Biomaterial-Mediated Reprogramming of the Wound Interface to Enhance Meniscal Repair

Endogenous repair of fibrous connective tissues is limited, and there exist few successful strategies to improve healing after injury. As such, new methods that advance repair by enhancing cell migration to the wound interface, extracellular matrix (ECM) production, and tissue integration would represent a marked clinical advance. Using the adult meniscus as a test platform, we hypothesized that ECM density and stiffness increase throughout tissue maturation, and that these age-related changes present biophysical barriers to interstitial cell migration during wound healing. We further posited that modulating the matrix could remove these impediments, enabling endogenous cells to reach the injury site. To test our hypotheses, we compared the microenvironment of fetal and adult meniscal ECM via atomic force microscopy (AFM) indentation and second harmonic generation (SHG) imaging of the collagenous matrix. We also explored interstitial cell mobility through fetal and adult native tissue environments using a three-dimensional ex vivo system. We further investigated strategies that might expedite cell migration, including enzymatic degradation of the ECM with collagenase to reduce matrix stiffness and increase porosity. To restrict these biological manipulations to the wound interface, we fabricated a delivery system in which selected biofactors were stored inside composite electrospun nanofibrous scaffolds and released upon hydration. The ability for bioactive scaffolds to enhance the cellularity and integration of meniscal injuries was evaluated in vivo using tissue explants in a subcutaneous implantation model, as well as an orthotopic meniscal injury model. Our findings suggest that matrix stiffness, density, and organization increase with meniscal development at the expense of cell mobility. Our results also indicate that partial digestion of the wound interface with collagenase improves repair by creating a more compliant and porous microenvironment that facilitates cell migration. Furthermore, when scaffolds containing collagenase-releasing fibers were placed inside meniscal defects, enzymatic digestion was localized and resulted in improved cellular colonization and closure of the wound site, similar to treatment with aqueous collagenase. This innovative approach of targeted delivery may aid the many patients that exhibit meniscal tears by promoting integrative repair, thereby circumventing the pathologic consequences of partial meniscus removal, and may find widespread application in the treatment of injuries to a variety of dense connective tissues

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse

AbstractHumans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the ‘blastema’) regrow the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. We hypothesized that regeneration is initiated and maintained by a gene regulatory network that recapitulates aspects of limb development, whereas a non-regenerative response exhibits fibrotic wound healing and minimal bone remodeling. To test these hypotheses, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. We show that digit regeneration is a level-dependent and spatiotemporally controlled process, with distal and proximal amputations showing significant differences in gene expression and tissue regrowth over time. Regeneration is characterized by the transient upregulation of genes that direct skeletal system development and limb morphogenesis, including distal Hox genes. By identifying the molecular pathways regulating regeneration, this work will lead to novel therapies that restore complex tissues after injury.Summary StatementMurine digit tip regeneration after distal amputation is orchestrated through a transient, limb-specific gene network by blastema cells. Proximal amputation activates an alternate transcriptional program that results in scar formation.</jats:sec

Digit regeneration is expedited in LG/J healer mice compared to SM/J non-healer mice

Abstract Limb loss resulting from disease or trauma affects an estimated 185,000 Americans annually, significantly reducing their quality of life. Consequently, successful attempts to regrow missing appendages could substantially improve the prognosis for amputees. In mice, the digit tip spontaneously regenerates resected tissues following distal amputation, whereas this capacity diminishes at more proximal levels after amputation. Moreover, regenerative potential is influenced by genetic variations among inbred mouse strains: LG/J (healer) mice exhibit superior reparative potential compared to SM/J (non-healer) mice. This study investigated the response to various levels of digit amputation in these mice to determine whether this strain-dependent healing response translates to the regeneration of complex tissues. Evaluation of skeletal regrowth, cell proliferation, and differential gene and protein expression reveals that digit regeneration is more robust in LG/J mice compared to SM/J mice at multiple amputation levels, suggesting that the regenerative capacity of composite tissues is genetically heritable in mice

Reformation of thiophene-functionalized phthalocyanine isomers for defect passivation to achieve stable and efficient perovskite solar cells

Lewis acid-base passivation is a significant technique to achieve structural stability of perovskite solar cells (PSCs) by overcoming the issues of wide grain boundaries, crystal defects, and the instability of PSCs. In this work, the combined effects of thiophene with phthalocyanine (Pc) as isomers (S2 and S3) on the photovoltaic performance of PSCs were studied for the first time. Through density functional the-ory calculations, we confirmed that the position of the S atom in the structure affects Lewis acid-base interactions with under-coordinated Pb2+ sites. The morphology of methylammonium lead iodide (MAPbI3) for passivated devices was improved and thin dense layers with compact surface and large grain size were observed, leading to improvement of the charge extraction ability and reduction of non-radiative recombination and the trap density. A highest power conversion efficiency of 18% was achieved for the Pc S3 passivated device, which was 6.69% more than that of the controlled device. Furthermore, the Pcs passivated devices demonstrated remarkable stability under high-moisture and high-temperature conditions. (c) 2021 Science Press and Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by ELSEVIER B.V. and Science Press. All rights reserved