The current status of various preclinical therapeutic approaches for tendon repair

Figures & data

Figure 1. Diagram illustrating the pathophysiology of tendinopathy. It is theorized that a variety of risk factors, containing mechanical abuse along with intrinsic and extrinsic variables, might continuously activate the onset of tendinopathy. First, these risk factors impede adequate tendon renovation, resulting in primary reactive tendinopathy, which still can mend. In addition, the accumulation and growth of risk factors result in tendon damage, which ultimately leads to tendon degeneration. Inadequate tendon function and load capacity ultimately result in tendinopathy, which causes tendon ripping or rupture [22].

Figure 2. The hierarchical structure of tendons [37].

Figure 3. Illustration showing the strategies for tendon repairs. In brief, biophysical stimulation and surgical approaches are practiced in clinical settings. While the other approaches are currently in the preclinical or translational phase. Reproduced with permission from [56].

Figure 4. Eccentric calves. (a, b) Start and finish of the straight-knee exercise. (c, d) Start and finish of the bent-knee exercise [79].

Figure 5. Distinct vectors in GT and gene transport procedures [116].

Figure 6. The basic mechanism of non-viral gene delivery [138].

Table 1. An overview of recent gene therapies for tendon healing.

Target gene	Function on tendon	Study type	Reference
COX	The COX inhibition has the potential to convert M1 to M2.	In vivo	[155]
IKKβ	In vivo inhibition of the KKβ/NF-B pathway could be effective in the treatment of RCT.	In vivo	[156]
Smad3	The delivery method acts as an excellent antiadhesion barrier, potentially lowering inflammation.	In vivo	[157]
ITGA9	Tenascin-C enhances tendon rejuvenation through STSC migration mediated by ITGA9.	In vitro	[158]
CLK2 DYRK1A	SM04755 decreases inflammation and improves tenocyte differentiation by suppressing CLK2 and DYRK1A	In vitro	[159]
Collagen III	PolyDMAEA-siRNA polyexes outperform PEI-siRNA polyexes in terms of efficiency.	In vitro	[160]
Flightless I	Flii has the potential to inhibit human tenocyte propagation and migration.	In vitro	[161]
Scleraxis	Scx raises tenomodulin levels.	In vitro	[162]

Table 2. Scaffolds that have been used in preclinical applications and those provided on the market and used for clinical applications.

Scaffolds	Preclinical applications	Clinical applications	References
Synthetic polymer scaffolds	Tailorable mechanical properties Controlled degradation rates Supports cell adhesion and proliferation	GORE-TEX^® Soft Tissue Patch TenoGlide^® Synthetic Polymer Scaffold	[223–225]
Hyaluronic acid-based scaffolds	Enhances cell viability and proliferation Provides a hydrated environment conducive to tissue repair Exhibits anti-inflammatory properties	HYAFF^® Scaffolds HYALOFAST^® Hyaluronic Acid-Based Scaffold	[226–228]
Collagen-based scaffolds	Encourages cell adhesion and proliferation Supports tendon tissue formation and alignment Enhances biomechanical properties of the repaired tendon	BioFiber^® Scaffold Integra^® Dermal Regeneration Template	[229,230]
Silk-based scaffolds	Biocompatible and biodegradable Offers tunable mechanical properties Supports cell attachment and proliferation	SeriScaffold^® Silk-Based Scaffold Ortho-ATI^® Silk-Based Scaffold	[231–233]
Electrospun nanofiber scaffolds	Mimics the native extracellular matrix structure Promotes cell attachment and migration Supports tissue regeneration and remodeling	Nanofiber-based products for tendon repair (e.g., OrthADAPT^® Bioresorbable Nanofiber Matrix)	[234,235]
Decellularized tissue scaffolds	Retains native tissue architecture and composition Provides a natural scaffold for cell infiltration and tissue regeneration	GraftJacket^® Regenerative Tissue Matrix ArthroFlex^® Decellularized Tendon Allograft	[236–238]

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Data availability statement

The data that support the findings of this study are available from the corresponding author (WL) upon reasonable request.