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Throughout the halogen bonding literature, electron withdrawing groups are relied upon heavily for tuning the interaction strength between the halogen bond donor and acceptor; however, the interplay of electronic effects associated with various substituents is less of a focus. This work utilizes computational techniques to study the degree of σ- and π-electron donating/accepting character of electron withdrawing groups in a prescribed set of halo-alkyne, halo-benzene, and halo-ethynyl benzene halogen bond donors. We examine how these factors affect the σ-hole magnitude of the donors as well as the binding strength of the corresponding complexes with an ammonia acceptor. Statistical analyses aid the interpretation of how these substituents influence the properties of the halogen bond donors and complexes, and show that the electron withdrawing groups that are both σ- and π-electron accepting form the strongest halogen bond complexes., (© 2024 The Author(s). ChemPhysChem published by Wiley-VCH GmbH.)

The ability to predict the strength of halogen bonds and properties of halogen bond (XB) donors has significant utility for medicinal chemistry and materials science. XBs are typically calculated through expensive ab initio methods. Thus, the development of tools and techniques for fast, accurate, and efficient property predictions has become increasingly more important. Herein, we employ three machine learning models to classify the XB donors and complexes by their principal halogen atom as well as predict the values of the maximum point on the electrostatic potential surface ( V S,max ) and interaction strength of the XB complexes through a molecular fingerprint and data-based analysis. The fingerprint analysis produces a root-mean-square error of ca. 7.5 and ca. 5.5 kcal mol -1 while predicting the V S,max for the halobenzene and haloethynylbenzene systems, respectively. However, the prediction of the binding energy between the XB donors and ammonia acceptor is shown to be within 1 kcal mol -1 of the density functional theory (DFT)-calculated energy. More accurate predictions can be made from the precalculated DFT data when compared to the fingerprint analysis.

Computational quantum chemical techniques were utilized to systematically examine how electron-donating groups affect the electronic and spectroscopic properties of halogen bond donors and their corresponding complexes. Unlike the majority of studies on halogen bonding, where electron-withdrawing groups are utilized, this work investigates the influence of electron-donating substituents within the halogen bond donors. Statistical analyses were performed on the descriptors of halogen bond donors in a prescribed set of archetype, halo-alkyne, halo-benzene, and halo-ethynyl benzene halogen bond systems. The σ-hole magnitude, binding and interaction energies, and the vibrational X···N local force constant (where X = Cl, Br, I, and At) were found to correlate very well in a monotonic and linear manner with all other properties studied. In addition, enhanced halogen bonds were found when the systems contained electron-donating groups that could form intramolecular hydrogen bonds with the electronegative belt of the halogen atom and adjacent linker features.

The relative contributions of halogen and hydrogen bonding to the interaction between graphitic carbon nitride monomers and halogen bond (XB) donors containing C-X and C≡C bonds were evaluated using computational vibrational spectroscopy. Conventional probes into select vibrational stretching frequencies can often lead to disconnected results. To elucidate this behavior, local mode analyses were performed on the XB donors and complexes identified previously at the M06-2X/aVDZ-PP level of theory. Due to coupling between low and high energy C-X vibrations, the C≡C stretch is deemed a better candidate when analyzing XB complex properties or detecting XB formation. The local force constants support this conclusion, as the C≡C values correlate much better with the σ-hole magnitude than their C-X counterparts. The intermolecular local stretching force constants were also assessed, and it was found that attractive forces other than halogen bonding play a supporting role in complex formation., (© 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Two graphitic carbon nitride ( g -C 3 N 4 ) molecular building blocks designed for halogen bond driven assembly are evaluated through computational quantum chemistry. Unlike those typically reported in the literature, these g -C 3 N 4 -based acceptors each offer three unique sites for halogen bond formation, which when introduced to their donor counterparts, lead to 1:1, 2:1, and 3:1 donor-acceptor complexes. Although halogen bonding interactions are present in all donor-acceptor complexes considered in the work, intermolecular hydrogen bonding emerges in complexes in which an iodine-based donor is directly involved. The halogen bond complexes identified herein feature linear halogen bonds and supportive intermolecular hydrogen bonds that lead to nearly additive electronic binding energies of up to -9.7 (dimers), -18.6 (trimers), and -26.5 kcal mol -1 (tetramers). Select vibrational stretching frequencies (ν C-X and ν C≡C ), and the perturbative shifts they incur upon halogen bond formation, are interrogated and compared to those observed in pyridine- and pyrimidine-based halogen-bonded complexes reported in the literature.

Background: Demand for collagen-based fillers has declined primarily because of limited long-term clinical benefit and the introduction of hyaluronic acid compositions. In situ polymerizing collagen is a noncrosslinked solution of porcine collagen containing a collagenase shield that undergoes fibrillogenesis on injected into tissues forming a natural matrix., Objective: Conduct a prospective, single-center, dual-phase open-label study in 8 subjects to evaluate the safety, tolerability, and efficacy of the porcine collagen composition., Methods: In Phase I, potential hypersensitivity of the collagen composition was evaluated after skin testing in the back (men) or forearms of subjects (women). In Phase II, subjects showing no signs of hypersensitivity received collagen injections into the nasolabial area followed by evaluation at 1, 4, 8, and 12 weeks using the Global Aesthetic Improvement Scale., Results: None of the subjects had signs of hypersensitivity and all continued in Phase II. The treating physician(s) reported no post-treatment adverse events. Improvement of the nasolabial fold was observed by the physicians and confirmed by assessment of high-resolution photographs and Global Aesthetic Improvement Scale scores over the 12-week treatment were maintained., Conclusion: In this pilot clinical study in situ polymerizing collagen was shown to be safe and effective throughout the 3-month study period.

Natural Eggshell Membrane (NEM(R)) is a new novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy articular cartilage and the surrounding synovium. The randomized, multicenter, double-blind, placebo-controlled Osteoarthritis Pain Treatment Incorporating NEM(R) clinical study was conducted to evaluate the efficacy and safety of NEM(R) as a treatment for pain and stiffness associated with osteoarthritis of the knee. Sixty-seven patients were randomly assigned to receive either oral NEM(R) 500 mg (n = 34) or placebo (n = 33) daily for 8 weeks. The primary endpoint was the change in overall Western Ontario and McMasters Universities (WOMAC) Osteoarthritis Index as well as pain, stiffness, and function WOMAC subscales measured at 10, 30, and 60 days. The clinical assessment was performed on the intent-to-treat population. Supplementation with NEM(R) produced an absolute rate of response that was statistically significant (up to 26.6%) versus placebo at all time points for both pain and stiffness, but was not significantly improved for function and overall WOMAC scores, although trending toward improvement. Rapid responses were seen for mean pain subscores (15.9% reduction, P = 0.036) and mean stiffness subscores (12.8% reduction, P = 0.024) occurring after only 10 days of supplementation. There were no serious adverse events reported during the study and the treatment was reported to be well tolerated by study participants. Natural Eggshell Membrane (NEM(R)) is an effective and safe option for the treatment of pain and stiffness associated with knee osteoarthritis. Supplementation with NEM(R), 500 mg taken once daily, significantly reduced both joint pain and stiffness compared to placebo at 10, 30, and 60 days.

Background: Natural Eggshell Membrane (NEM) is a novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. Two single center, open-label human clinical studies were conducted to evaluate the efficacy and safety of NEM as a treatment for pain and inflexibility associated with joint and connective tissue disorders., Methods: Eleven (single-arm trial) and 28 (double-arm trial) patients received oral NEM 500 mg once daily for four weeks. The primary outcome measure was to evaluate the change in general pain associated with the treatment joints/areas (both studies). In the single-arm trial, range of motion (ROM) and related ROM-associated pain was also evaluated. The primary treatment response endpoints were at seven and 30 days. Both clinical assessments were performed on the intent-to-treat (ITT) population within each study., Results: Single-arm trial: Supplementation with NEM produced a significant treatment response at seven days for flexibility (27.8% increase; P = 0.038) and at 30 days for general pain (72.5% reduction; P = 0.007), flexibility (43.7% increase; P = 0.006), and ROM-associated pain (75.9% reduction; P = 0.021). Double-arm trial: Supplementation with NEM produced a significant treatment response for pain at seven days for both treatment arms (X: 18.4% reduction; P = 0.021. Y: 31.3% reduction; P = 0.014). There was no clinically meaningful difference between treatment arms at seven days, so the Y arm crossed over to the X formulation for the remainder of the study. The significant treatment response continued through 30 days for pain (30.2% reduction; P = 0.0001). There were no adverse events reported during either study and the treatment was reported to be well tolerated by study participants., Conclusions: Natural Eggshell Membrane (NEM) is a possible new effective and safe therapeutic option for the treatment of pain and inflexibility associated with joint and connective tissue (JCT) disorders. Supplementation with NEM, 500 mg taken once daily, significantly reduced pain, both rapidly (seven days) and continuously (30 days). It also showed clinically meaningful results from a brief responder analysis, demonstrating that significant proportions of treated patients may be helped considerably from NEM supplementation. The Clinical Trial Registration numbers for these trials are: NCT00750230 and NCT00750854.

Objective: Wound histology and mesh bioincorporation following intraperitoneal fixation using laser-assisted soldering was evaluated., Methods: 2.8-3.2 kg NZW rabbits underwent laparotomy. Controls had 2x2 cm segments of Mersilene stapled to peritoneum. Group 2 segments were affixed with 55% collagen solder onlay by fiber-coupled diode laser (1.43 +/- 10 micro, 2.5 W CW, 4 mm spot, 60 degrees C set temperature). Group 4 had Mersilene inlaid into melted solder. Group 3 had solder-embedded Vicryl mesh affixed. Animals were euthanized at 0, 2, 4, 6 weeks. Fixed sections were assessed for integrity, inflammation, and fibrosis using H & E, Masson's Trichrome and Evans Van Gieson staining., Results: Histology demonstrated cell types, local mesh reaction, and progressive evidence of solder reabsorption mimicking normal healing and bioincorporation. Mersilene groups demonstrated normal arrangement of collagen-rich layers around mesh., Conclusion: Collagen-based tissue soldering permits normal wound healing and may mitigate use of staples. Further development of this strategy is warranted., ((c) 2005 Wiley-Liss, Inc.)

Objective: This study evaluated the incidence and persistence of adhesions following intraperitoneal onlay mesh fixation with tissue soldering in an experimental model., Methods: Anesthetized New Zealand white rabbits (n = 21), weighing 2.8-3.2 kg, underwent laparotomy. Controls (group 1 [n = 3]) had 2 x 2 cm Mersilene (Ethicon, Somerville, New Jersey) polyester mesh segments fixed to the peritoneum with staples (USSC, Norwalk, Connecticut). Group 2 (n = 7) rabbits had Mersilene mesh affixed by melting 55% collagen solder using a prototype laser (1.43 micro, 2.5 W CW, 4 mm spot size, 60 degrees C set temperature) over mesh. Group 3 (n = 6) rabbits had Vicryl (Ethicon, Somerville, New Jersey) polyglactin mesh embedded in 60% collagen solder placed onto the peritoneum and fixed with identical laser parameters as group 2. Group 4 (n = 5) rabbits had 55% collagen solder placed and Mersilene pressed into it after melting. Four segments were placed in each experimental animal. Animals were euthanized at 2, 4, or 6 weeks. Adhesions were graded (0 = none; I = filmy adhesions; II = omental; III = bowel adhesions gently lysed; IV = dense adhesions requiring sharp dissection)., Results: Grade III adhesions were observed in both control and group 4 animals at 2 weeks, persisting in group 4 animals at 6 weeks, but having lysed in controls at 6 weeks. No adhesions were present in group 3 specimens at any interval. Grade I adhesions were present in group 2 at 2 weeks at exposed mesh areas, and declined in frequency at 6 weeks. Evidence of reabsorption of the polyglactin mesh-solder composite was apparent in the group 3 specimens at 4 weeks, and complete resorption had occurred by 6 weeks postoperatively., Discussion: Laser-assisted solder fixation caused minimal adhesion formation when mesh was covered by solder. Adhesions were observed if Mersilene mesh material was exposed to the abdominal contents. Vicryl mesh-solder composites reabsorbed without inflammation, scarring, or adhesions at the sites of mesh fixation., Conclusion: Further development of this technology is warranted.

Background: In this study, we assessed the feasibility of laser-assisted tissue welding as a means of fixing mesh prostheses to the peritoneum. We then tested the initial tensile strength of the bonds., Methods: Fresh porcine peritoneal coupons were lap-joint bonded with laser-activated solder. Anesthetized New Zealand white rabbits and Yorkshire pigs also underwent laparotomy. Vicryl mesh (2.0 x 1.0 cm) was attached to the peritoneum using a laser system (1.43 mu, 2.5 W, 60 degrees C), solder formulations and configurations, and a 1 cm2 bond area. Control segments were affixed with 4.8-mm staples. After the animals were killed, the segments were excised en bloc. Tensile strength assessment was conducted by measuring peak force breaking strength., Results: The strength of the solder bonds were similar in all groups (range, 261.5 +/- 170.3-465.3 +/- 288.2 g/cm2) and were not statistically different from the controls (215.8 +/- 117.8 g/cm2)., Conclusions: These values are similar to the 200-500 g/cm2 acute strengths reported for sutured or stapled peritoneal closure. Mesh fixation by solder is feasible, and further development of this technology is warranted.

Mandibular fractures, resulting from either trauma or reconstructive surgery, can be challenging craniofacial problems. The morbidity of failed fracture healing is significant and may require bone grafting. Donor site morbidity and finite amounts of autogenous bone are major drawbacks of autogenous bone grafting. Similarly, the use of allografts and xenografts may be associated with an increased risk of rejection, infection, and nonunion. To circumvent the limitations of bone grafting, research efforts have focused on formulating a suitable bone substitute. The purpose of our study was to evaluate the efficacy of type I collagen implants in repairing critical sized mandibular defects in rats. Twelve male Sprague-Dawley rats (200-300g) were divided equally into control and experimental groups. Full thickness, round, four millimeter in diameter defects were created in the ramus of the right mandible of all rats using an electrical burr at low speed. The defects were irrigated of all bone chips, and either filled with a precisely fitted disk of allogenic collagen type I gel (experimental animals) or left empty (control animals). Animals were killed 6 weeks after surgery and healing of the bone defects was assessed in a blinded fashion using radiologic and histologic analysis. Radiologic analysis of the control group revealed a clear circular right mandibular defect in all animals, whereas the collagen disk implant group revealed an indistinct to nonexistent right mandibular defect in all animals. Densitometric analysis revealed a significant difference between these groups (* P = 0.01). Similarly, gross analysis of control mandibles revealed a 4mm round, soft-tissue filled defect, while implanted defects demonstrated gross bone spanning the defect. Finally, histologic analysis of all control mandibles revealed clearly demarcated bony edges at the defect border with connective tissue spanning the defect. In contrast, histological analysis of all implanted mandibles revealed indistinct bony edges at the defect border with a thin layer of osteoblasts and viable bone spanning the defects. We have demonstrated the ability of type I collagen to promote healing of a membranous bony defect that would not otherwise heal at 6 weeks. The suitability of type I collagen as a carrier matrix provides ample opportunity for tissue-engineered approaches to further facilitate bony defect healing. Promoting bone formation through tissue engineering matrices offers great promise for skeletal healing and reconstruction.

Endoscopic techniques are providing a minimally invasive approach to the treatment of vesicoureteral reflux and urinary incontinence. Bovine collagen has been used, but potential degradation over time and sensitivity reactions have limited its usefulness. We evaluate the use of an autologous collagen-based extracellular matrix preparation injected within the rabbit bladder submucosa and compare it to the stability of bovine collagen-injected similarly. Of 28 New Zealand white rabbits, 12 underwent injection of autologous collagen-based extracellular matrix, 12 bovine collagen, and four normal saline sham injections into the anterior bladder submucosa. Twelve collagen specimens were iodinated with iodine 125 ((125)I) paraaminobenzoate reagent. The (125)I-labeled rabbits were monitored with a gamma camera to assess the level of decay of radioactivity over 12 weeks. All animals were killed 12 weeks post-injection. Assessment of radioactivity showed minimal difference in radioisotope labeling between the autologous and bovine collagen (total counts and decay kinetics). Compared to bovine collagen, the autologous collagen- based extracellular matrix implants histologically showed increased fibroblastic and vascular infiltration focally. The most significant histologic difference was the marked inflammatory response associated with the bovine collagen implants. These data suggest that in the short term, autologous and bovine collagen appear to have similar stability. The response to autologous collagen-based extracellular matrix may increase longevity of the implant, primarily by reducing immunologic rejection and improving biocompatibility within the host tissue. Further long-term studies are necessary to assess the long-term stability of autologous collagen-based extracellular matrix. Neurourol. Urodynam. 18:487-495, 1999., (Copyright 1999 Wiley-Liss, Inc.)

Background: This study evaluates epithelialization, clarity, intraocular inflammation, and fibroblast ingrowth of a collagen corneal allograft derived from rabbit dermis., Methods: Dermal collagen fibers were dispersed intact and chemically modified to make them soluble. The allografts consisted of a fibrous, opaque peripheral zone and a central clear area. Twelve New Zealand white rabbits underwent penetrating keratoplasty with implantation of an allograft. The grafts were evaluated daily for clarify, anterior segment inflammation, and extent of reepithelialization with a slit-lamp microscope., Results: Epithelialization of the fibrous peripheral zone of the graft ranged from 0% to 90%. The central clear area did not epithelialize in any of the animals. Fibroblasts migrated into the peripheral zone in all eyes. Complications included ulceration of the central clear area in two eyes. There was no ulceration or leakage at the graft-host interface and no synechia, fibrous, or inflammatory retrocorneal membranes in any of the eyes., Conclusions: Our study is the first to describe the method of modifying dermal type I collagen into a clear corneal allograft. Survival of the corneal collagen allograft beyond 1 month may be limited by several factors including lack of epithelialization of the central clear area.

Growing interest in the endoscopic treatment of vesicoureteral reflux and urinary incontinence has led to the development of safe reliable techniques that use an injectable bulking agent. A variety of injectable materials has been studied, such as polytetrafluoroethylene, fat and bovine collagen. We evaluated autologous collagen extracted from the dermis of skin for potential use in the urinary tract. Therefore, an animal model was developed to study the biological behavior of autologous collagen within the bladder. Collagen was extracted from the skin of rabbits and radiolabeled with 125iodine. An aliquot of radiolabeled autologous collagen was injected submucosally in the bladder. The animals were monitored weekly under a gamma camera. The decay of the radiolabeled collagen was recorded during 50 days. The animals were then sacrificed and the bladder wall at the site of injection was studied histologically and on electron microscopy. Decay of the injected collagen within the urinary tract was similar to control material, indicative of good stability within the bladder. A mild inflammatory response with fibroblastic and vascular invasion of the collagen implant was observed. These preliminary data suggest that autologous collagen injected endoscopically can provide a safe reliable bulking material that could be used to treat urinary incontinence and lower grades of vesicoureteral reflux in children.

Background: Excimer laser photoablation effectively and precisely removes corneal tissue but may not smooth irregularities on the anterior corneal surface. An even surface might be obtained by applying a smoothing substance that fills in irregularities and ablates at the same rate as corneal tissue. Evaluation of collagen gel as a smoothing agent is reported., Methods: Pure, type I collagen solutions were prepared to remain soluble at physiological pH and to spontaneously gel when exposed to cationic buffers. Collagen gels were formed on the surface of enucleated porcine corneas and on human donor corneas and exposed to varying pulses of 193-nanometer excimer laser energy. Effects of collagen gel on ablation depth, corneal surface smoothness, and smoothing of roughened cornea were evaluated by examining scanning electron micrographs of control and treated specimens., Results: Collagen gels formed from 5 mg/ml collagen solutions dramatically altered the depth of photoablation. Photoablation of roughened cornea with collagen gels produced smooth corneal surfaces, whereas control eyes remained roughened and irregular. The smoothness of photoablated cornea surfaces improved when collagen gels were applied prior to photoablation., Conclusions: The rapidly gelling collagen solution appears to exhibit the functional properties required for an effective smoothing agent for excimer laser photoablation. The substance has low viscosity when applied to the corneal surface and forms a rigid gel when exposed to cationic buffer solution. In addition, the concentration of the collagen gel can be adjusted to provide different ablation rates.

Both synthetic and biological materials have been used for smoothing wrinkle lines and depressed scars. Injectable fillers provide a convenient and easy alternative to surgical methods to treat dermal defects. Optimally, injectable fillers augmenting dermal tissue should exhibit properties similar to the dermal collagen network, providing a stable matrix for long-term correction but also being subject to the dynamic changes that occur to dermal tissue during the aging processes. At present, only biological materials are available on a commercial basis, although a number of synthetic injectables are being evaluated in clinical trials. The long-term effectiveness of most commercial materials has been limited prompting questions about the cost-benefits of such treatment. In this regard, the effectiveness of the injectable fillers, particularly of biological materials, will be discussed as will the difficulties involved in determining the expected result (effectiveness) for specific materials and in providing methods of measuring effectiveness.

This paper provides a general review of the long-term compatibility of intraocular lenses (IOLs), with specific reference to the compatibility of synthetic polymers used to fabricate IOLs. The first IOL was implanted in 1949. It was composed of polymethylmethacrylate (PMMA) and placed in the posterior chamber of the eye. In 1990, approximately 1.4 million IOLs were implanted in the U.S., nearly all composed of PMMA and nearly all implanted in the posterior chamber of the eye. However, many changes have taken place in the past 40 years to improve the compatibility of IOLs and to make cataract surgery and IOL implantation among the safest and most effective major surgical procedures.

While D-Penicillamine is effective in the treatment of rheumatoid arthritis, its mechanism of action is unknown. In this study, effects of D-Penicillamine on collagenase production by adherent rheumatoid synovial cells were investigated. D-Penicillamine did not directly affect the synovial collagenase production. However, lymphocyte-free-supernatant (LFS) recovered from lymphocytes exposed to D-Penicillamine in vivo and in vitro significantly reduced collagenase production by adherent synovial cells. LFS from lymphocytes of normal subjects and from non-D-Penicillamine treated rheumatoid patients stimulated collagenase production. These investigations indicate that D-Pencillamine indirectly affects collagenase production by cultured synovial cells and suggests beneficial effects on controlling the primary disease process.

A standardized investigation to compare the biophysical characteristics of two sodium hyaluronate products, AMVISC and Healon, was conducted. Results showed that the two products exhibited similar biophysical properties. AMVISC exhibited an average kinematic viscosity of 41,554 centistokes and a calculated average molecular weight of 2.04 X 10(6) daltons. Healon exhibited an average kinematic viscosity of 47,271 centistokes and a calculated average molecular weight of 2.43 X 10(6) daltons.

A number of variables that can affect the results of xenogenic collagen implantation were studied by means of the pig model. Zyderm Collagen Implant was analyzed biochemically and was used to study the following variables: injection volume, collagen concentration, injection intervals, and needle gauge. The results of the study revealed the following: Injection volumes of 0.125 to 0.25 ml given at the same site resulted in the appearance of large "pools" of Zyderm Collagen Implant in the subcutaneous fat. However, injection volumes of 0.0625 to 0.1 ml given at the same site resulted in all of the implant's being retained in the dermis. There was no appreciable difference in the results achieved with two different concentrations of implant. Serial reinjections of 0.1 ml at 1-week intervals revealed increased amounts of implant material in the dermis. The use of a 30-gauge needle allowed more superficial placement than was possible with a 27-gauge needle.

In order to better define antiinflammatory activity in new agents, a test was devised utilizing both carrageenan induced paw edema and the reversed passive Arthus reaction in the same animal. The model of carrageenan induced rat paw edema is a standard laboratory assay used to predict classical "aspirin-like" antiinflammatory molecules. The reversed passive cutaneous Arthus reaction involves precipitating antigen-antibody complexes, complement and infiltrating polymorphonuclear leukocytes (PMN's) and can be used to identify agents that affect one or more of these factors specifically. Antiinflammatory compounds were given orally one hour prior to the administration of carrageenan and goat anti-rat serum. Comparisons were made between several non-steroidal compounds and the steroid hydrocortisone. All of the compounds tested gave good carrageenan activity, but only hydrocortisone produced significant Arthus lesion inhibition in this assay.

Tumor invasion has been correlated with the ability of tumor cells to produce collagenolytic enzymes which are capable of degrading normal host tissues. However, the human small cell carcinoma implanted subcutanouesly and growing progressively in athymic (nude) mice produced large quantities of collagenase but did not appear to significantly infultrate adjacent host tissue. In comparison, subcutaneously implanted murine Lewis lung tumors produced similar quantities of collagenase and were locally invasive. The human tumors were surrounded by a compact layer of fibroblast cells in a fibrous matrix. This fibrous sheath exhibited anticollagenase activity and indicated a mechanism of host tissue resistance to invasion via the formation of inhibitors to degradative enzymes produced by tumor cells.