Biological approaches to the repair and regeneration of the rotator cuff tendon-bone enthesis:a literature review

Entheses are highly specialised organs connecting ligaments and tendons to bones,facilitating force transmission,and providing mechanical strengths to absorb forces encountered.Two types of entheses,fibrocartilaginous and fibrous,exist in interfaces.The gradual fibrocartilaginous type is in rotator cuff tendons and is more frequently injured due to the poor healing capacity that leads to loss of the original structural and biomechanical properties and is attributed to the high prevalence of retears.Fluctuating methodologies and outcomes of biological approaches are challenges to overcome for them to be routinely used in clinics.Therefore,stratifying the existing literature according to different categories(chronicity,extent of tear,and studied population)would effectively guide repair approaches.This literature review supports tissue engineering approaches to promote rotator cuff enthesis healing employing cells,growth factors,and scaffolds period.Outcomes suggest its promising role in animal studies as well as some clinical trials and that combination therapies are more beneficial than individualized ones.It then highlights the importance of tailoring interventions according to the tear extent,chronicity,and the population being treated.Contributing factors such as loading,deficiencies,and lifestyle habits should also be taken into consideration.Optimum results can be achieved if biological,mechanical,and environmental factors are approached.It is challenging to determine whether variations are due to the interventions themselves,the animal models,loading regimen,materials,or tear mechanisms.Future research should focus on tailoring interventions for different categories to formulate protocols,which would best guide regenerative medicine decision making.

Engineering an enthesis-like graft for rotator cuff repair:An approach to fabricate highly biomimetic scaffold capable of zone-specifically releasing stem cell differentiation inducers

Rotator cuff(RC)attaches to humerus across a triphasic yet continuous tissue zones(bone-fibrocartilage-tendon),termed“enthesis”.Regrettably,rapid and functional enthesis regeneration is challenging after RC tear.The existing grafts bioengineered for RC repair are insufficient,as they were engineered by a scaffold that did not mimic normal enthesis in morphology,composition,and tensile property,meanwhile cannot simultaneously stimulate the formation of bone-fibrocartilage-tendon tissues.Herein,an optimized decellularization approach based on a vacuum aspiration device(VAD)was developed to fabricate a book-shaped decellularized enthesis matrix(O-BDEM).Then,three recombinant growth factors(CBP-GFs)capable of binding collagen were synthesized by fusing a collagen-binding peptide(CBP)into the N-terminal of BMP-2,TGF-β3,or GDF-7,and zone-specifically tethered to the collagen of O-BDEM to fabricate a novel scaffold(CBP-GFs/O-BDEM)satisfying the above-mentioned requirements.After ensuring the low immunogenicity of CBP-GFs/O-BDEM by a novel single-cell mass cytometry in a mouse model,we interleaved urine-derived stem cell-sheets into this CBP-GFs/O-BDEM to bioengineer an enthesis-like graft.Its high-performance on regenerating enthesis was determined in a canine model.These findings indicate this CBP-GFs/O-BDEM may be an excellent scaffold for constructing enthesis-like graft to patch large/massive RC tears,and provide breakthroughs in fabricating graded interfacial tissue.

Stem cell therapy in the management of shoulder rotator cuff disorders

Rotator cuff tears are frequent shoulder problems that are usually dealt with surgical repair. Despite improved surgical techniques, the tendon-to-bone healing rate is unsatisfactory due to difficulties in restoring the delicate transitional tissue between bone and tendon. It is essential to understand the molecular mechanisms that determine this failure. The study of the molecular environment during embryogenesis and during normal healing after injury is key in devising strategies to get a successful repair. Mesenchymal stem cells(MSC) can differentiate into different mesodermal tissues and have a strong paracrine, anti-inflammatory, immunoregulatory and angiogenic potential. Stem cell therapy is thus a potentially effective therapy to enhance rotator cuff healing. Promising results have been reported with the use of autologous MSC of different origins in animal studies: they have shown to have better healing properties, increasing the amount of fibrocartilage formation and improving the orientation of fibrocartilage fibers with less immunologic response and reduced lymphocyte infiltration. All these changes lead to an increase in biomechanical strength. However, animal research is still inconclusive and more experimental studies are needed before human application. Future directions include expanded stem cell therapy in combination with growth factors or different scaffolds as well as new stem cell types and gene therapy.