list of “ink design” is a new direction emphasized by this review.

PART 08 From Lab to Operating Room: Four Hurdles Remain

The paper’s outlook section maintains rare clarity, listing the translational barriers one by one.

For future directions, the paper names five: 4D printing (shape memory/magnetic response, dynamically remodeling with the joint mechanical environment after implantation), CRISPR preprogrammed stem cells (continuously secreting pro-chondrogenic factors), AI optimization of ink formulations and printing parameters, extracellular vesicle-based cell-free delivery, and immunomodulatory inks. Organoid × bioprinting fusion is also singled out as a focus — letting stem cells self-organize into cartilage organoids, then assembling them as “building blocks” into printed scaffolds, shortening printing time and improving regeneration efficiency.

📄 Paper Information

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