Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: E. coli beta-galactosidase with inhibitor, SARS-CoV-2 RNA-dependent RNA polymerase with covalently bound nucleotide analog, and SARS-CoV-2 ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. We found that (1) the quality of submitted ligand models and surrounding atoms varied, as judged by visual inspection and quantification of local map quality, model-to-map fit, geometry, energetics, and contact scores, and (2) a composite rather than a single score was needed to assess macromolecule+ligand model quality. These observations lead us to recommend best practices for assessing cryo-EM structures of liganded macromolecules reported at near-atomic resolution.

Camposampiero tubeless percutaneous nephrolithotomy (tPCNL): Easy, quick, effective, safe.

OBJECTIVES: To describe our technique to perform tubeless percutaneous nephrolithotomy (tPCNL) using hemostatic matrix (i.e. Floseal®) for the closure of the percutaneous tract, developed through the experience gained in our endourology specialized center. To evaluate the procedure efficacy and safety. METHODS: tPCNL performed in our center with Floseal® application from February 2017 to December 2019 were retrospectively reviewed. Clinical and surgical data were collected in order to evaluate the success of the procedure and possible complications. Camposampiero technique is reported in detail. RESULTS: Sixty-nine patients (45 males, mean age 58 years old) were included. In all patients the procedure was completed successfully and in 88% of subjects no further treatments were necessary; a low complication rate (6.9%) was reported. CONCLUSION: In our experience, tPCNL with Floseal application is feasible, safe, and effective.

Review of Caplan (1991) on cell-based therapeutic technology using Mesenchymal Stem Cells.

This classic discusses the original 1991 publication 'Mesenchymal Stem Cells (MSCs)' by Dr. Caplan on the emergence of a new therapeutic technology of self-cell repair using MSCs. After the original classic publication, a large number of methods to regenerate injured tissue have been reported. Currently, MSCs are used clinically to repair articular cartilage defects, liver cirrhosis, cerebral infarction, spinal cord injury, graft-versus-host disease and others. As a result, MSCs are considered one of the most important cell sources for regenerative medicine. An MSC has been demonstrated to be a multipotent stem cell in cell culture and was thought to contribute to the regeneration of injured tissue at transplant sites, but recently, the concept of MSCs has changed such that they are now referred to as "medicinal signaling cells," owing to their often indirect effects on tissue repair and regeneration. Regardless of the name, either mesenchymal stem cells or medicinal signaling cells, MSCs will be used to regenerate injured tissue more widely in the near future.

Identification of Macrocyclic Peptide Families from Combinatorial Libraries Containing Noncanonical Amino Acids Using Cheminformatics and Bioinformatics Inspired Clustering.

In the past decade, macrocyclic peptides gained increasing interest as a new therapeutic modality to tackle intracellular and extracellular therapeutic targets that had been previously classified as "undruggable". Several technological advances have made discovering macrocyclic peptides against these targets possible: 1) the inclusion of noncanonical amino acids (NCAAs) into mRNA display, 2) increased availability of next generation sequencing (NGS), and 3) improvements in rapid peptide synthesis platforms. This type of directed-evolution based screening can produce large numbers of potential hit sequences given that DNA sequencing is the functional output of this platform. The current standard for selecting hit peptides from these selections for downstream follow-up relies on the frequency counting and sorting of unique peptide sequences which can result in the generation of false negatives due to technical reasons including low translation efficiency or other experimental factors. To overcome our inability to detect weakly enriched peptide sequences among our large data sets, we wanted to develop a clustering method that would enable the identification of peptide families. Unfortunately, utilizing traditional clustering algorithms, such as ClustalW, is not possible for this technology due to the incorporation of NCAAs in these libraries. Therefore, we developed a new atomistic clustering method with a Pairwise Aligned Peptide (PAP) chemical similarity metric to perform sequence alignments and identify macrocyclic peptide families. With this method, low enriched peptides, including isolated sequences (singletons), can now be clustered into families providing a comprehensive analysis of NGS data resulting from macrocycle discovery selections. Additionally, upon identification of a hit peptide with the desired activity, this clustering algorithm can be used to identify derivatives from the initial data set for structure-activity relationship (SAR) analysis without requiring additional selection experiments.

Autologous microfragmented adipose tissue and leukocyte-poor platelet-rich plasma combined with hyaluronic acid show comparable clinical outcomes for symptomatic early knee osteoarthritis over a two-year follow-up period: a prospective randomized clinical trial.

PURPOSE: The purpose of this prospective randomized clinical trial is to compare the clinical outcomes of three injections of leucocyte-poor platelet-rich plasma (LP-PRP) and hyaluronic acid (HA) to a single dose of autologous microfragmented adipose tissue (AMAT) in patients with mild osteoarthritis at a two-year follow-up. METHODS: Eighty symptomatic knees in fifty patients (mean age: 62.38 ± 11.88 years) with Kellgren-Lawrence grade 0 to 2 osteoarthritis were non blinded, randomly allocated into two equal groups. Group 1 consisted of 40 knees that received autologous LP-PRP + HA; Group 2 consisted of 40 knees treated with a single dose of AMAT injection. The outcomes were measured by Tegner, Marx, Visual Analogue Scale (VAS) for pain, International Knee Documentation Committee, and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 (T1), 12 (T2), and 24 (T3) months. Adverse events were recorded at each follow-up timepoint. To assess score differences among subjects of the same gender and age, a subgroup analysis was performed. RESULTS: Both groups had significant clinical and functional improvement at 6, 12, and 24 months (p < 0.05). Comparing the two groups, the AMAT groups showed significantly higher pre-operative Marx score (3.35 ± 4.91 vs. 1.78 ± 3.91) and VAS score (5.03 ± 2.02 vs. 3.85 ± 1.68) (p < 0.05), higher VAS (3.89 ± 2.51 vs. 2.64 ± 2.00) at T2 and KOOS-ADL (79.60 ± 20.20 vs. 65.68 ± 23.62), and lower KOOS-Sports (50.30 ± 30.15 vs. 68.35 ± 30.39) at T3 (p < 0.05). No patient from either group had experienced major adverse effects. In the LP-PRP group 12 (30%) patients presented swelling, redness, and mild pain for one day after injection and two patients had synovitis for two days and required paracetamol and local ice. In AMAT group 5 (12.5%) patients had ecchymosis and bruising at the fat aspiration site for three days. CONCLUSION: AMAT did not show significant superior clinical improvement compared with three LP-PRP combined with HA injections in terms of functional improvement at different follow-up points. Both procedures were safe with no major complications reporting good results at mid-term follow-up, improving knee function, pain, and quality of live regardless of age and gender. LEVEL OF EVIDENCE: Level I-Prospective Randomized Clinical Trial.

Evidence-Based Approach to Orthobiologics for Osteoarthritis and Other Joint Disorders.

Osteoarthritis and cartilage lesions are a major cause of functional limitations which is why the goal of biological treatment is to preserve the native joint to delay the onset of OA. As a result of improvements in surgical techniques and technology, treatment options are more and more available, allowing the treatment of a whole range of injuries, from minor to extensive lesions both acute and chronic. In chondral lesion treatment, restoring hyaline-like cartilage provides improved durability of repaired tissue and desirable wear characteristics. Biological cell-based cartilage restoration treatment was developed to address the need for the long-term viability of repaired tissue. These procedures provide a reliable source of chondrocytes, whether directly or through the differentiation of multipotent precursor cells, capable of producing hyaline-like cartilage, with the minimal formation of fibrocartilage tissue. However, if arthritic changes begin biological therapies offer possibilities to delay. This chapter aims to discuss and give insights into these regenerative, joint preservation techniques for cartilage treatment and possible biological treatment in OA.

Conceptos actuales en el diagnóstico y tratamiento de las lesiones del hueso subcondral / Current concepts in the diagnosis and treatment of subchondral bone injuries

La patología ósea subcondral incluye una amplia gama de patologías, como la artrosis, las fracturas por insuficiencia espontánea, la osteonecrosis y los traumatismos articulares. Todas muestran hallazgos típicos de imágenes de resonancia magnética (RM) denominados lesiones de la médula ósea (LMO). Sin embargo, la etiología y la evolución de las LMO en múltiples afecciones aún no están claras. Además, todavía no existe un protocolo de tratamiento estándar de oro para las LMO, es por esto que se están probando una variedad de modalidades de tratamiento con la esperanza de que puedan reducir el dolor y detener la progresión de la enfermedad. Nuestro propósito es presentar una revisión sobre los conceptos actuales para el diagnóstico y tratamiento de las LMO. Se realizó una revisión de la literatura que incluyó búsquedas en las bases de datos PubMed, Cochrane y Medline utilizando las siguientes palabras clave: lesiones de médula ósea subcondral, hueso subcondral, subcondroplastia, concentrado de médula ósea, plasma rico en plaquetas (PRP) y aumento óseo subcondral. Podemos concluir que el uso de nuevas técnicas biológicas para tratar las LMO, como el PRP y las células de la médula ósea, ha mostrado resultados clínicos prometedores. La investigación futura de las LMO será necesaria para abordar mejor las diferentes patologías y determinar las estrategias terapéuticas adecuadas. Todavía se necesitan estudios randomizados y controlados de alta calidad junto a revisiones sistemáticas para generar guías y recomendaciones para el tratamiento de las LMO.

Subchondral bone pathology includes a wide range of pathologies, such as osteoarthritis, spontaneous insufficiency fractures, osteonecrosis, and trauma. They show typical magnetic resonance imaging (MRI) findings termed bone marrow lesions (BMLs). However, the etiology and evolution of BMLs in multiple conditions remains unclear. There is still no gold standard treatment protocol in treating BML, and a variety of treatment modalities have been tested in the hope that they might reduce pain and stop disease progression.Our purpose was to write a current concepts review about diagnosis and treatment options for BMLs. A literature review was performed that included searches of PubMed, Cochrane, and Medline databases using the following keywords: Bone marrow lesions, subchondral bone, subchondroplasty, bone marrow concentrate, platelet-rich plasma (PRP), subchondral bone augmentation.The use of novel biologic techniques to treat BMLs, such as PRP and Bone Marrow Cells, has yielded promising clinical outcomes. Future research of BMLs will be mandatory to address the different pathologies better and determining appropriate treatment strategies. There is still a need for high-quality RCTs studies and systematic reviews in the future to enhance further treatment strategy in preventing or treating BMLs of the knee.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Short-Term Efficacy of Using a Novel Low-Volume Bone Marrow Aspiration Technique to Treat Knee Osteoarthritis: A Retrospective Cohort Study.

Background: Intra-articular bone marrow concentrate (BMC) and aspirate (BMA) injections have been used with mixed results to treat osteoarthritis (OA). Given the various aspiration and concentration methods available for preparing bone marrow, more data are needed to identify the optimal bone marrow harvesting techniques to treat OA. Methods: This retrospective cohort study examined the effect of using low-volume BMAs harvested using the Marrow Cellution™ (MC) device on 160 patients (262 knees) suffering from pain due to knee OA, KL grades 2-4, that did not respond to conservative treatment. Changes in visual analog scores (VAS) for overall daily activity were examined over a six-month time frame in these patients (63.5 ± 0.97 years of age; 48.1% male). In addition, changes in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Patient Global Impression of Change (PGIC scores) were examined over the same time frame in a smaller subset of patients (95 patients including 172 knees). Results: There was a statistically significant improvement in VAS scores for overall daily activity 6 months postprocedure in the study population, 7.29 ± 0.27 vs. 3.76 ± 0.34 (p < 0.0001), as well as statistically significant improvements in WOMAC scores, 49.3 ± 4.27 vs. 66.3 ± 4.08 (p < 0.0001). On the individual level, 71% of the cases displayed VAS improvements and 61% of the cases displayed WOMAC improvements that exceeded levels previous studies determined to be the minimal clinically important difference (MCID) for knee OA treatments. The improvements in WOMAC scores were also seen in both the WOMAC pain subscore, 52.2 ± 4.39 vs. 72.2 ± 4.36 (p < 0.0001) and the WOMAC function subscore, 51.6 ± 4.67 vs. 69.0 ± 4.36 (p < 0.0001). In addition, the PGIC scores measuring patient satisfaction improved from 4.03 ± 0.26 at 6 weeks postprocedure to 4.65 ± 0.28 at 6 months postprocedure (p < 0.0001). Conclusions: Knee OA patients treated with MC BMA intra-articular injections exhibited significant reductions in VAS pain scores and significant improvements in WOMAC scores that exceeded the minimal clinically important difference thresholds. In addition, reductions in VAS pain scores and improvements in WOMAC scores correlated with higher PGIC scores.

Collaborative Assessment of Molecular Geometries and Energies from the Open Force Field.

Force fields form the basis for classical molecular simulations, and their accuracy is crucial for the quality of, for instance, protein-ligand binding simulations in drug discovery. The huge diversity of small-molecule chemistry makes it a challenge to build and parameterize a suitable force field. The Open Force Field Initiative is a combined industry and academic consortium developing a state-of-the-art small-molecule force field. In this report, industry members of the consortium worked together to objectively evaluate the performance of the force fields (referred to here as OpenFF) produced by the initiative on a combined public and proprietary dataset of 19,653 relevant molecules selected from their internal research and compound collections. This evaluation was important because it was completely blind; at most partners, none of the molecules or data were used in force field development or testing prior to this work. We compare the Open Force Field "Sage" version 2.0.0 and "Parsley" version 1.3.0 with GAFF-2.11-AM1BCC, OPLS4, and SMIRNOFF99Frosst. We analyzed force-field-optimized geometries and conformer energies compared to reference quantum mechanical data. We show that OPLS4 performs best, and the latest Open Force Field release shows a clear improvement compared to its predecessors. The performance of established force fields such as GAFF-2.11 was generally worse. While OpenFF researchers were involved in building the benchmarking infrastructure used in this work, benchmarking was done entirely in-house within industrial organizations and the resulting assessment is reported here. This work assesses the force field performance using separate benchmarking steps, external datasets, and involving external research groups. This effort may also be unique in terms of the number of different industrial partners involved, with 10 different companies participating in the benchmark efforts.

Articular cartilage delamination at eight years following cellular-based repair procedures: a case reports.

This report describes two cases of late cartilage delamination in two young adults after two different autologous cell-based techniques for cartilage restoration: 1. Matrix-assisted autologous chondrocyte implantation (MACI) and 2. Hyaluronic acid-bone marrow aspirate concentrate (HA-BMAC). Both cases demonstrate that even in patients who do not present with any ongoing symptoms after primary surgery, a cellular-based graft's subsequent delamination can occur later. It is possible that regardless of the technique used or the time passed since the surgery, a graft failure may occur at some level, causing delamination of a previously asymptomatic cartilage restoration graft and a traumatic event with long-term follow-up. Surgeons must be alert to this injury and describe histologic findings to determine where failure occurs.

Computational Site Saturation Mutagenesis of Canonical and Non-Canonical Amino Acids to Probe Protein-Peptide Interactions.

Technologies for discovering peptides as potential therapeutics have rapidly advanced in recent years with significant interest from both academic and pharmaceutical labs. These advancements in turn drive the need for new computational tools to design peptides for purposes of advancing lead molecules into the clinic. Here we report the development and application of a new automated tool, AutoRotLib, for parameterizing a diverse set of non-canonical amino acids (NCAAs), N-methyl, or peptoid residues for use with the computational design program Rosetta. In addition, we developed a protocol for designing thioether-cyclized macrocycles within Rosetta, due to their common application in mRNA display using the RaPID platform. To evaluate the utility of these new computational tools, we screened a library of canonical and NCAAs on both a linear peptide and a thioether macrocycle, allowing us to quickly identify mutations that affect peptide binding and subsequently measure our results against previously published data. We anticipate in silico screening of peptides against a diverse chemical space will be a fundamental component for peptide design and optimization, as more amino acids can be explored in a single in silico screen than an in vitro screen. As such, these tools will enable maturation of peptide affinity for protein targets of interest and optimization of peptide pharmacokinetics for therapeutic applications.

Comparison of logP and logD correction models trained with public and proprietary data sets.

In drug discovery, partition and distribution coefficients, logP and logD for octanol/water, are widely used as metrics of the lipophilicity of molecules, which in turn have a strong influence on the bioactivity and bioavailability of potential drugs. There are a variety of established methods, mostly fragment or atom-based, to calculate logP while logD prediction generally relies on calculated logP and pKa for the estimation of neutral and ionized populations at a given pH. Algorithms such as ClogP have limitations generally leading to systematic errors for chemically related molecules while pKa estimation is generally more difficult due to the interplay of electronic, inductive and conjugation effects for ionizable moieties. We propose an integrated machine learning QSAR modeling approach to predict logD by training the model with experimental data while using ClogP and pKa predicted by commercial software as model descriptors. By optimizing the loss function for the ClogD calculated by the software, we build a correction model that incorporates both descriptors from the software and available experimental logD data. Additionally, we calculate logP from the logD model using the software predicted pKa's. Here, we have trained models using publicly or commercial available logD data to show that this approach can improve on commercial software predictions of lipophilicity. When applied to other logD data sets, this approach extends the domain of applicability of logD and logP predictions over commercial software. Performance of these models favorably compare with models built with a larger set of proprietary logD data.

Minimally Invasive Cell-Based Therapy for Symptomatic Bone Marrow Lesions of the Knee: A Prospective Clinical Study at 1 Year.

Bone marrow lesions (BMLs) are typical findings in magnetic resonance imaging present in different pathologies, such as spontaneous insufficiency fractures, osteonecrosis, transient BML syndromes, osteoarthritis, and trauma. The etiology and evolution of BMLs in multiple conditions remain unclear. There is still no gold standard protocol for the treatment of symptomatic BMLs in the knee. The biologic augmentation by Osteo Core Plasty™ is a new treatment modality showing promising results reducing pain with the aim to stop the progression of the disease. The purpose of this prospective study is to report the clinical outcomes and safety of Osteo Core Plasty for the treatment of symptomatic BMLs in the knee. Fifteen patients with symptomatic BMLs of the knee treated with the Osteo Core Plasty technique were included and followed prospectively for a minimum of 12 months. Each patient was evaluated before the surgery and respectively at 6 and 12 months using the Tegner Score, Marx Score, the International Knee Documentation Committee, the Knee Injury and Osteoarthritis Outcome Score divided in pain, activity daily living and quality of life subscale, and the Visual Analog Scale for pain. All clinical scores except Tegner and Marx score showed an overall statistically significant improvement through the entire follow-up (P < 0.05) and a significant improvement (P < 0.05) between each follow-up period (T0 vs. T1; T0 vs. T2; T1 vs. T2). No complications were reported. These preliminary results confirm that biological subchondral bone augmentation by Osteo Core Plasty technique is a safe and effective minimally invasive treatment option for symptomatic BMLs in the knee at 1-year follow-up. There is still a need for high-quality randomized controlled trials studies and systematic reviews in the future to enhance further treatment strategies in preventing or treating BMLs of the knee.

Platelets and Adipose Stroma Combined for the Treatment of the Arthritic Knee.

Knee osteoarthritis (OA) leads to significant pain and disability, prompting new cell-based injections to lessen the symptoms. Biological therapies such as autologous microfragmented adipose tissue (AMAT) and a stromal vascular fraction (SVF) are a common source for harvesting mesenchymal and progenitor cells. Platelet-rich plasma (PRP) is associated with cytokines and growth factors. Recent studies have reported good clinical outcomes with AMAT, SVF, and PRP in knee osteoarthritis treatment. However, the preparation, processing, and application technique are vital to achieving satisfactory results. Many studies have examined outcomes after AMAT, SVF, or PRP injection, with encouraging results. Still, there is a lack of studies describing a technique that combines both methods, the timing, and the amount of SVF or PRP injected. This technical note's objective was to describe a standardized new technique composed of platelet and adipose stroma to treat knee osteoarthritis (OA) and the processing method.

Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine.

The rise in musculoskeletal disorders has prompted medical experts to devise novel effective alternatives to treat complicated orthopedic conditions. The ever-expanding field of regenerative medicine has allowed researchers to appreciate the therapeutic value of bone marrow-derived biological products, such as the bone marrow aspirate (BMA) clot, a potent orthobiologic which has often been dismissed and regarded as a technical complication. Numerous in vitro and in vivo studies have contributed to the expansion of medical knowledge, revealing optimistic results concerning the application of autologous bone marrow towards various impactful disorders. The bone marrow accommodates a diverse family of cell populations and a rich secretome; therefore, autologous BMA-derived products such as the "BMA Matrix", may represent a safe and viable approach, able to reduce the costs and some drawbacks linked to the expansion of bone marrow. BMA provides -it eliminates many hurdles associated with its preparation, especially in regards to regulatory compliance. The BMA Matrix represents a suitable alternative, indicated for the enhancement of tissue repair mechanisms by modulating inflammation and acting as a natural biological scaffold as well as a reservoir of cytokines and growth factors that support cell activity. Although promising, more clinical studies are warranted in order to further clarify the efficacy of this strategy.

A Prospective Study Comparing Leukocyte-Poor Platelet-Rich Plasma Combined with Hyaluronic Acid and Autologous Microfragmented Adipose Tissue in Patients with Early Knee Osteoarthritis.

The objective of this study was to compare the clinical efficacy of repeated doses of leucocyte-poor platelet-rich plasma (LP-PRP) plus hyaluronic acid (HA) to a single dose of autologous microfragmented adipose tissue (AMAT) injections in patients with early osteoarthritis (OA) symptoms. Eighty knees in 50 patients (mean age: 61.3 years) were randomly allocated into two equal groups in a nonblinded design and prospectively followed for 12 months. Group 1 received three intra-articular injections (1 month apart) using autologous LP-PRP+HA. Group 2 received a single dose of AMAT injection. Outcomes were measured by PROMs Tegner, Marx, visual analog scale, and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months. Both groups had significant clinical and functional improvement at 6 and 12 months. The differences between groups were statistically significant in Tegner score and KOOS symptoms (both P < 0.05) at 6 months in group 2. The test with statistically significant differences (P < 0.05) at 12 months was Tegner (P < 0.001), with group 2 having a higher median than group 1. LP-PRP+HA and AMAT lead to clinical and functional improvement at 6 and 12 months. AMAT showed better clinical results in Tegner and KOOS symptoms at 6 months and Tegner at 12 months. Understanding which therapy offers the most benefits with the least risk can significantly improve the quality of life for millions of people affected by OA. Long-term randomized controlled studies are needed to verify differences in efficacy.

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

Two-year clinical outcomes of autologous microfragmented adipose tissue in elderly patients with knee osteoarthritis: a multi-centric, international study.

PURPOSE: The aim of this study is to evaluate the outcomes of autologous microfragmented adipose tissue (MFAT) injection in elderly patients with knee osteoarthritis (OA). We hypothesized that MFAT knee infiltration for the treatment of knee OA would yield good clinical results out to two years follow-up. METHODS: Multi-centric, international, open-label study conducted by orthopedic surgery, and/or regenerative medicine facilities utilizing patient registries. Subjects recruited for eligibility. The primary outcome measure was Knee Injury and Osteoarthritis Outcome Score (KOOS). Outcomes and patient factors were compared to baseline, at six, 12, and 24 months. Statistical models were used to assess KOOS subscores and probability of exceeding the Minimally Clinically Important Difference (MCID) or Patient Acceptable Symptom State (PASS), and to assess the effect of the treatment variables on KOOS - Pain. RESULTS: Seventy-five patients, 120 primary treatments, mean age 69.6 years, (95%CI 68.3-70.9), BMI 28.4 (95%CI 27.3-29.6), with KL grade 2 to 4 knee OA treated with a single MFAT injection. KL grades 2 (15.1%), 3 (56.3%), and 4 (28.6%), with 20.8% of knees having previously undergone surgery. Patients with KL grade 2 disease had the best results in KOOS - Pain (P = 0.001), at six, 12, and 24 months. Including advanced KL grade 3 and 4 osteoarthritis patients, significant functional and quality of life success was seen in 106/120 treatments (88.3%, 66 patients) at all follow-up time points. Fourteen treatments (11.7%, 9 patients) failed prior to the study endpoint. CONCLUSION: This study shows that a single-dose MFAT injection leads to clinical, functional, and quality of life improvement at two years in elderly patients, in KL grades 2 to 4 of knee osteoarthritis. These findings provide evidence that this treatment modality could be a safe and effective option to other commonly available treatments in carefully selected patients.