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International Journal of Bioprinting 3D scaffold prevents tendon ossification

1. Introduction and reconstructing tendon architecture. While effective
in restoring tendon function, surgical procedures carry
Achilles tendon injury commonly manifests as risks of post-operative complications such as infection
tendinopathy, particularly in athletes and middle-aged/ and reinjury. 14,15 Traditional therapeutic strategies often
elderly populations. The high incidence of this injury prove inadequate for restoring the original biomechanical
is primarily associated with intensive physical activity, function of the Achilles tendon.
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overuse, and age-related degenerative changes. Post-injury
clinical manifestations typically include pain, swelling, and Recent advancements in tissue engineering have
restricted mobility, significantly impairing patients’ quality opened new avenues for tendon repair. By combining
of life and athletic performance. 2 scaffolds, cells, and growth factors, tissue engineering
facilitates tendon regeneration and functional recovery.
Heterotopic ossification (HO) following Achilles The selection of biomaterials is pivotal in designing
tendon injury refers to the pathological formation of tissue-engineered scaffolds. An ideal scaffold must exhibit
ectopic bone within tendon tissues or adjacent soft tissues excellent biocompatibility and mechanical properties to
and is a frequent complication. Research indicates that HO support cell adhesion and proliferation while maintaining
in tendons often occurs after severe trauma or surgical sufficient mechanical strength to endure physiological
intervention. For instance, HO incidence rates reach loads. Additionally, the scaffold’s microstructure should
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54% following distal biceps tendon repair, and 52.1% of closely resemble native tissue architecture to direct cell
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patients develop HO after severe radial head fractures. alignment and tissue regeneration. 18
Furthermore, the prevalence of HO in the Achilles tendon
increases with age—potentially due to upregulated bone Three-dimensional (3D) bioprinting demonstrates
morphogenetic protein (BMP) expression in tendon stem/ significant advantages in the fabrication of tissue-
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progenitor cells (TSPCs). The pathological progression engineered scaffolds. First, this technology allows
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of HO involves endochondral ossification, encompassing precise control over scaffold geometry and internal
microstructure, enabling the design of personalized and
three distinct phases: the inflammatory stage, complex architectures. Second, 3D bioprinting enables the
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chondrogenesis, and terminal osteogenesis. Although the simultaneous deposition of cells and biomaterials, creating
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precise mechanisms remain incompletely elucidated, HO cell-laden scaffolds with biological activity, which is critical
development is closely linked to inflammatory responses, for promoting tissue regeneration. Additionally, the
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aberrant activation of osteogenic signaling pathways, and mechanical properties and biological functions of scaffolds
alterations in mechanical stress. 7–10 Emerging evidence can be optimized by modulating printing parameters such as
suggests that the inflammatory cascade and hypoxic nozzle pressure and layer thickness. 22,23 Bioink formulation
microenvironment during the acute phase of tendon is central to 3D bioprinting, primarily composed of
injury may potentiate HO initiation. Crucially, the biomaterials and seed cells. The selection of biomaterials
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BMP signaling pathway has been identified as a pivotal remains an active research area, with current options
regulator of ectopic bone formation. Age-dependent broadly classified into synthetic polymers and natural
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upregulation of BMP expression in injured tendons biomaterials. Natural biomaterials have attracted extensive
enhances the osteogenic differentiation capacity of TSPCs, scientific interest due to their superior biocompatibility
thereby accelerating HO pathogenesis. Furthermore, and low cytotoxicity. 24,25 Xu et al. constructed a
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alterations in mechanical loading—whether excessive poly(lactide-co-glycolide) (PLGA)/type I collage biphasic
or insufficient—have been implicated as HO triggers, as scaffold using 3D bioprinting technology, which effectively
demonstrated by load-dependent osteogenic induction in promoted tendon repair and inhibited HO, achieving an
a preclinical model. 10 86% reduction in heterotopic bone volume. However,
Currently, there is no unified standard for treating fragments released during collagen degradation can act as
HO following Achilles tendon injury. Common potent initiators, activating inflammatory mechanisms that
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clinical approaches include conservative and surgical may interfere with the tissue repair process. Moreover,
therapies. Conservative treatments primarily involve the acidic degradation products of PLGA may alter the
pharmacological interventions, such as non-steroidal anti- local pH, thereby inducing inflammatory responses and
inflammatory drugs to reduce inflammation and inhibit compromising biocompatibility. 28
HO progression, as well as physical therapy to promote Silk fibroin (SF), a natural biomaterial, has attracted
healing by improving local blood circulation and enhancing considerable interest due to its exceptional biocompatibility
tendon flexibility. However, these approaches show limited and tunable biodegradability. 29–31 In its native state, SF
efficacy, especially in advanced ossification stages. predominantly adopts a random coil conformation.
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Surgical treatments focus on removing HO bone tissue However, chemical modifications in hydroxyl-rich
Volume 11 Issue 4 (2025) 298 doi: 10.36922/IJB025210203