The extracellular matrix (ECM) is the primary biomechanical environment that interacts with tendon cells (tenocytes). Stresses applied via muscle contraction during skeletal movement transfer across structural hierarchies to the tenocyte nucleus in native uninjured tendons. Alterations to ECM structural and mechanical properties due to mechanical loading and tissue healing may affect this multiscale strain transfer and stress transmission through the ECM. This study explores the interface between dynamic loading and tendon healing across multiple length scales using living tendon explants. Results show that macroscale mechanical and structural properties are inferior following high magnitude dynamic loading (fatigue) in uninjured living tendon and that these effects propagate to the microscale. Although similar macroscale mechanical effects of dynamic loading are present in healing tendon compared to uninjured tendon, the microscale properties differed greatly during early healing. Regression analysis identified several variables (collagen and nuclear disorganization, cellularity, and F-actin) that directly predict nuclear deformation under loading. Finite element modeling predicted deficits in ECM stress transmission following fatigue loading and during healing. Together, this work identifies the multiscale response of tendon to dynamic loading and healing, and provides new insight into microenvironmental features that tenocytes may experience following injury and after cell delivery therapies.

The objective of this study was to examine the ability of 3D implants with trabecular-bone-inspired porosity and micro-/nano-rough surfaces to enhance vertical bone ingrowth. Porous Ti-6Al-4V constructs were fabricated via laser-sintering and processed to obtain micro-/nano-rough surfaces. Male and female human osteoblasts were seeded on constructs to analyze cell morphology and response. Implants were then placed on rat calvaria for 10 weeks to assess vertical bone ingrowth, mechanical stability and osseointegration. All osteoblasts showed higher levels of osteocalcin, osteoprotegerin, vascular endothelial growth factor and bone morphogenetic protein 2 on porous constructs compared to solid laser-sintered controls. Porous implants placed in vivo resulted in an average of 3.1 ± 0.6 mm vertical bone growth and osseointegration within implant pores and had significantly higher pull-out strength values than solid implants. New bone formation and pull-out strength was not improved with the addition of demineralized bone matrix putty. Scanning electron images and histological results corroborated vertical bone growth. This study indicates that Ti-6Al-4V implants fabricated by additive manufacturing to have porosity based on trabecular bone and post-build processing to have micro-/nano-surface roughness can support vertical bone growth in vivo, and suggests that these implants may be used clinically to increase osseointegration in challenging patient cases.

Nicotine is harmful to many bodily systems; however, the effects of nicotine on intra-substance tendon healing remain largely unexplored. The purpose of this study was to examine the functional, structural, and biomechanical effects of nicotine on the healing of Achilles tendons in rats after an acute full-thickness injury. Sixty Sprague-Dawley rats were enrolled in this study. Half were exposed to 0.9% saline and half to 61ng/mL of nicotine for 3 months via subcutaneous osmotic pumps. At 3 months, all rats underwent blunt full thickness transection of the left Achilles tendon and were immobilized for one week in plantarflexion. In-vivo assays were conducted prior to injury, at 21 days, and at 42 days post-injury and included the following: functional limb assessment, passive joint mechanics, and vascular evaluation. Rats were sacrificed at 21 and 42 days for biomechanical testing and histologic evaluation. Rats exposed to nicotine demonstrated decreased vascularity, greater alteration in gait mechanics, and increased passive ROM of the ankle joint. Biomechanically, the nicotine tendons failed at lower maximum loads, were less stiff, had smaller cross-sectional areas and had altered viscoelastic properties. Histologically, nicotine tendons demonstrated decreased vessel density at the injury site.

Replenishment of tenocytes to the injury site is an ideal strategy to improve healing response and accelerate the tendon ECM regeneration. The present study focused on the synthesis and characterization of a hybrid hydrogel scaffold system poly(propylene‐fumarate)‐alginate‐polyvinyl alcohol‐acrylic acid (PAPA) using poly(propylene‐fumarate) (PPF), alginate, polyvinyl alcohol (PVA) and acrylic acid and the in vitro investigation of bidirectional mobility of swine shoulder tenocytes (SST) for its potential application in rotator‐cuff tendon regeneration. IR analysis revealed the presence of alginate, PPF and PVA segments on the surface, SEM and AFM analyses revealed the porous and nano‐topographical features of PAPA, respectively, swelling was 712.6 ± 84.21% with the EWC (%) of 87.59 ± 1.26 having the diffusional exponent and swelling constant 0.551 and 1.8, respectively. PAPA was biodegradable, cytocompatible and supported long‐term survival of SSTs. SEM imaging revealed the adhesion, colonization, and sheet formation of SSTs within the PAPA hydrogel network. The SSTs seeded on the PAPA scaffolds were peculiar for their bidirectional migration as the anterograde movement was completed in 9 days whereas the retrograde infiltration occurred up to the depth of 198 μm. These findings suggest the promising translational potential of PAPA scaffold system in the management of rotator cuff tendon injury.

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