**4. Synthetic materials**

If synthetic polymers are used for (tendon) tissue engineering, the fabrication process highly decides upon its biocompatibility and its effectiveness as graft. As nicely shown by Prof. Ratner, the same polymer, once applied as a porous foam and once as a dense block, can evoke quite different reactions of the body: while the porous material is penetrated by ingrowing cells as well as vasculature and there is practically no foreign body reaction, the dense block is encapsulated as a foreign body going along with an inflammation reaction [75]—*in vivo veritas* [76]. Hence, the processing of a synthetic material, mostly polymers in tendon tissue engineering, has to be optimized in order to get a biocompatible material that fulfills the requirements encountered in tendon tissue engineering.

Many polymers have been synthesized and modified in order to get suitable materials in terms of implants for tendon repair and regeneration; polyglycolic acid (PGA) [75, 77], polylactic-co-glycolic acid (PLGA) [78], PLGA/alginate composite [6], polylactic acid (PLA) [79–81], poly-l-lactic acid (PLLA) [82–84], polycaprolactone (PCL) [85], polycaprolactone/ polyethylene oxide (PCL/PEO) [7], polyurethane (PU) [86, 87], polyethylene terephthalate (PET) [88, 89], DegraPol® [90, 91] (**Figure 2**), nanocarbon fiber [92], and polyurea [93], among others. The architecture of the synthetic materials has to be chosen carefully, as gene expression of (stem) cells may be significantly influenced by the microenvironment that the cells encounter [94].

dynamic cell culture and cell-seeded TECs, physical experimental parameters like frequency, amplitude, medium flow rate, etc., have to be carefully tuned in order to get the desired dif-

Other concepts in tendon tissue engineering are based on decellularization of a natural xenograft in order to avoid immunorejection [4, 109–111] or decellularization of a primarily cellseeded construct in order to generate a scaffold coated with the components of the ECM of a certain cell type (instructive ECM) cultivated under well-defined conditions [112, 113]. Such decellularized graft materials can be applied in daily clinical practice more easily than cell-

Furthermore, there are gene therapy strategies including adeno-associated viral type 2 vector (AAV2) and micro-RNA related gene therapy aiming at improving strength of the repaired tendon as well as decreasing adhesion formation to the surrounding tissue [115, 116]. Moreover, some approaches deal with delivering certain (growth) factors, supporting the regeneration

TGF-β1 plays an important role during tendon healing and has an influence on adhesion formation, an unwanted side effect during tendon healing. Therefore, regulation of TGF-β1 through application of micro-RNA specifically inhibiting the function of TGF-β1 was tested in a chicken flexor tendon model [119]; TGF-β protein expression in the tendons decreased on increasing the vector dosage. As a consequence, the adhesion extent significantly decreased 6 and 8 weeks post-injury; however, tendon strength unfortunately was also reduced [119]. Another study showed that gene therapy to produce supernormal amounts of bFGF or VEGF supported the intrinsic tendon healing in a chicken flexor tendon model—with a significantly higher tendon strength by 68–91% from week 2 after AAV2-bFGF treatment and by 82–210% from week 3 after AAV2-VEGF compared to controls [120]. At the same time, adhesion formation was not

Because decorin and IL-10 downregulate TGF-β1, another approach included co-delivery of decorin and IL-10 transgenes from a collagen hydrogel system to a tenocyte culture *in vitro*. As expected, TGF-β1 was downregulated and simultaneously also collagen I and III and fibronectin. The authors concluded that this approach might be a useful tool against scar formation (extensive fibrosis), the system has not yet been tested *in vivo*, however [121]. Moreover, another AAV-based approach was the delivery of VEGF to chicken flexor tendons; after com-

injected before they were surgically repaired [122]. The outcome was a significantly increased ultimate strength 4, 6 and 8 weeks post-operation, while the adhesion was unaffected [122]. Hence, such gene therapy approaches might get more significance also in daily clinical life, as they are easily performed (injection of a small volume only) and show promising effects.

Another nice example has been shown using Scx-transduced tendon-derived stem cells in a rat unilateral patellar tendon window injury model. For transplantation, a TEC based on fibrin and transduced cells was used. Tendon repair was significantly improved in terms of histology and biomechanics *in vivo*. *In vitro* results showed that Scx-transduced tendonderived stem cells expressed tendon- and also cartilage-related genes to a higher level; as for

particles of AAV2-VEGF or saline (as control) were

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ferentiation (if stem cell-based) and the intended biomechanics [105–108].

seeded TECs; because storage is facilitated without (living) cells [114].

process of tendons [117, 118].

adversely affected.

plete transection of these tendons, 2 × 10<sup>9</sup>

**Figure 2.** Application of DegraPol®. An electrospun DegraPol® tube is placed around a fully transected rabbit Achilles tendon (A) in order to deliver a growth factor to the repair site. The laceration is sutured by a 4-strand Becker suture and the tube is pulled over (B).
