Biologic agents for anterior cruciate ligament healing: A systematic review

AIM To systematically review the currently available literature concerning the application of biologic agents such as platelet-rich plasma (PRP) and stem cells to promote anterior cruciate ligament (ACL) healing. METHODS A systematic review of the literature was performed on the use of biologic agents (i.e., PRP or stem cells) to favor ACL healing during reconstruction or repair. The following inclusion criteria for relevant articles were used: Clinical reports of any level of evidence, written in English language, on the use of PRP or stem cells during ACL reconstruction/repair. Exclusion criteria were articles written in other languages, reviews, or studies analyzing other applications of PRP/stem cells in knee surgery not related to promoting ACL healing. RESULTS The database search identified 394 records that were screened. A total of 23 studies were included in the final analysis: In one paper stem cells were applied for ACL healing, in one paper there was a concomitant application of PRP and stem cells, whereas in the remaining 21 papers PRP was used. Based on the ACL injury pattern, two papers investigated biologic agents in ACL partial tears whereas 21 papers in ACL reconstruction. Looking at the quality of the available literature, 17 out of 21 studies dealing with ACL reconstruction were randomized controlled trials. Both studies on ACL repair were case series. CONCLUSION There is a paucity of clinical trials investigating the role of stem cells in promoting ACL healing both in case of partial and complete tears. The role of PRP is still controversial and the only advantage emerging from the literature is related to a better graft maturation over time, without documenting beneficial effects in terms of clinical outcome, bone-graft integration and prevention of bony tunnel enlargement

Cell-based treatment options facilitate regeneration of cartilage, ligaments and meniscus in demanding conditions of the knee by a whole joint approach

Purpose This article provides an update on the current therapeutic options for cell-based regenerative treatment of the knee with a critical review of the present literature including a future perspective on the use of regenerative cell-based approaches. Special emphasis has been given on the requirement of a whole joint approach with treatment of comorbidities with aim of knee cartilage restoration, particularly in demanding conditions like early osteoarthritis. Methods This narrative review evaluates recent clinical data and published research articles on cell-based regenerative treatment options for cartilage and other structures around the knee Results Cell-based regenerative therapies for cartilage repair have become standard practice for the treatment of focal, traumatic chondral defects of the knee. Specifically, matrix-assisted autologous chondrocyte transplantation (MACT) shows satisfactory long-term results regarding radiological, histological and clinical outcome for treatment of large cartilage defects. Data show that regenerative treatment of the knee requires a whole joint approach by addressing all comorbidities including axis deviation, instability or meniscus pathologies. Further development of novel biomaterials and the discovery of alternative cell sources may facilitate the process of cell-based regenerative therapies for all knee structures becoming the gold standard in the future. Conclusion Overall, cell-based regenerative cartilage therapy of the knee has shown tremendous development over the last years and has become the standard of care for large and isolated chondral defects. It has shown success in the treatment of traumatic, osteochondral defects but also for degenerative cartilage lesions in the demanding condition of early OA. Future developments and alternative cell sources may help to facilitate cell-based regenerative treatment for all different structures around the knee by a whole joint approach

Biological Reconstruction of Localized Full-Thickness Cartilage Defects of the Knee: A Systematic Review of Level 1 Studies with a Minimum Follow-Up of 5 Years

Objective The objective of this study was to evaluate the best available mid- to long-term evidence of surgical procedures for the treatment of localized full-thickness cartilage defects of the knee. Design Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of Level 1 randomized clinical trials (RCTs), meta-analyses of RCTs and systematic reviews with a minimum follow-up of 5 years. Data extracted included patient demographics, defect characteristics, clinical and radiological outcomes, as well as treatment failures. Results Six RCTs and 3 Level 1 systematic reviews were included. Two RCTs compared microfracture (MFx) to periosteum-covered autologous chondrocyte implantation (ACI-P), 1 to matrix-associated ACI (M-ACI) and 2 to osteochondral autograft transplantation (OAT). One study compared OAT to collagen membrane covered ACI (ACI-C). The 3 Level 1 systematic reviews/meta-analyses assessed the outcome of MFx, OAT, and various ACI methods in RCTs. OAT showed significantly better outcomes compared with MFx. In the 2 RCTs comparing ACI-P and MFx, no significant differences in clinical outcomes were seen, whereas significantly better outcomes were reported for M-ACI versus MFx in 1 study including patients with larger defects (5 cm2), and for ACI-C versus OAT in terms of Cincinnati Score. Higher failure rates were reported for MFx compared with OAT and for OAT compared with ACI-C, while no significant differences in failure rates were observed for ACI-P compared to MFx. Conclusion Restorative cartilage procedures (ACI-C or M-ACI and OAT) are associated with better long-term clinical outcomes including lower complication and failure rates when compared with reparative techniques (MFx). Among the restorative procedures, OAT seems to be inferior to ACI especially in larger defects after longer follow-up periods. Level of evidence: Level I: Systematic review of Level I studie

The Importance of Physioxia in Mesenchymal Stem Cell Chondrogenesis and the Mechanisms Controlling Its Response

Articular cartilage covers the surface of synovial joints and enables joint movement. However, it is susceptible to progressive degeneration with age that can be accelerated by either previous joint injury or meniscectomy. This degenerative disease is known as osteoarthritis (OA) and it greatly affects the adult population. Cell-based tissue engineering provides a possible solution for treating OA at its earliest stages, particularly focal cartilage lesions. A candidate cell type for treating these focal defects are Mesenchymal Stem Cells (MSCs). However, present methods for differentiating these cells towards the chondrogenic lineage lead to hypertrophic chondrocytes and bone formation in vivo. Environmental stimuli that can stabilise the articular chondrocyte phenotype without compromising tissue formation have been extensively investigated. One factor that has generated intensive investigation in MSC chondrogenesis is low oxygen tension or physioxia (2–5% oxygen). In vivo articular cartilage resides at oxygen tensions between 1–4%, and in vitro results suggest that these conditions are beneficial for MSC expansion and chondrogenesis, particularly in suppressing the cartilage hypertrophy. This review will summarise the current literature regarding the effects of physioxia on MSC chondrogenesis with an emphasis on the pathways that control tissue formation and cartilage hypertrophy

Orthopaedic surgeons display a positive outlook towards artificial intelligence: A survey among members of the AGA Society for Arthroscopy and Joint Surgery.

PURPOSE The purpose of this study was to evaluate the perspective of orthopaedic surgeons on the impact of artificial intelligence (AI) and to evaluate the influence of experience, workplace setting and familiarity with digital solutions on views on AI. METHODS Orthopaedic surgeons of the AGA Society for Arthroscopy and Joint Surgery were invited to participate in an online, cross-sectional survey designed to gather information on professional background, subjective AI knowledge, opinion on the future impact of AI, openness towards different applications of AI, and perceived advantages and disadvantages of AI. Subgroup analyses were performed to examine the influence of experience, workplace setting and openness towards digital solutions on perspectives towards AI. RESULTS Overall, 360 orthopaedic surgeons participated. The majority indicated average (43.6%) or rudimentary (38.1%) AI knowledge. Most (54.5%) expected AI to substantially influence orthopaedics within 5-10 years, predominantly as a complementary tool (91.1%). Preoperative planning (83.8%) was identified as the most likely clinical use case. A lack of consensus was observed regarding acceptable error levels. Time savings in preoperative planning (62.5%) and improved documentation (81%) were identified as notable advantages while declining skills of the next generation (64.5%) were rated as the most substantial drawback. There were significant differences in subjective AI knowledge depending on participants' experience (p = 0.021) and familiarity with digital solutions (p < 0.001), acceptable error levels depending on workplace setting (p = 0.004), and prediction of AI impact depending on familiarity with digital solutions (p < 0.001). CONCLUSION The majority of orthopaedic surgeons in this survey anticipated a notable positive impact of AI on their field, primarily as an assistive technology. A lack of consensus on acceptable error levels of AI and concerns about declining skills among future surgeons were observed. LEVEL OF EVIDENCE Level IV, cross-sectional study

Physioxia Has a Beneficial Effect on Cartilage Matrix Production in Interleukin-1 Beta-Inhibited Mesenchymal Stem Cell Chondrogenesis

Osteoarthritis (OA) is a degenerative condition that involves the production of inflammatory cytokines (e.g., interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)) that stimulate degradative enzymes, matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) resulting in articular cartilage breakdown. The presence of interleukin-1 beta (IL-1 beta) is one reason for poor clinical outcomes in current cell-based tissue engineering strategies for treating focal early osteoarthritic defects. Mesenchymal stem cells (MSCs) are a potential cell source for articular cartilage regeneration, although IL-1 beta has been shown to inhibit in vitro chondrogenesis. In vivo, articular chondrocytes reside under a low oxygen environment between 2-5% oxygen (physioxia) and have been shown to enhance in vitro MSC chondrogenic matrix content with reduced hypertrophic marker expression under these conditions. The present investigation sought to understand the effect of physioxia on IL-1 beta inhibited MSC chondrogenesis. MSCs expanded under physioxic (2% oxygen) and hyperoxic (20%) conditions, then chondrogenically differentiated as pellets in the presence of TGF-beta 1 and either 0.1 or 0.5 ng/mL IL-1 beta. Results showed that there were donor variations in response to physioxic culture based on intrinsic GAG content under hyperoxia. In physioxia responsive donors, MSC chondrogenesis significantly increased GAG and collagen II content, whilst hypertrophic markers were reduced compared with hyperoxia. In the presence of IL-1 beta, these donors showed a significant increase in cartilage matrix gene expression and GAG content relative to hyperoxic conditions. In contrast, a set of MSC donors were unresponsive to physioxia and showed no significant increase in matrix production independent of IL-1 beta presence. Thus, physioxia has a beneficial effect on MSC cartilage matrix production in responsive donors with or without IL-1 beta application. The mechanisms controlling the MSC chondrogenic response in both physioxia responsive and unresponsive donors are to be elucidated in future investigations

Fibronectin Adherent Cell Populations Derived From Avascular and Vascular Regions of the Meniscus Have Enhanced Clonogenicity and Differentiation Potential Under Physioxia

The meniscus is composed of an avascular inner region and vascular outer region. The vascular region has been shown to contain a progenitor population with multilineage differentiation capacity. Strategies facilitating the isolation and propagation of these progenitors can be used to develop cell-based meniscal therapies. Differential adhesion to fibronectin has been used to isolate progenitor populations from cartilage, while low oxygen or physioxia (2% oxygen) enhances the meniscal phenotype. This study aimed to isolate progenitor populations from the avascular and vascular meniscus using differential fibronectin adherence and examine their clonogenicity and differentiation potential under hyperoxia (20% oxygen) and physioxia (2% oxygen). Human vascular and avascular meniscus cells were seeded onto fibronectin-coated dishes for a short period and monitored for colony formation under either hyperoxia or physioxia. Non-fibronectin adherent meniscus cells were also expanded under both oxygen tension. Individual fibronectin adherent colonies were isolated and further expanded, until approximately ten population doublings (passage 3), whereby they underwent chondrogenic, osteogenic, and adipogenic differentiation. Physioxia enhances clonogenicity of vascular and avascular meniscus cells on plastic or fibronectin-coated plates. Combined differential fibronectin adhesion and physioxia isolated a progenitor population from both meniscus regions with trilineage differentiation potential compared to equivalent hyperoxia progenitors. Physioxia isolated progenitors had a significantly enhanced meniscus matrix content without the presence of collagen X. These results demonstrate that combined physioxia and fibronectin adherence can isolate and propagate a meniscus progenitor population that can potentially be used to treat meniscal tears or defects

Partial Anterior Cruciate Ligament Ruptures: Advantages by Intraligament Autologous Conditioned Plasma Injection and Healing Response Technique—Midterm Outcome Evaluation

The historical treatment options for partial anterior cruciate ligament (ACL) ruptures were conservative therapy or ACL reconstruction by injured bundle or entire ACL replacement. In awareness of the regenerative potential of biologic agents such as mesenchymal stem cells or platelet rich plasma (PRP), the healing response technique was developed to preserve the injured ACL with belter outcomes lhan ihe conservative therapy. Further improvement of this technique seems to be obtained by the additional application of PRP products. Thus, the aim of this study was to evaluate the midterm outcome after intraligament autologous conditioned plasma (ACP) by a clinical, scoring, and functional performance assessment. 42 patients were evaluated in this study. The failure rate was 9.5%. Outcome evaluation showed good to excellent results. The scores were IKDC subjective 83.2 (SD 14.5), Lysholm 85.5 (SD 15.5), Tegner 4.7 (SD 1.7), and Cincinnati 85.4 (SD 15.5) afler a mean follow-up of 33 months. Clinical examination showed stable Lachman tesl, negative pivot shift phenomenon, and a significant reduction in AP-laxity compared to preoperative status (rolimeter preoperative: 1.9 (SD1.4); postoperative 0.6 (SD1.8), p=0.001) in all patients. Functional performance testing showed no significant differences between the injured and healthy side. Return to sport was achieved after a mean of 5.8 months (SD 3.6) in 71.1% of the included patients. In summary, this new treatment option revealed in midterm follow-up promising results to treat partial ACL lesions with a reduced need for conversion to ACL reconstruction and with a high percentage of return to preinjury sport activity

Early Functional Rehabilitation after Meniscus Surgery: Are Currently Used Orthopedic Rehabilitation Standards Up to Date?

Meniscus therapy is a challenging process. Besides the respective surgical procedure such as partial meniscectomy, meniscus repair, or meniscus replacement, early postoperative rehabilitation is important for meniscus regeneration and return to sport and work as well as long-term outcome. Various recommendations are available. However, the current literature lacks information concerning the actual early rehabilitation in daily routine recommended by orthopedic surgeons. Thus, the purpose of this study was to investigate currently used standard early rehabilitation protocols in the daily routine of orthopedic surgeons. This study investigated the recommendations and concepts for early rehabilitation after meniscus therapy given by German, Austrian, and Swiss orthopedic institutions. Standardized criteria such as weight bearing, range of motion, use of an orthosis, and rehabilitation training were analyzed according to the conducted surgical procedure: partial meniscectomy, meniscus repair, or meniscus replacement. The analysis of standard rehabilitation concepts for partial meniscectomy (), meniscus repair (), and meniscus replacement () showed significantly earlier functional rehabilitation in all criteria after partial meniscectomy in contrast to meniscus repair techniques (). In addition, significant restrictions were found in full weight bearing, full range of motion, and the use of braces. In summary, a wide range of recommendations for weight bearing, ROM, brace therapy, and mobilization is available, particularly after meniscus repair and meniscus replacement. Most concepts are in accordance with those described in the current literature. Further research is necessary to enhance the scientific evidence on currently used early rehabilitation concepts after meniscus therapy