Biological tissue aging: mechanisms and impact
Biological tissue aging is closely linked to the progressive development of degenerative conditions such as osteoarthritis (OA), which is described as the most common complex musculoskeletal disorder and is characterized by degeneration of the articular cartilage, joint pain, dysfunction, and progressive loss of cartilage. In weight-bearing joints such as the hips and knees, chronic mechanical stress contributes to structural deterioration of cartilage and subchondral bone, leading to restricted movement, swelling, and disability with a consequent deterioration in quality of life. Age, heredity, lifestyle, obesity, and local biomechanical factors such as joint laxity or malalignment are reported as relevant risk factors that modulate the onset and progression of degenerative joint disease.
In OA, joint degeneration is described as an active disease process characterized by an imbalance between tissue repair and destruction, with poor intrinsic healing power and regeneration. This limited regenerative capacity is related to poor vascularization of articular cartilage and the absence of direct access to progenitor cells from the bone marrow in the joint compartment. As degeneration progresses, radiographic changes such as joint space narrowing, osteophyte formation, subchondral sclerosis, and cysts can be graded using systems such as the Kellgren–Lawrence classification for the knee and the Tönnis grading scale for the hip, which describe a continuum from no signs of osteoarthritis to severe deformity and avascular necrosis.
The clinical impact of tissue aging and degeneration in OA is reflected in pain, stiffness, and functional limitation. Patients typically present with joint pain, swelling, morning stiffness, and progressively restricted movements, which translate into major disability and impaired quality of life. Conventional conservative treatments for OA, including physical therapy, weight loss, lifestyle modification, pharmacologic therapies, steroid injections, and intra-articular hyaluronic acid, are largely palliative and do not reverse or repair the degenerative nature of the disease. As a result, many patients ultimately progress to surgical interventions such as joint replacement when structural damage and symptoms become severe.
Beyond the joint, aging of mesenchymal tissues is associated with changes in the cellular and extracellular compartments that influence regenerative potential. Mesenchymal stromal cells, including adipose-derived stromal/stem cells (ASCs), are present in many tissues and exhibit differentiation and paracrine properties that support tissue homeostasis and repair. With aging and chronic degeneration, the balance between catabolic and anabolic signals in these tissues is altered, and the local microenvironment becomes less favorable for spontaneous regeneration. This biological context has stimulated interest in autologous regenerative strategies that aim to harness viable stromal and progenitor cell populations, together with their associated extracellular matrix (ECM) and bioactive factors, to counteract degenerative changes in aged tissues.
Loss of regenerative capacity with age
The loss of regenerative capacity in aged tissues is exemplified by the poor intrinsic healing of osteoarthritic joints, where degeneration predominates over repair. OA is described as an active process with an imbalance between repair and destruction, and joints affected by OA show poor vascularization and lack direct access to bone marrow progenitor cells, limiting spontaneous regeneration. In advanced radiographic grades, such as Tönnis grade 3 for the hip, large cysts, severe joint space narrowing, severe deformity of the femoral head, and avascular necrosis are observed, indicating profound structural compromise that the tissue cannot adequately repair.
Clinically, this reduced regenerative capacity manifests as persistent pain, stiffness, and functional decline despite standard conservative measures. Goals of conservative OA management are largely palliative, focusing on relieving pain, slowing decline, improving biomechanics, and delaying arthroplasty, rather than restoring normal tissue structure. None of the commonly used conservative treatments, including intra-articular hyaluronic acid or steroid injections, have been shown in these reports to reverse the degenerative nature of OA. This therapeutic gap underscores the limited capacity of aged joint tissues to regenerate under usual clinical conditions.
At the cellular level, mesenchymal stromal cells such as adipose-derived stem cells (ADSCs) retain multipotent differentiation capacity and secrete bioactive molecules with angiogenic, antifibrotic, antiapoptotic, and immunomodulatory properties. However, in chronically degenerated tissues, the local environment is characterized by ongoing inflammation, mechanical overload, and matrix degradation, which can impair the effectiveness of endogenous repair mechanisms. In OA, cartilage avascularity and the lack of direct progenitor cell access further limit the recruitment and activity of reparative cells at the site of damage.
Despite these constraints, clinical and preclinical work with autologous adipose tissue suggests that viable stromal and progenitor cells can be harvested from adult patients, including middle-aged and older individuals, and remain capable of proliferation and differentiation. Studies evaluating adipose tissue harvested with small-port cannulas or micro-superficial enhanced fluid fat injection (micro-SEFFI) systems have demonstrated that lipoaspirate samples contain viable mesenchymal stromal cells with preserved proliferation and multilineage differentiation potential. These findings indicate that, even in the context of tissue aging, autologous adipose tissue can serve as a reservoir of regenerative cells that may be mobilized therapeutically to compensate for local loss of regenerative capacity in degenerated tissues.
Rationale for autologous regenerative use
Autologous Regenerative Therapy (ART) is described as an innovative medical discipline that aims to regenerate injured tissues or stimulate their repair using the patient’s own cells, following principles of tissue engineering in an easy, reproducible, and relatively rapid procedure. The technique utilizes autologous mesenchymal stem/stromal cells (MSCs), particularly those derived from adipose tissue, in a single medical session. The rationale for autologous use is grounded in the multipotent nature of MSCs, whose differentiation is guided by signals from the surrounding environment and specific growth factors, making them suitable elements to support healing in lesions involving different tissues.
Adipose tissue has been identified as a rich and accessible source of multipotent MSCs, similar to those found in bone marrow. Adipose-derived stem cells are especially concentrated in the stromal vascular fraction (SVF) of adipose tissue and have been widely used in orthopedic and regenerative applications due to their intrinsic capacity to support regeneration of cartilage, tendons, and bone. ADSCs can differentiate into multiple lineages, including adipocytes, chondrocytes, myocytes, hepatocytes, and endothelial cells, and they secrete bioactive molecules that stimulate angiogenesis and exert antifibrotic, antiapoptotic, and immunomodulatory effects. These properties provide a mechanistic basis for their use in degenerative conditions associated with tissue aging.
Regenerative therapy based on the injection of micro-fragmented adipose tissue is described as a promising treatment for degenerative diseases or disorders that are not adequately managed with conventional care, and it is also considered a promising approach in antiaging therapy. This strategy exploits the properties of SVF cells naturally present in adipose tissue, including MSCs, pericytes, endothelial progenitor cells, and adipocyte progenitors, which together form an interrelated cell population with regenerative potential. The minimally invasive harvesting and minimal manipulation of adipose tissue can yield micro-fragmented grafts with a good amount of viable cells, supporting their use as a regenerative substrate.
In the context of osteoarthritis, intra-articular injection of autologous micro-fragmented adipose tissue has been applied as a means to deliver ADSCs, cytokines, growth factors, pre-adipocytes, and mature adipocytes directly into the degenerated joint. The approach is based on the belief in the reparative effect of autologous fat grafts on damaged tissue and their natural lubricating effect within the joint space. Clinical experience with hip and knee OA suggests that such autologous regenerative treatments can be performed in a standardized, relatively simple session and may improve pain, range of motion, stiffness, and quality of life, while being well tolerated due to the autologous nature of the injected material.
Cellular and extracellular components involved
Autologous adipose tissue used for regenerative purposes contains a complex mixture of cellular and extracellular components. The key cellular elements include adipose-derived stem cells (ADSCs), which reside predominantly in the stromal vascular fraction and exhibit multipotent differentiation capacity toward adipogenic, chondrogenic, osteogenic, myogenic, hepatogenic, and endothelial lineages. In addition to ADSCs, the SVF contains adipocyte progenitors, pericytes, endothelial progenitor cells, and transit-amplifying cells, forming an interrelated population that contributes to tissue repair and neovascularization.
These stromal cells display antifibrotic, antiapoptotic, immunomodulatory, and pro-angiogenic properties, which are thought to underlie several observed clinical effects of adipose tissue grafting, such as improved skin trophism, accelerated closure of complex wounds or ulcers, and enhanced skin appearance after radiotherapy damage. In the joint environment, similar paracrine mechanisms may support cartilage and synovial homeostasis, modulate inflammation, and promote microvascular support to subchondral and periarticular tissues. The presence of mature adipocytes and pre-adipocytes in the graft also contributes to volumetric and mechanical effects, including lubrication in intra-articular applications.
The extracellular matrix (ECM) within adipose tissue provides a structural scaffold and biochemical milieu that influence stromal cell behavior. Studies on marrow-derived ECM have shown that decellularized matrices can modulate MSC proliferation, migration, and differentiation potential, highlighting the importance of ECM composition in maintaining stem cell function. In adipose-derived preparations such as SEFFI and micro-SEFFI, microscopic and analytical characterization has revealed tissue structures composed of small fat clusters, ECM fragments, and cell aggregates, with high fluidity suitable for injection. These ECM components may help preserve cell viability and provide a supportive microenvironment after grafting.
Harvesting and processing techniques significantly influence the cellularity and ECM characteristics of autologous adipose grafts. Comparative studies have shown that adipose tissue harvested with small-port cannulas (0.8–1 mm side holes) yields viable tissue with cell viability comparable to that obtained from standard liposuction followed by enzymatic digestion, with an increase in cell viability observed over time in culture. Micro-SEFFI systems using even smaller side portholes (0.3–0.5 mm) produce highly fluid micrografts with reduced cluster size, facilitating superficial and precise injections while still allowing isolation of mesenchymal stromal cells that retain proliferation and differentiation capacity. Together, these data support the concept that minimally manipulated micro-fragmented adipose tissue provides a combination of viable stromal cells and ECM suitable for autologous regenerative applications in aged and degenerated tissues.
Therapeutic targets in aged tissues
In the context of tissue aging and degeneration, key therapeutic targets for autologous regenerative approaches include structural cartilage defects, subchondral bone changes, synovial inflammation, and periarticular soft tissue degeneration. In osteoarthritis, degeneration of articular cartilage with progressive loss of cartilage thickness and integrity is central to symptom development and functional decline. Autologous adipose-derived SVF and micro-fragmented adipose tissue have been applied intra-articularly with the aim of supporting cartilage repair and modulating the joint microenvironment, leveraging the chondrogenic potential and paracrine activity of ADSCs.
Tendons, ligaments, and periarticular soft tissues are also affected by aging and degenerative processes, contributing to pain, instability, and impaired biomechanics. ADSCs and SVF cells have been used in orthopedic fields thanks to their intrinsic capacity to regenerate cartilage, tendons, and bones, indicating that these structures are relevant therapeutic targets for autologous regenerative therapy. Intra-articular and periarticular delivery of micro-fragmented adipose tissue may therefore address not only cartilage surfaces but also supporting soft tissues that are critical for joint stability and function.
Beyond the musculoskeletal system, micro-fragmented adipose tissue has been used to improve skin trophism, accelerate closure of complex wounds and ulcers, and enhance skin appearance after radiotherapy, indicating that aged or damaged cutaneous and subcutaneous tissues are important targets for autologous regenerative interventions. In aesthetic and antiaging contexts, autologous fat grafting and SVF/ASC-enriched fat grafts have been applied to restore facial volume and improve skin quality, with micrograft techniques enabling treatment of areas with varying skin thickness.
Urogenital tissues have also been explored as targets for adipose-derived regenerative therapies. For example, injection of micro-fragmented adipose tissue has been reported as a promising therapy in gynecologic conditions such as genitourinary syndrome of menopause, and periurethral injection of autologous adipose-derived regenerative cells has been investigated for male stress urinary incontinence. These applications highlight the broader concept that aged or functionally compromised soft tissues, including mucosal, muscular, and connective tissue compartments, may benefit from the trophic and structural support provided by autologous adipose-derived cell and tissue preparations.
Evidence from preclinical and clinical use
Clinical evidence for autologous adipose-derived therapies in tissue aging and degeneration includes observational studies and clinical experiences in osteoarthritis and aesthetic or reconstructive indications. In a retrospective observational study of 250 patients with hip and knee OA treated with intra-articular injection of autologous fat micrograft using a SEFFI-based device, the procedure was described as safe, standardized, and effective, with a mean patient age of 52.4 years and inclusion of individuals with initial-stage degenerative OA. Patients underwent radiographic and MRI evaluation before treatment and were followed at 1, 3, 6, and 12 months postoperatively.
Clinically, the range of motion of treated knees and hips increased by an average of 10 degrees at 3 months, and patients reported reduced stiffness. Visual Analog Scale (VAS) scores demonstrated progressive pain reduction, with the best scores at 6 months postoperatively, and continued benefit up to 6–12 months in hips. In this cohort, 85% of patients reported satisfaction one year after treatment, with considerable improvement in pain and quality of life, and only a small proportion proceeded to joint replacement over longer follow-up. The donor site course was uneventful aside from minimal discomfort, edema, and ecchymosis, and the injected joints showed only transient swelling and low-grade pain for 3–7 days, with no reported infections or major complications.
The same study concluded that autologous adipose-derived SVF for OA treatment was safe and feasible, with a low complication rate, and suggested that treatment with mesenchymal stem cells could be considered an option for improving quality of life in patients with mild or moderate OA, or in more severe cases for patients who refuse surgical treatment. The authors noted that results were variable and not yet predictable and highlighted limitations such as the retrospective design, absence of a control group, limited sample size, and the need for longer follow-up and further studies.
Preclinical and translational evidence supports the biological plausibility of these clinical findings. Studies comparing harvesting and processing techniques for adipose tissue grafts have shown that guided harvesting with small-port cannulas yields micro-fragmented adipose tissue containing viable and proliferative cells, with cell viability comparable to enzymatically digested SVF preparations. Characterization of SEFFI and micro-SEFFI-derived tissues has demonstrated the presence of mesenchymal stromal cells with preserved proliferation and differentiation toward adipogenic, osteogenic, and chondrogenic lineages, supporting their regenerative potential in musculoskeletal and soft tissue applications. Collectively, these data indicate that autologous adipose-derived therapies represent a feasible and biologically grounded approach to address tissue aging and degeneration, while underscoring the need for controlled clinical trials and standardized protocols to better define indications, outcomes, and long-term safety.
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