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Success Criteria and Preclinical Testing of Multifunctional Hydrogels for Tendon Regeneration.

ABSTRACT: Tendon injuries are difficult to heal, in part, because intrinsic tendon healing, which is dominated by scar tissue formation, does not effectively regenerate the native structure and function of healthy tendon. Further, many current treatment strategies also fall short of producing regenerated tendon with the native properties of healthy tendon. There is increasing interest in the use of cell-instructive strategies to limit the intrinsic fibrotic response following injury and improve the regenerative capacity of tendon in vivo. We have established multifunctional, cell-instructive hydrogels for treating injured tendon that afford tunable control over the biomechanical, biochemical, and structural properties of the cell microenvironment. Specifically, we incorporated integrin-binding domains (RGDS) and assembled multifunctional collagen mimetic peptides that enable cell adhesion and elongation of stem cells within synthetic hydrogels of designed biomechanical properties and evaluated these materials using targeted success criteria developed for testing in mechanically demanding environments such as tendon healing. The in vitro and in situ success criteria were determined based on systematic reviews of the most commonly reported outcome measures of hydrogels for tendon repair and established standards for testing of biomaterials. We then showed, using validation experiments, that multifunctional and synthetic hydrogels meet these criteria. Specifically, these hydrogels have mechanical properties comparable to developing tendon; are noncytotoxic both in two-dimensional bolus exposure (hydrogel components) and three-dimensional encapsulation (full hydrogel); are formed, retained, and visualized within tendon defects over time (2-weeks); and provide mechanical support to tendon defects at the time of in situ gel crosslinking. Ultimately, the in vitro and in situ success criteria evaluated in this study were designed for preclinical research to rigorously test the potential to achieve successful tendon repair before in vivo testing and indicate the promise of multifunctional and synthetic hydrogels for continued translation. Impact statement Tendon healing results in a weak scar that forms due to poor cell-mediated repair of the injured tissue. Treatments that tailor the instructions experienced by cells during healing afford opportunities to regenerate the healthy tendon. Engineered cell-instructive cues, including the biomechanical, biochemical, and structural properties of the cell microenvironment, within multifunctional synthetic hydrogels are promising therapeutic strategies for tissue regeneration. In this article, the preclinical efficacy of multifunctional synthetic hydrogels for tendon repair is tested against rigorous in vitro and in situ success criteria. This study indicates the promise for continued preclinical translation of synthetic hydrogels for tissue regeneration.

SUBMITTER: Locke RC

PROVIDER: S-EPMC7869878 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PURPOSE:The gracilis tendon (GT) is a commonly used autologous graft in Orthopaedic surgery. The majority of information on knee function and outcomes after hamstring harvest is related to both semitendinosus and GT harvest. Little is known regarding isolated harvest of a GT. It was hypothesized that isolated GT harvest would lead to altered gait patterns (e.g. augmented anterior-posterior translation or rotation in the tibiofemoral joint) and consequently a higher prevalence of cartilage lesions and meniscal tears in knees. METHODS:GT harvesting was performed on patients with chronic acromioclavicular joint instability without previous knee injuries or surgeries. MRI of both knees and thighs were performed. Knee MRI were evaluated using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Inter- and intraobserver reliabilities, cross-sectional areas of different muscles, fatty infiltration of the gracilis muscle (GM) and GT regeneration were evaluated. The contralateral limb served as reference. The observers were blinded towards the identity of the patients and the operatively treated side. RESULTS:After a mean time of 44 months after surgery testing was performed on 12 patients. No significant side-to-side differences were found using WORMS, although there was a trend towards increased cartilage lesions after GT harvest (median healthy knee 4.8 and GT harvested knee 7.8 p = 0.086). Inter- and intraobserver repeatability was high with 0.899 (95% confidence interval (CI) 0.708-0.960) and 0.988 (95% CI 0.973-0.995), respectively. A significant hypotrophy of the GM with a mean decrease of 25.3%, 18.4% and 16.9% occurred at 25% (p = 0.016), 50% (p = 0.007) and 75% (p = 0.002) of the length of the femur from distal. No compensatory hypertrophy of other thigh muscles or increased fatty infiltration of the GM was found. Tendon regeneration took place in eight out of 12 patients. In case of regeneration, the regenerated tendon inserted in a more proximal place. CONCLUSION:Isolated harvest of the GT for shoulder procedures did not affect knee MRI significantly indicating therefore in general suitable graft utilization for surgeries outside of the knee. GT regenerated in most patients with just a more proximal insertion and a hypotrophy of the muscle belly.

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Success Criteria and Preclinical Testing of Multifunctional Hydrogels for Tendon Regeneration.

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