Stages Of Tissue Repair Research Articles

Diagnosis and Treatment Based on Functional Movement Impairment: A New Model of Functional Restoration Directed to Correction of Pathoanatomic and Pathophysiology of Tissues-Part I

One of the most prevalent diseases in humans is musculoskeletal dysfunction. The source of these problems is usually multifactorial, including mechanical, psychological, and chemical. A specific diagnosis is rarely achieved for most musculoskeletal disorders, especially chronic conditions. This can be one of the reasons for the ineffectiveness of the various treatments offered. Various models have been proposed to address this problem to make more accurate diagnoses and effective treatments. Each of these models has its limitations. It seems that the previous models had limited information, such as the type of damaged tissue, the stage of tissue repair, the functional aspect of the disorder, other parts of the movement chain disorder, psychological features, and a lack of correlation between medical diagnosis and physiotherapy diagnosis. In the present study, an attempt is made to provide a new and more comprehensive model by considering the limitations of other models. In the first step, the therapist or physician identifies the biomechanical source of the disorder. The patient’s functional movement impairments are identified, and a Neuro-Musculo-Skeletal disorder related to functional movement impairment is assessed. Finally, to label the patient’s problem, medical (Patho-Anatomical Model) and physical therapy (Movement System Classification Models) views are considered. Therefore, the medical diagnosis of the patient is expressed along with the joints that play a role in aggravating the patient’s symptoms with movement. One case study is provided at the end to clarify the method of diagnosis. Future research is necessary to improve the validity of the methodology.

Bioactive nanomaterials kickstart early repair processes and potentiate temporally modulated healing of healthy and diabetic wounds

Slow-healing and chronic wounds represent a major global economic and medical burden, and there is significant unmet need for novel therapies which act to both accelerate wound closure and enhance biomechanical recovery of the skin. Here, we report a new approach in which bioactives that augment early stages of wound healing can kickstart and engender effective wound closure in healthy and diabetic, obese animals, and set the stage for subsequent tissue repair processes. We demonstrate that a nanomaterial dressing made of silk fibroin and gold nanorods (GNR) stimulates a pro-neutrophilic, innate immune, and controlled inflammatory wound transcriptomic response. Further, Silk-GNR, lasered into the wound bed, in combination with exogeneous histamine, accelerates early-stage processes in tissue repair leading to effective wound closure. Silk-GNR and histamine enhanced biomechanical recovery of skin, increased transient neoangiogenesis, myofibroblast activation, epithelial-to-mesenchymal transition (EMT) of keratinocytes and a pro-resolving neutrophilic immune response, which are hitherto unknown activities for these bioactives. Predictive and temporally coordinated delivery of growth factor nanoparticles that modulate later stages of tissue repair further accelerated wound closure in healthy and diabetic, obese animals. Our approach of kickstarting healing by delivering the “right bioactive at the right time” stimulates a multifactorial, pro-reparative response by augmenting endogenous healing and immunoregulatory mechanisms and highlights new targets to promote tissue repair.

Preferential stimulation of melanocytes by M2 macrophages to produce melanin through vascular endothelial growth factor

Post-inflammatory hyperpigmentation is a skin discoloration process that occurs following an inflammatory response or wound. As the skin begins to heal, macrophages first exhibit a proinflammatory phenotype (M1) during the early stages of tissue repair and then transition to a pro-healing, anti-inflammatory phenotype (M2) in later stages. During this process, M1 macrophages remove invading bacteria and M2 macrophages remodel surrounding tissue; however, the relationship between macrophages and pigmentation is unclear. In this study, we examined the effect of macrophages on melanin pigmentation using human induced pluripotent stem cells. Functional melanocytes were differentiated from human induced pluripotent stem cells and named as hiMels. The generated hiMels were then individually cocultured with M1 and M2 macrophages. Melanin synthesis decreased in hiMels cocultured with M1 macrophages but significantly increased in hiMels cocultured with M2 macrophages. Moreover, the expression of vascular endothelial growth factor was increased in M2 cocultured media. Our findings suggest that M2 macrophages, and not M1 macrophages, induce hyperpigmentation in scarred areas of the skin during tissue repair.

17 A Tissue-engineered Bi-layer Skin Substitute Polarizes Macrophages Towards an M2 Phenotype

IntroductionCellular and/or Tissue Product made of stratified keratinocyte-containing epidermis and fibroblast-embedded collagen dermis, has been shown to promote healing in patients with deep partial- thickness burns. The biological mechanisms behind these effects are poorly understood. Macrophages, the primary cell type of the innate immune system, are major regulators of all stages of tissue repair. They accomplish these diverse functions by shifting phenotype throughout the healing process from a pro- inflammatory population to a diverse population of phenotypes that orchestrate resolution of inflammation and healing. In burn injuries this transition is impaired. We hypothesized that skin substitutes promote this healthy transition in macrophage phenotype. The aim of this study was to analyze the crosstalk between skin substitutes and macrophages and to determine the influence of direct contact, secreted factors, and the substrate used in fabrication of the skin substitutes.MethodsPrimary human macrophages (N=4 donors) were co-cultured either directly or indirectly with a skin substitute via separation by transwell inserts. Macrophages were also cultured directly on the collagen scaffolds used in the skin substitute fabrication process or on low-activation plastic as an unactivated control. After 1 and 3 days, the macrophages were stained with a 10-marker flow cytometry panel to characterize macrophage phenotype: general marker (CD45), M1-related markers (CCR7, CD80, CD38 and PD-L1) and M2-related markers (CD206, CD209, CD163 and CXCR4). For a more thorough evaluation, multidimensional analysis was used to identify unique populations of macrophages. Large-scale Dimensionality reduction using triplets and clustering analysis with using FlowSOM algorithms were performed. Statistical analysis of individual marker expression or cell composition within clusters was performed with one-way ANOVA.ResultsIn response to both direct and indirect interaction with skin substitutes, macrophages generally decreased M1 marker expression after 1 day in culture and increased M2 marker expression after 3 days. The suppression of M1 markers occurred when macrophages were co-cultured with skin substitutes, and in response to acellular collagen. The upregulation of M2 markers occurred only in response to direct or indirect interaction with cellular skin substitutes. Furthermore, multidimensional single cell analysis showed that contact with the skin substitutes also promoted unique populations of phenotypes that do not fit into the classical M1/M2 paradigm.ConclusionsThese results suggest that a potential mechanism by which skin substitutes promote healing is by promoting a transition of macrophages towards pro-reparative phenotypes.

Inflammation and Bone Repair: From Particle Disease to Tissue Regeneration.

When presented with an adverse stimulus, organisms evoke an immediate, pre-programmed, non-specific innate immune response. The purpose of this reaction is to maintain the organism's biological integrity and function, mitigate or eradicate the injurious source, and re-establish tissue homeostasis. The initial stage of this protective reaction is acute inflammation, which normally reduces or terminates the offending stimulus. As the inflammatory reaction recedes, the stage of tissue repair and regeneration follows. If the above sequence of events is perturbed, reconstitution of normal biological form and function will not be achieved. Dysregulation of these activities may result in incomplete healing, fibrosis, or chronic inflammation. Our laboratory has studied the reaction to wear particles from joint replacements as a paradigm for understanding the biological pathways of acute and chronic inflammation, and potential translational treatments to reconstitute lost bone. As inflammation is the cornerstone for healing in all anatomical locations, the concepts developed have relevance to tissue engineering and regenerative medicine in all organ systems. To accomplish our goal, we developed novel in vitro and in vivo models (including the murine femoral continuous intramedullary particle infusion model), translational strategies including modulation of macrophage chemotaxis and polarization, and methods to interfere with key transcription factors NFκB and MyD88. We purposefully modified MSCs to facilitate bone healing in inflammatory scenarios: by preconditioning the MSCs, and by genetically modifying MSCs to first sense NFκB activation and then overexpress the anti-inflammatory pro-regenerative cytokine IL-4. These advancements provide significant translational opportunities to enhance healing in bone and other organs.

BIOMODULATORY POTENTIAL OF LOW-LEVEL LASER ON NEOANGIOGENESIS AND REMODELING TISSUE. A LITERATURE REVIEW

Introduction: In recent years, cellular biostimulation induced by low-level laser therapy has been widely studied. Among some of the processes stimulated by low-level laser are cell cycle, phenotypic modulation as well as vascular changes, such as vasodilation and neoangiogenesis. The increased number of new blood vessels accelerates inflammation, and also increases wound healing. Neoangiogenesis is still an important process of tissue repair, since it always precedes collagen synthesis and matrix extracellular remodeling. Increasing scientific evidence has shown that photobiomodulation stimulates neoangiogenesis, fibroblast proliferation and collagen biosynthesis. Objective: Review the literature about the effects of low level laser therapy on neoangiogenesis and fibroplasia and describe how these processes occur in the tissue subjected to an injury. Methods and Matereials: The search tool used was the Medline / Pubmed and the following keywords were used: remodeling, wound healing, neoangiogenesis, fibroplasia, laser therapy, low-level laser. Manuscripts published from 1990 to 2017 were selected. Results: Increasing scientific evidence has shown that photobiomodulation stimulates neoangiogenesis, fibroblast proliferation and collagen biosynthesis. Conclusion: Neoangiogenesis always precedes collagen synthesis and matrix extracellular remodeling. However, little is known of the action of laser therapy in the late stages of tissue repair.

THE DYNAMIC OF THE ENERGY METABOLISM OF THE CELLS OF WHITE RATS SKIN CONNECTIVE TISSUE UNDER CONDITIONS OF THE BURN INJURY AND HYPERGLYCEMIA

Relevance. Macrophages exist in the wound in several phenotypic states, and the effect of these cells on intercellular co-operation at each stage of tissue repair depends on their specific phenotype. Depending on the microenvironment, they can quickly change their functional phenotype from proinflammatory M1 to anti-inflammatory M2, and vice versa. However, the effect of the functional phenotype of macrophages on cellular metabolism is not unilateral, the change in the features of metabolism, especially energy, also significantly affects the phenotype of cells.
 Objective. The aim of this work is to analyze the oxidoreductases activity of neutrophils, macrophages and fibroblasts in the connective tissue of the white rats skin under conditions of local thermal damage when there is a carbohydrate metabolism violation to predict the efficiency of the tissue regeneration during the repair process.
 Material and methods. There were carried out the histochemical and pathomorphological researches of the skin burn wound healing dynamic (3, 7, 14, 21 days) of the white mature male rats (Wistar line) with the weight of 180-210g without somatic pathology (control group, n=28) and with stable uncorrected hyperglycemia modeled by streptozotocin (n=28). It has been carried out the histochemical study of oxidoreductase enzymes activity on the cryostat sections (10 μm thickness): succinate dehydrogenase (SDH), lactate dehydrogenase (LDH), NADH- dehydrogenase (NADH-DH). The histochemical index of the oxidoreductase enzymes activity was being calculated by the semi-quantitative method.
 Results. The study of the cells’ quantitative changes in the connective tissue regenerate and the reactions of energy metabolism against the background of hyperglycemia has some features. The consistency of the connective tissue infiltration by the leukocytes of different types during reparative regeneration after burn injury was being happened in a classical scenario with a quantitative predominance of cells in a group of animals without somatic pathology that points to the reduction of blood reactivity under conditions of glycemia. In the dynamics of the healing process the change of the LDH and NADH-DH activity in the macrophages and fibroblasts had a tendency to increase on the 7th and 14th days of the experiment and differed significantly during observation from the parameters in the 3d day (p<0,05). The most exemplary for study of the dynamics of the oxidation-reduction enzymes activity in the cells of the regenerate was the ratio of SDH/LDH. Comparing the data of the control group of animals and under conditions of hyperglycemia the most expressed and multidirectional changes of the oxidation-reduction enzymes’ activity occurred in macrophages in the different phases of the reparative process.
 Conclusions. We believe that such differences can indirectly indicate the untimely change of the macrophages’ functional phenotype during restorative processes in the tissues. So as the macrophages are the "main conductor" of intercellular relationships it is suggested that this mechanism may be one of the reasons for the ineffective wound healing under diabetes mellitus.

THE DYNAMIC OF THE ENERGY METABOLISM OF THE CELLS OF WHITE RATS SKIN CONNECTIVE TISSUE UNDER CONDITIONS OF THE BURN INJURY AND HYPERGLYCEMIA

Relevance. Macrophages exist in the wound in several phenotypic states, and the effect of these cells on intercellular co-operation at each stage of tissue repair depends on their specific phenotype. Depending on the microenvironment, they can quickly change their functional phenotype from proinflammatory M1 to anti-inflammatory M2, and vice versa. However, the effect of the functional phenotype of macrophages on cellular metabolism is not unilateral, the change in the features of metabolism, especially energy, also significantly affects the phenotype of cells.
 Objective. The aim of this work is to analyze the oxidoreductases activity of neutrophils, macrophages and fibroblasts in the connective tissue of the white rats skin under conditions of local thermal damage when there is a carbohydrate metabolism violation to predict the efficiency of the tissue regeneration during the repair process.
 Material and methods. There were carried out the histochemical and pathomorphological researches of the skin burn wound healing dynamic (3, 7, 14, 21 days) of the white mature male rats (Wistar line) with the weight of 180-210g without somatic pathology (control group, n=28) and with stable uncorrected hyperglycemia modeled by streptozotocin (n=28). It has been carried out the histochemical study of oxidoreductase enzymes activity on the cryostat sections (10 μm thickness): succinate dehydrogenase (SDH), lactate dehydrogenase (LDH), NADH- dehydrogenase (NADH-DH). The histochemical index of the oxidoreductase enzymes activity was being calculated by the semi-quantitative method.
 Results. The study of the cells’ quantitative changes in the connective tissue regenerate and the reactions of energy metabolism against the background of hyperglycemia has some features. The consistency of the connective tissue infiltration by the leukocytes of different types during reparative regeneration after burn injury was being happened in a classical scenario with a quantitative predominance of cells in a group of animals without somatic pathology that points to the reduction of blood reactivity under conditions of glycemia. In the dynamics of the healing process the change of the LDH and NADH-DH activity in the macrophages and fibroblasts had a tendency to increase on the 7th and 14th days of the experiment and differed significantly during observation from the parameters in the 3d day (p<0,05). The most exemplary for study of the dynamics of the oxidation-reduction enzymes activity in the cells of the regenerate was the ratio of SDH/LDH. Comparing the data of the control group of animals and under conditions of hyperglycemia the most expressed and multidirectional changes of the oxidation-reduction enzymes’ activity occurred in macrophages in the different phases of the reparative process.
 Conclusions. We believe that such differences can indirectly indicate the untimely change of the macrophages’ functional phenotype during restorative processes in the tissues. So as the macrophages are the "main conductor" of intercellular relationships it is suggested that this mechanism may be one of the reasons for the ineffective wound healing under diabetes mellitus.

Cell-instructive alginate-collagen hybrid gels for guided bone regeneration

Event Abstract Back to Event Cell-instructive alginate-collagen hybrid gels for guided bone regeneration Evi Lippens1, 2, 3, Manav Mehta1, 2, 3, Sidi A. Bencherif1, 2, Kangwon Lee1, 2, James C. Weaver2, Georg N. Duda2, 3 and David J. Mooney1, 2 1 Harvard University, John A. Paulson School of Engineering and Applied Sciences, United States 2 Wyss Institute for Biologically Inspired Engineering at Harvard, United States 3 Charité-Universitätsmedizin Berlin, Julius Wolff Institute, Germany The natural repair process is characterized by the recruitment of progenitor cells to the site of injury, induction of these cells to expand, and finally directing cell fate to restore tissue function. A biomaterial strategy that mimics and/or boosts this natural repair process has potential to be a successful approach for bone defect healing[1]. A hybrid scaffold based on a highly porous alginate cryogel filled with a collagen hydrogel was developed towards this end, with cell-instructive biochemical cues retained in the different material compartments. In vitro 2D cell migration, cell proliferation and osteogenic differentiation assays were first performed to screen various growth factors. These assays indicated the strong potential of PDGF-ab as a chemoattractant and mitogen for osteoprogenitors, while BMP-2 showed the strongest mineralization potential of the tested factors. The alginate composition and cryogelation temperature were subsequently optimized to obtain cryogels with aligned pores to promote cell infiltration, and tailored release kinetics. PDGF-ab was incorporated into the collagen gel component, as this led to its rapid release from the scaffold, in order to recruit host stem cells to the scaffold and induce their proliferation. BMP-2 was incorporated into the alginate cryogel component, as that led to a delayed release, in order to trigger the recruited mesenchymal stem cells to differentiate down the osteogenic lineage. In vitro cell culture experiments with rat mesenchymal stem cells and preliminary subcutaneous implantation tests confirmed colonization of the scaffold with cells within 7 days. BMP-2 release was confirmed to promote the osteogenic differentiation of cells in the scaffold at the three week time point in vitro. This functionalized hybrid scaffold is expected to ultimately enhance the different stages of tissue repair in bone healing, from cell recruitment to specific stem cell differentiation. Financial support for this study was provided from an Einstein Visiting Fellowship for DJM, funding of the Einstein Foundation Berlin through the Charité – Universitätsmedizin Berlin, Berlin-Brandenburg School for Regenerative Therapies GSC 203, an early career award for MM from the Deutsche Forschungsgemeinschaft-Nachwuchsakademie and support from the NIH (R01 DE013033).

Platelet-Rich Plasma Application and Heterotopic Bone Formation Following Total Hip Arthroplasty

ABSTRACTActivated blood platelets play a critical, early role in the wound healing response by releasing several types of growth factors at the site of injury which mediate the initial stages of tissue repair. Autologously derived platelet-rich plasma has been applied during surgery as a healing aid and some studies have shown benefit with total joint arthroplasty procedures such as in the knee. However, little has been published regarding the use of platelet-rich plasma during total hip arthroplasty. The hip is especially prone to develop islands of heterotopic bone following arthroplasty which can lead to pain, limited motion, and even ankylosis of the joint. If this condition is exacerbated by platelet-rich plasma, this could present a barrier to the use of this adjuvant in total hip arthroplasty. This retrospective, controlled clinical study examined the effect of platelet rich plasma application during closure following total hip arthroplasty on heterotopic ossification. By one year, 21.3% of the control patients developed heterotopic bone (91 patients, 94 hips, Brooker grades I–III) compared to 12.9% of the treatment patients (76 patients, 85 hips, Brooker grades I–II). These differences were not significant (p = 0.478, power = 0.90). Thus, the use of platelet-rich plasma in this procedure does not appear to influence the incidence or severity of heterotopic ossification which should help to justify further clinical research to more fully understand whether this autologous blood product has a role in total hip arthroplasty.

Plasma and cellular fibronectin: distinct and independent functions during tissue repair

Fibronectin (FN) is a ubiquitous extracellular matrix (ECM) glycoprotein that plays vital roles during tissue repair. The plasma form of FN circulates in the blood, and upon tissue injury, is incorporated into fibrin clots to exert effects on platelet function and to mediate hemostasis. Cellular FN is then synthesized and assembled by cells as they migrate into the clot to reconstitute damaged tissue. The assembly of FN into a complex three-dimensional matrix during physiological repair plays a key role not only as a structural scaffold, but also as a regulator of cell function during this stage of tissue repair. FN fibrillogenesis is a complex, stepwise process that is strictly regulated by a multitude of factors. During fibrosis, there is excessive deposition of ECM, of which FN is one of the major components. Aberrant FN-matrix assembly is a major contributing factor to the switch from normal tissue repair to misregulated fibrosis. Understanding the mechanisms involved in FN assembly and how these interplay with cellular, fibrotic and immune responses may reveal targets for the future development of therapies to regulate aberrant tissue-repair processes.

Tissue repair and the dynamics of the extracellular matrix

Repair of tissue after injury depends on the synthesis of a fibrous extracellular matrix to replace lost or damaged tissue. Newly deposited extracellular matrix is then re-modeled over time to emulate normal tissue. The extracellular matrix directs repair by regulating the behavior of the wide variety of cell types that are mobilized to the damaged area in order to rebuild the tissue. Acute inflammation, re-epithelialization, and contraction all depend on cell–extracellular matrix interactions and contribute to minimize infection and promote rapid wound closure. Matricellular proteins are up-regulated during wound healing where they modulate interactions between cells and the extracellular matrix to exert control over events that are essential for efficient tissue repair. Here, we discuss how the extracellular matrix changes during the stages of tissue repair, how matricellular proteins affect cell–extracellular matrix interactions, and how these proteins might be exploited for use therapeutically.

Role of zinc in the healing of venous leg ulcers: a literature review

The role of nutrition remains one of the most poorly understood areas in wound healing, and nurses often miss an ideal opportunity to hasten healing because they do not consider ways of improving or maintaining the patient’s nutritional status. One particular nutrient, zinc, has been the subject of extensive debate. The role of zinc in cellular development and the later stages of tissue repair is fairly well understood. This review of the literature examines the effectiveness of both oral zinc supplementation and the topical application of zinc in patients with venous leg ulceration. Although the evidence is inconclusive, there are reports of improved healing rates following oral zinc supplementation in patients with zinc deficiency. Furthermore, one study advocates the use of topical zinc in patients with leg ulceration, because of the likelihood that circulatory insufficiency will reduce the uptake of zinc by the tissues.

The distribution of FGF-2 and TGF-beta within the lacrimal gland of rabbits.

Growth factors have diverse functions and are distributed throughout the body. A number have been detected in the lacrimal gland, eg, EGF,1,2 FGF-2,3 TGF-α,4 TGF-β,5 and HGF.6 In many tissues, FGF-2 and TGF-β have an inverse functional relationship. FGF-2, released in response to tissue damage, activates proteases that function in degradation of extracellular matrix molecules. TGF-β, released during later stages of tissue repair, inhibits proteases, thereby stabilizing extracellular matrix molecules. Although both FGF-2 and TGF-β are present within the lacrimal gland, their sites of synthesis and localization have not been documented. FGF-2 and TGF-β also have been shown to exert inverse functional effects on the synthesis and release of PRL, an immunomodulating hormone that we have localized within the lacrimal gland.7 The present study was undertaken to determine the sites of localization of FGF-2 and TGF-β within the lacrimal gland, as a basis for elucidating their functional roles in the lacrimal gland’s response to corneal injury or other initiators of lacrimal gland inflammation.

Injury induces in vivo expression of platelet-derived growth factor (PDGF) and PDGF receptor mRNAs in skin epithelial cells and PDGF mRNA in connective tissue fibroblasts.

Platelet-derived growth factor (PDGF) stimulates many of the processes important in tissue repair, including proliferation of fibroblasts and synthesis of extracellular matrices. In this study we have demonstrated with in situ hybridization and immunocytochemistry the reversible expression of c-sis/PDGF-2 and PDGF receptor (PDGF-R) b mRNAs and their respective protein products in epithelial cells and fibroblasts following cutaneous injury in pigs. Epithelial cells in control, unwounded skin did not express c-sis and PDGF-R mRNAs, and fibroblasts expressed only PDGF-R mRNA. The expression levels in the injured site were correlated with the stage of tissue repair, being highest during the initial stages of the repair process and declining at the time of complete re-epithelialization and tissue remodeling. It is suggested that the controlled, reversible expression of a potent mitogen and its receptor induced by injury may function in an autocrine/paracrine manner on both epithelial cells and fibroblasts to bring about their sustained proliferation during the normal healing process. These studies provide a molecular basis for understanding the mechanisms contributing to normal tissue repair. We suggest the possibility that a defect in these mechanisms may be associated with defective wound healing. It is also conceivable that "chronic" injury may induce irreversible gene expression leading to pathologic, unregulated cell growth.

The mitogenic activity of peritoneal tissue repair cells: Control by growth factors

The purpose of this study was to determine the proliferative activity of tissue repair fibroblasts recovered directly from injured peritoneum at various times after surgery and to test the mitogenic response of tissue repair cells (TRC) to growth factors. Rabbits underwent bilateral peritoneal abrasion (5 × 5 cm) with sterile gauze until punctate bleeding developed. Postsurgical (Days 2, 5, 7, and 10) tissue repair cells were recovered from the injured peritoneum by scraping with a scalpel blade. Although tissue repair cells consisted of a mixed cell type after 4 days in culture, recovered cells were essentially fibroblasts. These TRC were then pulsed with [ 3H]thymidine after 4 days in culture. The incorporation of thymidine into Postsurgical Day 5 TRC increased significantly compared to that of Day 2 TRC ( P < 0.05). Incorporation then decreased with time following surgery. Fibroblast growth factor (FGF) and epidermal growth factor (EGF) stimulated the incorporation of thymidine into TRC. However, the response of Postsurgical Day 7 and 10 TRCs to 1 μg/ml EGF was significantly greater than those of Postsurgical Day 2 and 5 TRCs (Day 2 TRC, 166 ± 7.4; Day 10 TRC, 420 ± 96% of control cells without EGF, P < 0.05). Platelet-derived growth factor (PDGF, 10 ng/ml) also stimulated the incorporation of thymidine into Day 10 TRCs, but this stimulatory activity (129.9 ± 8.5% of control) was less than EGF or FGF. IL-1α and IL-2 did not stimulate the incorporation of thymidine into TRC at a concentration of 100 pg/ml, but these cytokines did stimulate protein synthesis by TRC. Our data suggest that, following surgery, fibroblasts migrate into injured tissue, proliferate, and differentiate in vivo in a time-related manner and that growth factors may function as modulators of the proliferation and function of these cells. The effects of these factors on TRC may be dependent upon the stage of tissue repair.