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Extracellular Matrix (ECM) scaffolds and biomaterials have been widely used for decades across a variety of diverse clinical applications and have been implanted in millions of patients worldwide. ECM-based biomaterials have been especially successful in soft tissue repair applications but their utility in other clinical applications such as for regeneration of bone or neural tissue is less well understood. The beneficial healing outcome with the use of ECM biomaterials is the result of their biocompatibility, their biophysical properties and their ability to modify cell behavior after injury. As a consequence of successful clinical outcomes, there has been motivation for the development of next-generation formulations of ECM materials ranging from hydrogels, bioinks, powders, to whole organ or tissue scaffolds. The continued development of novel ECM formulations as well as active research interest in these materials ensures a wealth of possibilities for future clinical translation and innovation in regenerative medicine. The clinical translation of next generation formulations ECM scaffolds faces predictable challenges such as manufacturing, manageable regulatory pathways, surgical implantation, and the cost required to address these challenges. The current status of ECM-based biomaterials, including clinical translation, novel formulations and therapies currently under development, and the challenges that limit clinical translation of ECM biomaterials are reviewed herein., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cytokine storm describes a life-threatening, systemic inflammatory syndrome characterized by elevated levels of proinflammatory cytokines and immune cell hyperactivation associated with multi-organ dysfunction. Matrix-bound nanovesicles (MBV) are a subclass of extracellular vesicle shown to down-regulate proinflammatory immune responses. The objective of this study was to assess the efficacy of MBV in mediating influenza-induced acute respiratory distress syndrome and cytokine storm in a murine model. Intravenous administration of MBV decreased influenza-mediated total lung inflammatory cell density, proinflammatory macrophage frequencies, and proinflammatory cytokines at 7 and 21 days following viral inoculation. MBV decreased long-lasting alveolitis and the proportion of lung undergoing inflammatory tissue repair at day 21. MBV increased the proportion of activated anti-viral CD4 + and CD8 + T cells at day 7 and memory-like CD62L + CD44 + , CD4 + , and CD8 + T cells at day 21. These results show immunomodulatory properties of MBV that may benefit the treatment of viral-mediated pulmonary inflammation with applicability to other viral diseases such as SARS-CoV-2.

Matrix-bound nanovesicles (MBV) are a distinct subtype of extracellular vesicles that are firmly embedded within biomaterials composed of extracellular matrix (ECM). MBV both store and transport a diverse, tissue specific portfolio of signaling molecules including proteins, miRNAs, and bioactive lipids. MBV function as a key mediator in ECM-mediated control of the local tissue microenvironment. One of the most important mechanisms by which MBV in ECM bioscaffolds support constructive tissue remodeling following injury is immunomodulation and, specifically, the promotion of an anti-inflammatory, pro-remodeling immune cell activation state. Recent in vivo studies have shown that isolated MBV have therapeutic efficacy in rodent models of both retinal damage and rheumatoid arthritis through the targeted immunomodulation of pro-inflammatory macrophages towards an anti-inflammatory activation state. While these results show the therapeutic potential of MBV administered independent of the rest of the ECM, the in vitro and in vivo safety and biodistribution profile of MBV remain uncharacterized. The purpose of the present study was to thoroughly characterize the pre-clinical safety profile of MBV through a combination of in vitro cytotoxicity and MBV uptake studies and in vivo toxicity, immunotoxicity, and imaging studies. The results showed that MBV isolated from porcine urinary bladder are well-tolerated and are not cytotoxic in cell culture, are non-toxic to the whole organism, and are not immunosuppressive compared to the potent immunosuppressive drug cyclophosphamide. Furthermore, this safety profile was sustained across a wide range of MBV doses. STATEMENT OF SIGNIFICANCE: Matrix-bound nanovesicles (MBV) are a distinct subtype of bioactive extracellular vesicles that are embedded within biomaterials composed of extracellular matrix (ECM). Recent studies have shown therapeutic efficacy of MBV in models of both retinal damage and rheumatoid arthritis through the targeted immunomodulation of pro-inflammatory macrophages towards an anti-inflammatory activation state. While these results show the therapeutic potential of MBV, the in vitro and in vivo biocompatibility and biodistribution profile of MBV remain uncharacterized. The results of the present study showed that MBV are a well-tolerated ECM-derived therapy that are not cytotoxic in cell culture, are non-toxic to the whole organism, and are not immunosuppressive. Collectively, these data highlight the translational feasibility of MBV therapeutics across a wide variety of clinical applications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interest: This study was sponsored by ECM Therapeutics Inc., Warrendale PA. GSH and SFB are employees of and own stock in ECM Therapeutics Inc. The other authors have no financial conflicts or competing interests to disclose., (Copyright © 2022. Published by Elsevier Ltd.)

Skeletal muscle has a robust, inherent ability to regenerate in response to injury from acute to chronic. In severe trauma, however, complete regeneration is not possible, resulting in a permanent loss of skeletal muscle tissue referred to as volumetric muscle loss (VML). There are few consistently reliable therapeutic or surgical options to address VML. A major limitation in investigation of possible therapies is the absence of a well-characterized large animal model. In this study, we present results of a comprehensive transcriptomic, proteomic, and morphologic characterization of wound healing following VML in a novel canine model of VML which we compare to a nine-patient cohort of combat-associated VML. The canine model is translationally relevant as it provides both a regional (spatial) and temporal map of the wound healing processes that occur in human VML. Collectively, these data show the spatiotemporal transcriptomic, proteomic, and morphologic properties of canine VML healing as a framework and model system applicable to future studies investigating novel therapies for human VML. Impact Statement The spatiotemporal transcriptomic, proteomic, and morphologic properties of canine volumetric muscle loss (VML) healing is a translational framework and model system applicable to future studies investigating novel therapies for human VML.

Soft tissue injuries such as volumetric muscle loss (VML) are often too large to heal normally on their own, resulting in scar formation and functional deficits. Decellularized extracellular matrix (dECM) scaffolds placed into these wounds have shown the ability to modulate the immune response and drive constructive healing. This provides a potential solution for functional tissue regeneration, however, these acellular dECM scaffolds are challenging to fabricate into complex geometries. 3D bioprinting is uniquely positioned to address this, being able to create patient-specific scaffolds based on clinical 3D imaging data. Here, a process to use freeform reversible embedding of suspended hydrogels (FRESH) 3D bioprinting and computed tomography (CT) imaging to build large volume, patient-specific dECM patches (≈12 × 8 × 2 cm) for implantation into canine VML wound models is developed. Quantitative analysis shows that these dECM patches are dimensionally accurate and conformally adapt to the surface of complex wounds. Finally, this approach is extended to a human VML injury to demonstrate the fabrication of clinically relevant dECM scaffolds with precise control over fiber alignment and micro-architecture. Together these advancements represent a step towards an improved, clinically translatable, patient-specific treatment for soft tissue defects from trauma, tumor resection, and other surgical procedures., (© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations., (© 2022. The Author(s).)

The purpose of this review was to update the complication profile of reverse total shoulder arthroplasty (rTSA) post-2010, given greater procedural familiarity, improved learning curves, enhanced implant designs, and increased attention to the nuances of patient selection. Three electronic databases were searched and screened in duplicate from 1 January 2010 to 16 December 2018 based on predetermined criteria. Twenty-two studies examining 1455 patients (26% male; mean age: 73.4 ± 3.6; mean follow-up: 23.4 ± 14.3 months) were reviewed. Post-operative motion ranged a mean 122.4° ± 11.5° flexion, 109° ± 19.4° abduction, and 33° ± 11.2°/41° ± 5° external/internal rotation. Post-operative mean Constant score was 58.9 ± 10.1, American Shoulder Elbow Surgeon score was 73.4 ± 6.1, Simple Shoulder Test score was 63.5 ± 6.5, and a Visual Analog Scale pain score was 1.6 ± 0.9. The overall complication rate was 18.2% and major complication rate was 15.4%. Compared to pre-2010, the overall complication rate of 18.2% is lower than previous rates of 19%-68%, with the rate of "major" complications dropping three-fold from 15.4% to 4.6%. The data suggest that rTSA is a safe and efficacious alternative to aTSA and HA, and the "stale" nature of previous complication profiles are points fundamental to perioperative discussions surrounding rTSA., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2019 The British Elbow & Shoulder Society.)

Revision anterior cruciate ligament (ACL) procedures are increasing in incidence and possess markedly inferior clinical outcomes (76% satisfaction) and return-to-sports (57%) rates than their primary counterparts. Given their complexity, a universal language is required to identify and communicate the technical challenges faced with revision procedures and guide treatment strategies. The proposed REV: ision using I: maging to guide S: taging and E: valuation (REVISE) ACL (anterior cruciate ligament) Classification can serve as a foundation for this universal language that is feasible and practical with acceptable inter-rater agreement. A focus group of sports medicine fellowship-trained orthopaedic surgeons was assembled to develop a classification to assess femoral/tibial tunnel "usability" (placement, widening, overlap) and guide the revision reconstruction strategy (one-stage vs. two-stage) post-failed ACL reconstruction. Twelve board-certified sports medicine orthopaedic surgeons independently applied the classification to the de-identified computed tomographic (CT) scan data of 10 patients, randomly selected, who failed ACL reconstruction. An interclass correlation coefficient (ICC) was calculated (with 95% confidence intervals) to assess agreement among reviewers concerning the three major classifications of the proposed system. Across surgeons, and on an individual patient basis, there was high internal validity and observed agreement on treatment strategy (one-stage vs. two-stage revision). Reliability testing of the classification using CT scan data demonstrated an ICC (95% confidence interval) of 0.92 (0.80-0.98) suggesting "substantial" agreement between the surgeons across all patients for all elements of the classification. The proposed REVISE ACL Classification, which employs CT scan analysis to both identify technical issues and guide revision ACL treatment strategy (one- or two-stage), constitutes a feasible and practical system with high internal validity, high observed agreement, and substantial inter-rater agreement. Adoption of this classification, both clinically and in research, will help provide a universal language for orthopaedic surgeons to discuss these complex clinical presentations and help standardize an approach to diagnosis and treatment to improve patient outcomes. The Level of Evidence for this study is 3., Competing Interests: C.M. reports other from Arthrex Inc outside the submitted work. M.B. reports personal fees from LifeNet Health, other from Smith and Nephew, and other from Arthrex Inc outside the submitted work. O.A. reports and Speakers Bureau for Conmed. A.B. reports personal fees from Arthrex during the conduct of the study. V.M. reports other from Smith & Nephew outside the submitted work., (Thieme. All rights reserved.)

Purpose: To examine existing literature on objective and patient-reported outcomes and complications after anterior cruciate ligament reconstruction (ACLR) with bone-quadriceps-tendon (B-QT) or soft tissue-quadriceps tendon (S-QT) to further clarify the role of graft type in primary ACLR., Methods: In accordance with PRISMA guidelines, PubMed, Embase, and Medline were searched in October 2019 for English-language, human studies of all evidence levels on patients undergoing primary ACLR with B-QT or S-QT autograft., Results: 24 of 1,381 studies satisfied criteria, with 20 using B-QT (1,534 patients, mean age 29.6 years [range 14 to 59], mean follow-up 41.2 months [range 12 to 120]) and 5 using S-QT (181 patients, mean age 32.4 years [range 15 to 58), mean follow-up 25.5 months [range 12 to 46]). International Knee Documentation Committee (IKDC) scores were 67.3 to 89.5 with B-QT and 80.4 to 81.6 with S-QT. Lysholm scores were 85.7 to 97.4 with B-QT and 81.6 to 89.2 with S-QT. More B-QT patients demonstrated rotatory laxity on pivot shift compared with S-QT (0% to 39% versus 0%, respectively). The most common complication was graft rupture, and no differences were observed between graft choices (B-QT 0% to 9% versus S-QT 0% to 3.8%)., Conclusions: The main findings from this review report that more B-QT patients demonstrated postoperative rotatory instability than S-QT patients, and that there are no differences in graft rupture between the 2 graft choices. Although statistical conclusions may not be drawn because of heterogeneity in reporting, it appears that the B-QT group featured much wider major and minor complication profiles., Level of Evidence: IV, systematic review of level I-IV studies., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

This review is aimed to compare suspensory and aperture quadriceps tendon autograft femoral and tibial fixations in primary anterior cruciate ligament reconstruction (ACL-R), and the clinical outcomes and complication profiles of each fixation method. Greater understanding of the optimal graft fixation technique for quadriceps tendon (QT) autografts may assist surgeons in improving outcomes after ACL-R. PubMed, Embase, and Medline were searched from database inception to September 2017, and again to July 2018, and identified 3,670 articles, 21 studies of which satisfied inclusion/exclusion criteria. Across included studies, 1,155 QT ACL-R patients (mean age, 28.7 years [range, 15-59 years], with mean postoperative follow-up of 36.1 months [range, 3.4-120 months]), were analyzed. Suspensory fixation on both sides demonstrated a higher percentage of patients (81.7%) achieving the highest rating of "A or B" on the International Knee Documentation Committee (IKDC) knee ligament examination form compared with aperture fixation on both sides (67.7%). Moreover, suspensory fixation had a lower side-to-side difference in anterior laxity (1.6 mm) when compared with aperture fixation (2.3 mm). Among studies which reported graft failure, all of which employed aperture fixation, the rate was 3.2%. Across available data, primary ACL-R using QT grafts appears to have successful short-term outcomes with a short-term graft failure rate of 3% independent of fixation method. While there is limited data regarding the comparison of aperture and suspensory soft-tissue quadriceps tendon (SQT) fixation in ACL-R, the findings of this systematic review suggest that suspensory fixation and aperture fixation in both the femoral and tibial tunnels are equally efficacious based on clinical outcome data on IKDC grade and measured laxity. This is a level IV, systematic review study., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Hydrogels composed of extracellular matrix (ECM) have been used as a substrate for 3D organoid culture, and in numerous preclinical and clinical applications to facilitate repair and reconstruction of a variety of tissues. However, these ECM hydrogel materials are fabricated using lengthy methods that have focused on enzymatic digestion of the ECM with an acid protease in an acidic solution; or the use of chaotropic extraction buffers and dialysis procedures which can affect native protein structure and function. Herein we report a method to prepare hydrogels from ECM bioscaffolds using ultrasonic cavitation. The solubilized ECM can be induced to rapidly self-assemble into a gel by adjusting temperature, and the material properties of the gel can be tailored by adjusting ECM concentration and sonication parameters. The present study shows that ECM bioscaffolds can be successfully solubilized without enzymatic digestion and induced to repolymerize into a gel form capable of supporting cell growth. STATEMENT OF SIGNIFICANCE: ECM hydrogels have been used in numerous preclinical studies to facilitate repair of tissue following injury. However, there has been relatively little advancement in manufacturing techniques, thereby impeding progress in advancing this technology toward the clinic. Laboratory techniques for producing ECM hydrogels have focused on protease digestion methods, which require lengthy incubation times. The significance of this work lies in the development of a fundamentally different approach whereby an ECM hydrogel is rapidly formed without the need for acidic solutions or protease digestion. The ultrasonic cavitation method described herein represents a marked improvement in rheological properties and processing time over traditional enzymatic methods, and may lend itself as a platform for large-scale manufacturing of ECM hydrogels., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was sponsored by ECM Therapeutics Inc., Warrendale PA. GSH, JLD, and SFB are employees of and own stock in ECM Therapeutics Inc. The other authors have no financial conflicts or competing interests to disclose., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Cope's gray treefrog, Dryophytes chrysoscelis, withstands the physiological challenges of corporeal freezing, partly by accumulating cryoprotective compounds of hepatic origin, including glycerol, urea, and glucose. We hypothesized that expression of genes related to cryoprotectant mobilization and stress tolerance would be differentially regulated in response to cold. Using high-throughput RNA sequencing (RNA-Seq), a hepatic transcriptome was generated for D. chrysoscelis, and gene expression was compared among frogs that were warm-acclimated, cold-acclimated, and frozen., Results: A total of 159,556 transcripts were generated; 39% showed homology with known transcripts, and 34% of all transcripts were annotated. Gene-level analyses identified 34,936 genes, 85% of which were annotated. Cold acclimation induced differential expression both of genes and non-coding transcripts; freezing induced few additional changes. Transcript-level analysis followed by gene-level aggregation revealed 3582 differentially expressed genes, whereas analysis at the gene level revealed 1324 differentially regulated genes. Approximately 3.6% of differentially expressed sequences were non-coding and of no identifiable homology. Expression of several genes associated with cryoprotectant accumulation was altered during cold acclimation. Of note, glycerol kinase expression decreased with cold exposure, possibly promoting accumulation of glycerol, whereas glucose export was transcriptionally promoted by upregulation of glucose-6-phosphatase and downregulation of genes of various glycolytic enzymes. Several genes related to heat shock protein response, DNA repair, and the ubiquitin proteasome pathway were upregulated in cold and frozen frogs, whereas genes involved in responses to oxidative stress and anoxia, both potential sources of cellular damage during freezing, were downregulated or unchanged., Conclusion: Our study is the first to report transcriptomic responses to low temperature exposure in a freeze-tolerant vertebrate. The hepatic transcriptome of Dryophytes chrysoscelis is responsive to cold and freezing. Transcriptomic regulation of genes related to particular pathways, such as glycerol biosynthesis, were not all regulated in parallel. The physiological demands associated with cold and freezing, as well as the transcriptomic responses observed in this study, are shared with several organisms that face similar ecophysiological challenges, suggesting common regulatory mechanisms. The role of transcriptional regulation relative to other cellular processes, and of non-coding transcripts as elements of those responses, deserve further study.

Purpose: This review explores the current literature regarding both the clinical indications and utility of minimally invasive in-office needle arthroscopy (IONA) relative to conventional imaging modalities., Methods: In compliance with R-AMSTAR (Revised Assessment of Multiple Systematic Reviews) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, 3 databases (MEDLINE, Embase, and PubMed) were searched in July 2018, in addition to the conference abstract databases of 5 prominent meetings between 2013 and 2018, for studies using IONA for diagnostic purposes. Study quality was assessed with the Methodological Index for Non-Randomized Studies (MINORS) criteria., Results: Among 932 conference abstracts and 369 studies identified, 11 publications involving 404 patients (395 knees and 9 shoulders) were included, with 9 clinical studies and 2 cost analyses. The median Methodological Index for Non-Randomized Studies (MINORS) score was 9 for noncomparative and 23 for comparative studies. Among the 9 clinical studies, IONA had a superior sensitivity, specificity, positive predictive value, and negative predictive value to magnetic resonance imaging (MRI) in the evaluation of knee osteoarthritis, anterior cruciate ligament insufficiency, and meniscal tears. IONA was comparable or inferior to MRI in the same parameters for the diagnosis of osteochondral defects and rotator cuff tears. In the 2 cost analyses, IONA had lower costs when used in place of MRI for treatment algorithms involving medial meniscal tears and rotator cuff tears but not lateral meniscal tears., Conclusions: IONA holds potential for cost savings and improved diagnostic accuracy relative to MRI, primarily for intra-articular meniscal, ligamentous, and chondral defects of the knee. However, its current indications for use in other joints are limited to rotator cuff tears in the shoulder, making its diagnostic value in other joints much more limited. The current quality and breadth of evidence are significantly lacking, with numerous practical shortcomings. To improve acceptance of IONA, priority should be placed on establishing defined protocols, indications, contraindications, and patient perspectives for the procedure., Level of Evidence: Level IV, systematic review of Level II, III, and IV studies., (Copyright © 2019 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the outcomes of SLAP repair versus biceps tenodesis (BT) for the index treatment of isolated type II SLAP tears., Methods: A search of PubMed, MEDLINE, and EMBASE was performed in April 2018 for English-language studies that presented outcomes data on patients with isolated type II SLAP tears treated with either SLAP repair or BT at the primary surgical time point., Results: Twenty-three studies (i.e., 2 randomized control trials, 7 retrospective cohort, 3 prospective cohort, 4 case-control, and 7 case series) were included. Isolated type II SLAP tears were treated via SLAP repair in 781 patients with a mean age of 35 years (range, 22-58 years) and a mean postoperative follow-up of 35 months (range, 3-63 months). BT was performed in 100 patients with a mean age of 44 years (range, 18-64 years) and a mean postoperative follow-up of 32 months (range, 24-75 months). Similar postoperative scores were noted in both the SLAP repair and BT groups for American Shoulder and Elbow Surgeons, Constant, University of California, Los Angeles, and visual analog scale pain scores. The rate of return to sports was 20% to 95% for SLAP repair and 73% to 100% for BT. Reoperation rates for SLAP repair and BT were 2.9% to 40% and 0% to 15.3%, respectively., Conclusions: This study suggests that SLAP repair and BT are both acceptable as index treatment for isolated type II SLAP tears. SLAP repair remains the most commonly performed index procedure; however, BT appears equally efficacious and may represent an attractive alternative., Level of Evidence: Level IV, systematic review of Level I through IV studies., (Copyright © 2019 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

The results of a 5-year clinical study show that patients treated with complete maxillary dentures and mandibular overdentures demonstrate less vertical alveolar bone reduction than patients with complete maxillary and mandibular dentures.